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1
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Shao J, Fan R, Shao M, Dai M, Huang G, Guo Q, Cao L. A sporadic case of benign recurrent intrahepatic cholestasis in a growth-impaired young male. Sci Prog 2025; 108:368504251335415. [PMID: 40261314 PMCID: PMC12035385 DOI: 10.1177/00368504251335415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/24/2025]
Abstract
Benign recurrent intrahepatic cholestasis (BRIC) is a rare genetic liver disorder characterized by recurrent episodes of jaundice and severe pruritus without significant liver damage. Here, we present the case of a man in his early 20s, standing 143 cm tall, who has experienced recurrent jaundice and pruritus over an 18-year period. Laboratory investigations and liver biopsy examination indicated typical intrahepatic cholestasis with normal gamma-glutamyl transpeptidase levels, excluding viral, metabolic, and autoimmune causes. Further genetic analysis confirmed the diagnosis of BRIC with two compound heterozygous mutations in ATP8B1 gene on chromosome 18: NM_001374385.1: c.2081T > C p. (Ile694Thr) (rs541474497) in exon 18 and NC_000018.10 (NM_001374385.1): c.1631-2A > G in intron 15. To our knowledge, the latter has not been reported. Family lineage analysis and Sanger sequencing showed that these mutations were de novo rather than hereditary. Treatment with ursodeoxycholic acid and cholestyramine resulted in complete resolution of jaundice and pruritus, with normalization of serum bilirubin level after six months of therapy.
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Affiliation(s)
- Jiasheng Shao
- Department of Immunology and Rheumatology, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China
- Ren Ji Hospital, Jiading Branch, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Tulane National Primate Research Center, Tulane University School of Medicine, Covington, LA, USA
| | - Rong Fan
- Genomics, Center for Molecular and Cellular Bioengineering, Biotechnology Center, Technische Universität, Dresden, Germany
| | - Minhua Shao
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes for Biomedical Sciences, Fudan University, Shanghai, China
| | - Min Dai
- Department of Immunology and Rheumatology, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China
- Ren Ji Hospital, Jiading Branch, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Gang Huang
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Qiang Guo
- Department of Immunology and Rheumatology, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China
- Ren Ji Hospital, Jiading Branch, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liou Cao
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Renji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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2
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Shin HW, Takatsu H. Substrates, regulation, cellular functions, and disease associations of P4-ATPases. Commun Biol 2025; 8:135. [PMID: 39875509 PMCID: PMC11775268 DOI: 10.1038/s42003-025-07549-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Accepted: 01/14/2025] [Indexed: 01/30/2025] Open
Abstract
P4-ATPases, a subfamily of the P-type ATPase superfamily, play a crucial role in translocating membrane lipids from the exoplasmic/luminal leaflet to the cytoplasmic leaflet. This process generates and regulates transbilayer lipid asymmetry. These enzymes are conserved across all eukaryotes, and the human genome encodes 14 distinct P4-ATPases. Initially identified as aminophospholipid translocases, P4-ATPases have since been found to translocate other phospholipids, including phosphatidylcholine, phosphatidylinositol, and even glycosphingolipids. Recent advances in structural analysis have significantly improved our understanding of the lipid transport machinery associated with P4-ATPases, as documented in recent reviews. In this review, we highlight the emerging evidence related to substrate diversity, the regulation of cellular localization, enzymatic activities, and their impact on organism homeostasis and diseases.
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Affiliation(s)
- Hye-Won Shin
- Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan.
| | - Hiroyuki Takatsu
- Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan
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3
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Takatsu H, Nishimura N, Kosugi Y, Ogawa H, Nakayama K, Colin E, Platzer K, Abou Jamra R, Redler S, Prouteau C, Ziegler A, Shin HW. De Novo Missense Variations of ATP8B2 Impair Its Phosphatidylcholine Flippase Activity. Mol Cell Biol 2024; 44:473-488. [PMID: 39219493 PMCID: PMC11529410 DOI: 10.1080/10985549.2024.2391829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 07/11/2024] [Accepted: 07/27/2024] [Indexed: 09/04/2024] Open
Abstract
P4-ATPases comprise a family of lipid flippases that translocate lipids from the exoplasmic (or luminal) to the cytoplasmic leaflet of biological membranes. Of the 14 known human P4-ATPases, ATP8B2 is a phosphatidylcholine flippase at the plasma membrane, but its physiological function is not well understood. Although ATP8B2 could interact with both CDC50A and CDC50B, it required only the CDC50A interaction for its exit from the endoplasmic reticulum and subsequent transport to the plasma membrane. Three de novo monoallelic missense variations of ATP8B2 were found in patients with intellectual disability. None of these variations affected the interaction of ATP8B2 with CDC50A or its localization to the plasma membrane. However, variations of either of two amino acid residues, which are conserved in all P4-ATPases, significantly reduced the phosphatidylcholine flippase activity of ATP8B2. Furthermore, mutations in the corresponding residues of ATP8B1 and ATP11C were found to decrease their flippase activities toward phosphatidylcholine and phosphatidylserine, respectively. These results indicate that the conserved amino acid residues are crucial for the enzymatic activities of the P4-ATPases.
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Affiliation(s)
- Hiroyuki Takatsu
- Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Narumi Nishimura
- Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Yusuke Kosugi
- Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
- Division of Systems Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Haruo Ogawa
- Department of Structural Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Kazuhisa Nakayama
- Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Estelle Colin
- Department of Medical Genetics, Angers University Hospital, Angers, France
| | - Konrad Platzer
- Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
| | - Rami Abou Jamra
- Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
| | - Silke Redler
- Institute of Human Genetics, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
| | - Clément Prouteau
- Department of Medical Genetics, Angers University Hospital, Angers, France
| | - Alban Ziegler
- Department of Medical Genetics, Angers University Hospital, Angers, France
| | - Hye-Won Shin
- Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
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4
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Matsell E, Andersen JP, Molday RS. Functional and in silico analysis of ATP8A2 and other P4-ATPase variants associated with human genetic diseases. Dis Model Mech 2024; 17:dmm050546. [PMID: 38436085 PMCID: PMC11073571 DOI: 10.1242/dmm.050546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 02/21/2024] [Indexed: 03/05/2024] Open
Abstract
P4-ATPases flip lipids from the exoplasmic to cytoplasmic leaflet of cell membranes, a property crucial for many biological processes. Mutations in P4-ATPases are associated with severe inherited and complex human disorders. We determined the expression, localization and ATPase activity of four variants of ATP8A2, the P4-ATPase associated with the neurodevelopmental disorder known as cerebellar ataxia, impaired intellectual development and disequilibrium syndrome 4 (CAMRQ4). Two variants, G447R and A772P, harboring mutations in catalytic domains, expressed at low levels and mislocalized in cells. In contrast, the E459Q variant in a flexible loop displayed wild-type expression levels, Golgi-endosome localization and ATPase activity. The R1147W variant expressed at 50% of wild-type levels but showed normal localization and activity. These results indicate that the G447R and A772P mutations cause CAMRQ4 through protein misfolding. The E459Q mutation is unlikely to be causative, whereas the R1147W may display a milder disease phenotype. Using various programs that predict protein stability, we show that there is a good correlation between the experimental expression of the variants and in silico stability assessments, suggesting that such analysis is useful in identifying protein misfolding disease-associated variants.
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Affiliation(s)
- Eli Matsell
- Department of Biochemistry & Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada
| | | | - Robert S. Molday
- Department of Biochemistry & Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada
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5
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Duan HD, Li H. Consensus, controversies, and conundrums of P4-ATPases: The emerging face of eukaryotic lipid flippases. J Biol Chem 2024; 300:107387. [PMID: 38763336 PMCID: PMC11225554 DOI: 10.1016/j.jbc.2024.107387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 05/04/2024] [Accepted: 05/07/2024] [Indexed: 05/21/2024] Open
Abstract
The cryo-EM resolution revolution has heralded a new era in our understanding of eukaryotic lipid flippases with a rapidly growing number of high-resolution structures. Flippases belong to the P4 family of ATPases (type IV P-type ATPases) that largely follow the reaction cycle proposed for the more extensively studied cation-transporting P-type ATPases. However, unlike the canonical P-type ATPases, no flippase cargos are transported in the phosphorylation half-reaction. Instead of being released into the intracellular or extracellular milieu, lipid cargos are transported to their destination at the inner leaflet of the membrane. Recent flippase structures have revealed multiple conformational states during the lipid transport cycle. Nonetheless, critical conformational states capturing the lipid cargo "in transit" are still missing. In this review, we highlight the amazing structural advances of these lipid transporters, discuss various perspectives on catalytic and regulatory mechanisms in the literature, and shed light on future directions in further deciphering the detailed molecular mechanisms of lipid flipping.
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Affiliation(s)
- H Diessel Duan
- Department of Structural Biology, Van Andel Institute, Grand Rapids, Michigan, USA.
| | - Huilin Li
- Department of Structural Biology, Van Andel Institute, Grand Rapids, Michigan, USA.
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Yang S, Song C. Switching Go̅ -Martini for Investigating Protein Conformational Transitions and Associated Protein-Lipid Interactions. J Chem Theory Comput 2024; 20:2618-2629. [PMID: 38447049 PMCID: PMC10976636 DOI: 10.1021/acs.jctc.3c01222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 02/22/2024] [Accepted: 02/22/2024] [Indexed: 03/08/2024]
Abstract
Proteins are dynamic biomolecules that can transform between different conformational states when exerting physiological functions, which is difficult to simulate using all-atom methods. Coarse-grained (CG) Go̅-like models are widely used to investigate large-scale conformational transitions, which usually adopt implicit solvent models and therefore cannot explicitly capture the interaction between proteins and surrounding molecules, such as water and lipid molecules. Here, we present a new method, named Switching Go̅-Martini, to simulate large-scale protein conformational transitions between different states, based on the switching Go̅ method and the CG Martini 3 force field. The method is straightforward and efficient, as demonstrated by the benchmarking applications for multiple protein systems, including glutamine binding protein (GlnBP), adenylate kinase (AdK), and β2-adrenergic receptor (β2AR). Moreover, by employing the Switching Go̅-Martini method, we can not only unveil the conformational transition from the E2Pi-PL state to E1 state of the type 4 P-type ATPase (P4-ATPase) flippase ATP8A1-CDC50 but also provide insights into the intricate details of lipid transport.
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Affiliation(s)
- Song Yang
- Peking-Tsinghua
Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
- Center
for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
| | - Chen Song
- Peking-Tsinghua
Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
- Center
for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
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7
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Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:122-294. [DOI: 10.1016/b978-0-7020-8228-3.00003-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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8
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Dieudonné T, Kümmerer F, Laursen MJ, Stock C, Flygaard RK, Khalid S, Lenoir G, Lyons JA, Lindorff-Larsen K, Nissen P. Activation and substrate specificity of the human P4-ATPase ATP8B1. Nat Commun 2023; 14:7492. [PMID: 37980352 PMCID: PMC10657443 DOI: 10.1038/s41467-023-42828-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 10/23/2023] [Indexed: 11/20/2023] Open
Abstract
Asymmetric distribution of phospholipids in eukaryotic membranes is essential for cell integrity, signaling pathways, and vesicular trafficking. P4-ATPases, also known as flippases, participate in creating and maintaining this asymmetry through active transport of phospholipids from the exoplasmic to the cytosolic leaflet. Here, we present a total of nine cryo-electron microscopy structures of the human flippase ATP8B1-CDC50A complex at 2.4 to 3.1 Å overall resolution, along with functional and computational studies, addressing the autophosphorylation steps from ATP, substrate recognition and occlusion, as well as a phosphoinositide binding site. We find that the P4-ATPase transport site is occupied by water upon phosphorylation from ATP. Additionally, we identify two different autoinhibited states, a closed and an outward-open conformation. Furthermore, we identify and characterize the PI(3,4,5)P3 binding site of ATP8B1 in an electropositive pocket between transmembrane segments 5, 7, 8, and 10. Our study also highlights the structural basis of a broad lipid specificity of ATP8B1 and adds phosphatidylinositol as a transport substrate for ATP8B1. We report a critical role of the sn-2 ester bond of glycerophospholipids in substrate recognition by ATP8B1 through conserved S403. These findings provide fundamental insights into ATP8B1 catalytic cycle and regulation, and substrate recognition in P4-ATPases.
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Affiliation(s)
- Thibaud Dieudonné
- DANDRITE, Nordic EMBL Partnership for Molecular Medicine, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
- Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), 91198, Gif-sur-Yvette, France.
| | - Felix Kümmerer
- Structural Biology and NMR Laboratory & Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Michelle Juknaviciute Laursen
- DANDRITE, Nordic EMBL Partnership for Molecular Medicine, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Charlott Stock
- DANDRITE, Nordic EMBL Partnership for Molecular Medicine, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Rasmus Kock Flygaard
- DANDRITE, Nordic EMBL Partnership for Molecular Medicine, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Syma Khalid
- Department of Biochemistry, University of Oxford, Oxford, UK
| | - Guillaume Lenoir
- Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), 91198, Gif-sur-Yvette, France
| | - Joseph A Lyons
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
- Interdisciplinary Nanoscience Centre (iNANO) Aarhus University, Aarhus, Denmark
| | - Kresten Lindorff-Larsen
- Structural Biology and NMR Laboratory & Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Poul Nissen
- DANDRITE, Nordic EMBL Partnership for Molecular Medicine, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
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9
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Kato K, Umetsu S, Togawa T, Ito K, Kawabata T, Arinaga-Hino T, Tsumura N, Yasuda R, Mihara Y, Kusano H, Ito S, Imagawa K, Hayashi H, Inui A, Yamashita Y, Mizuochi T. Clinicopathologic Features, Genetics, Treatment, and Long-Term Outcomes in Japanese Children and Young Adults with Benign Recurrent Intrahepatic Cholestasis: A Multicenter Study. J Clin Med 2023; 12:5979. [PMID: 37762919 PMCID: PMC10532077 DOI: 10.3390/jcm12185979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 09/13/2023] [Accepted: 09/13/2023] [Indexed: 09/29/2023] Open
Abstract
BACKGROUND Few reports of benign recurrent intrahepatic cholestasis (BRIC) have focused on East Asian patients. We describe the clinicopathologic features, genetics, treatment, and outcomes in Japanese BRIC patients. METHODS We recruited patients with BRIC type 1 (BRIC-1) or 2 (BRIC-2) treated at four pediatric centers and one adult center between April 2007 and March 2022. Demographics, clinical course, laboratory results, molecular genetic findings concerning ATP8B1 and ABCB11 genes, histopathology, and treatment response were examined retrospectively. RESULTS Seven Japanese patients with BRIC were enrolled (four male, three female; four BRIC-1 and three BRIC-2). The median age at onset for BRIC-1 was 12 years; for BRIC-2, it was 1 month. Intermittent cholestatic attacks numbered from one to eight during the 11 years of median follow-up. Six patients received a mainstream education; only one patient attended special education. None developed cirrhosis. Three with BRIC-1 showed compound heterozygosity for a variant ATP8B1 gene, while one was heterozygous; two BRIC-2 patients showed compound heterozygosity in ABCB11 and one was heterozygous. Liver biopsy specimens obtained during cholestatic attacks showed fibrosis varying from none to moderate; inflammation was absent or mild. Rifampicin administered to three patients for cholestatic attacks was effective in all, as was cholestyramine in two of three. CONCLUSIONS To our knowledge, this is the first East Asian multicenter study of BRIC patients. Onset age and number of cholestatic attacks varied. Rifampicin and cholestyramine were effective against attacks. No patient developed cirrhosis; most had normal growth and development. The long-term outcomes were satisfactory.
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Affiliation(s)
- Ken Kato
- Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Shuichiro Umetsu
- Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohamashi Tobu Hospital, Yokohama 230-0012, Japan
| | - Takao Togawa
- Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
| | - Koichi Ito
- Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
| | - Takayoshi Kawabata
- Department of Pediatrics, Ishikawa Prefectural Central Hospital, Kanazawa 920-8530, Japan
| | - Teruko Arinaga-Hino
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Naoya Tsumura
- Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Ryosuke Yasuda
- Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Yutaro Mihara
- Department of Pathology, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Hironori Kusano
- Department of Pathology, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Shogo Ito
- Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
| | - Kazuo Imagawa
- Department of Child Health, Institute of Medicine, University of Tsukuba, Tsukuba 305-8546, Japan
| | - Hisamitsu Hayashi
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo 113-0033, Japan
| | - Ayano Inui
- Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohamashi Tobu Hospital, Yokohama 230-0012, Japan
| | - Yushiro Yamashita
- Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Tatsuki Mizuochi
- Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume 830-0011, Japan
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10
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Zöllner J, Finer S, Linton KJ, van Heel DA, Williamson C, Dixon PH. Rare variant contribution to cholestatic liver disease in a South Asian population in the United Kingdom. Sci Rep 2023; 13:8120. [PMID: 37208429 PMCID: PMC10199085 DOI: 10.1038/s41598-023-33391-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 04/12/2023] [Indexed: 05/21/2023] Open
Abstract
This study assessed the contribution of five genes previously known to be involved in cholestatic liver disease in British Bangladeshi and Pakistani people. Five genes (ABCB4, ABCB11, ATP8B1, NR1H4, TJP2) were interrogated by exome sequencing data of 5236 volunteers. Included were non-synonymous or loss of function (LoF) variants with a minor allele frequency < 5%. Variants were filtered, and annotated to perform rare variant burden analysis, protein structure, and modelling analysis in-silico. Out of 314 non-synonymous variants, 180 fulfilled the inclusion criteria and were mostly heterozygous unless specified. 90 were novel and of those variants, 22 were considered likely pathogenic and 9 pathogenic. We identified variants in volunteers with gallstone disease (n = 31), intrahepatic cholestasis of pregnancy (ICP, n = 16), cholangiocarcinoma and cirrhosis (n = 2). Fourteen novel LoF variants were identified: 7 frameshift, 5 introduction of premature stop codon and 2 splice acceptor variants. The rare variant burden was significantly increased in ABCB11. Protein modelling demonstrated variants that appeared to likely cause significant structural alterations. This study highlights the significant genetic burden contributing to cholestatic liver disease. Novel likely pathogenic and pathogenic variants were identified addressing the underrepresentation of diverse ancestry groups in genomic research.
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Affiliation(s)
| | - Sarah Finer
- Institute for Population Health Sciences, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Kenneth J Linton
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - David A van Heel
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Catherine Williamson
- Department of Women and Children's Health, School of Life Course Sciences, FOLSM, King's College London, 2.30W Hodgkin Building, Guy's Campus, London, SE1 1UL, UK.
| | - Peter H Dixon
- Department of Women and Children's Health, School of Life Course Sciences, FOLSM, King's College London, 2.30W Hodgkin Building, Guy's Campus, London, SE1 1UL, UK
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11
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Sakuragi T, Nagata S. Regulation of phospholipid distribution in the lipid bilayer by flippases and scramblases. Nat Rev Mol Cell Biol 2023:10.1038/s41580-023-00604-z. [PMID: 37106071 PMCID: PMC10134735 DOI: 10.1038/s41580-023-00604-z] [Citation(s) in RCA: 93] [Impact Index Per Article: 46.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/09/2023] [Indexed: 04/29/2023]
Abstract
Cellular membranes function as permeability barriers that separate cells from the external environment or partition cells into distinct compartments. These membranes are lipid bilayers composed of glycerophospholipids, sphingolipids and cholesterol, in which proteins are embedded. Glycerophospholipids and sphingolipids freely move laterally, whereas transverse movement between lipid bilayers is limited. Phospholipids are asymmetrically distributed between membrane leaflets but change their location in biological processes, serving as signalling molecules or enzyme activators. Designated proteins - flippases and scramblases - mediate this lipid movement between the bilayers. Flippases mediate the confined localization of specific phospholipids (phosphatidylserine (PtdSer) and phosphatidylethanolamine) to the cytoplasmic leaflet. Scramblases randomly scramble phospholipids between leaflets and facilitate the exposure of PtdSer on the cell surface, which serves as an important signalling molecule and as an 'eat me' signal for phagocytes. Defects in flippases and scramblases cause various human diseases. We herein review the recent research on the structure of flippases and scramblases and their physiological roles. Although still poorly understood, we address the mechanisms by which they translocate phospholipids between lipid bilayers and how defects cause human diseases.
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Affiliation(s)
- Takaharu Sakuragi
- Biochemistry & Immunology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Shigekazu Nagata
- Biochemistry & Immunology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.
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12
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Nayagam JS, Foskett P, Strautnieks S, Agarwal K, Miquel R, Joshi D, Thompson RJ. Clinical phenotype of adult-onset liver disease in patients with variants in ABCB4, ABCB11, and ATP8B1. Hepatol Commun 2022; 6:2654-2664. [PMID: 35894240 PMCID: PMC9512461 DOI: 10.1002/hep4.2051] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/17/2022] [Accepted: 05/31/2022] [Indexed: 11/26/2022] Open
Abstract
Variants in ATP8B1, ABCB11, and ABCB4 underlie the most prevalent forms of progressive familial intrahepatic cholestasis. We aim to describe variants in these genes in a cohort of patients with adult-onset liver disease, and explore a genotype-phenotype correlation. Patients with onset of liver disease aged above 18 who underwent sequencing of cholestasis genes for clinical purposes over a 5-year period were identified. Bioinformatic analysis of variants was performed. Liver histology was evaluated in patients with variants. Of the 356 patients tested, at least one variant was identified in 101 (28.4%): 46 ABCB4, 35 ABCB11, and 28 ATP8B1. Patients with ABCB4 variants had chronic liver disease (71.7%) and pregnancy-associated liver dysfunction (75%), with a younger age of onset in more severe genotypes (p = 0.046). ABCB11 variants presented with pregnancy-associated liver dysfunction (82.4%) and acute/episodic cholestasis (40%), with no association between age of onset and genotype severity. ATP8B1 variants were associated with chronic liver disease (75%); however, they were commonly seen in patients with an alternate etiology of liver disease and variants were of low predicted pathogenicity. In adults with suspected genetic cholestasis, variants in cholestasis genes were frequently identified and were likely to contribute to the development of liver disease, particularly ABCB4 and ABCB11. Variants were often in heterozygous state, and they should no longer be considered recessive Mendelian traits. Sequencing cholestasis genes in selected patients with adult-onset disease should be considered, with interpretation in close collaboration with histopathologists and geneticists.
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Affiliation(s)
- Jeremy S. Nayagam
- Institute of Liver StudiesKing's College HospitalLondonUK
- Institute of Liver Studies, Immunology & Microbial SciencesKing's College LondonLondonUK
| | - Pierre Foskett
- Institute of Liver StudiesKing's College HospitalLondonUK
| | | | - Kosh Agarwal
- Institute of Liver StudiesKing's College HospitalLondonUK
| | - Rosa Miquel
- Liver Histopathology LaboratoryInstitute of Liver StudiesKing's College HospitalLondonUK
| | - Deepak Joshi
- Institute of Liver StudiesKing's College HospitalLondonUK
| | - Richard J. Thompson
- Institute of Liver StudiesKing's College HospitalLondonUK
- Institute of Liver Studies, Immunology & Microbial SciencesKing's College LondonLondonUK
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13
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Guerrero L, Paradela A, Corrales FJ. Targeted Proteomics for Monitoring One-Carbon Metabolism in Liver Diseases. Metabolites 2022; 12:779. [PMID: 36144184 PMCID: PMC9501948 DOI: 10.3390/metabo12090779] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/18/2022] [Accepted: 08/19/2022] [Indexed: 11/16/2022] Open
Abstract
Liver diseases cause approximately 2 million deaths per year worldwide and had an increasing incidence during the last decade. Risk factors for liver diseases include alcohol consumption, obesity, diabetes, the intake of hepatotoxic substances like aflatoxin, viral infection, and genetic determinants. Liver cancer is the sixth most prevalent cancer and the third in mortality (second in males). The low survival rate (less than 20% in 5 years) is partially explained by the late diagnosis, which remarks the need for new early molecular biomarkers. One-carbon metabolism integrates folate and methionine cycles and participates in essential cell processes such as redox homeostasis maintenance and the regulation of methylation reactions through the production of intermediate metabolites such as cysteine and S-Adenosylmethionine. One-carbon metabolism has a tissue specific configuration, and in the liver, the participating enzymes are abundantly expressed-a requirement to maintain hepatocyte differentiation. Targeted proteomics studies have revealed significant differences in hepatocellular carcinoma and cirrhosis, suggesting that monitoring one-carbon metabolism enzymes can be useful for stratification of liver disease patients and to develop precision medicine strategies for their clinical management. Here, reprogramming of one-carbon metabolism in liver diseases is described and the role of mass spectrometry to follow-up these alterations is discussed.
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Affiliation(s)
- Laura Guerrero
- Centro Nacional de Biotecnología (CNB), CSIC. C/Darwin 3, 28049 Madrid, Spain
| | - Alberto Paradela
- Centro Nacional de Biotecnología (CNB), CSIC. C/Darwin 3, 28049 Madrid, Spain
| | - Fernando J. Corrales
- Centro Nacional de Biotecnología (CNB), CSIC. C/Darwin 3, 28049 Madrid, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
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14
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Shin HW, Takatsu H. Regulatory Roles of N- and C-Terminal Cytoplasmic Regions of P4-ATPases. Chem Pharm Bull (Tokyo) 2022; 70:524-532. [DOI: 10.1248/cpb.c22-00042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Hye-Won Shin
- Graduate School of Pharmaceutical Sciences, Kyoto University
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15
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Abstract
Bile acid transport is a complex physiologic process, of which disruption at any step can lead to progressive intrahepatic cholestasis (PFIC). The first described PFIC disorders were originally named as such before identification of a genetic cause. However, advances in clinical molecular genetics have led to the identification of additional disorders that can cause these monogenic inherited cholestasis syndromes, and they are now increasingly referred to by the affected protein causing disease. The list of PFIC disorders is expected to grow as more causative genes are discovered. Here forth, we present a comprehensive overview of known PFIC disorders.
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Affiliation(s)
- Sara Hassan
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA. https://twitter.com/SaraHassanMD
| | - Paula Hertel
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine, Texas Children's Hospital, 6621 Fannin Street, Houston, TX 77030, USA.
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16
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Bing H, Li YL, Li D, Zhang C, Chang B. Case Report: A Rare Heterozygous ATP8B1 Mutation in a BRIC1 Patient: Haploinsufficiency? Front Med (Lausanne) 2022; 9:897108. [PMID: 35783636 PMCID: PMC9243653 DOI: 10.3389/fmed.2022.897108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 06/01/2022] [Indexed: 11/25/2022] Open
Abstract
Benign recurrent intrahepatic cholestasis (BRIC) is an autosomal recessive disorder characterized by recurrent cholestasis. ATPase class I, type 8B, member 1 (ATP8B1) encodes familial intrahepatic cholestasis 1 (FIC1), which acts as a phosphatidylserine reversing enzyme in the tubule membrane of hepatocytes to mediate the inward translocation of phosphatidylserine (PS). At present, dozens of ATP8B1 pathogenic mutations have been identified that mainly cause BRIC1 and progressive familial intrahepatic cholestasis 1 (PFIC1). The diagnosis of BRIC1 is based on symptoms, laboratory tests, imaging, liver histology, and genetic testing. BRIC1 treatment seeks to prevent recurrence and reduce disease severity. At present, the main treatment methods include ursodeoxycholic acid (UDCA), rifampin, cholestyramine and haemofiltration, and endoscopic nasobiliary drainage (ENBD). Here, we report a 17-year-old patient with cholestasis who has a rare heterozygous ATP8B1 gene mutation (p.T888K). The patient was treated with UDCA, glucocorticoids and haemofiltration, after which bilirubin levels gradually returned to normal. This case was thought to be caused by an ATP8B1 heterozygous mutation, which may be related to haploinsufficiency (HI).
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Affiliation(s)
- Hao Bing
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang, China
- Department of Gastroenterology, Shengjing Hospital Affiliated by China Medical University, Shenyang, China
| | - Yi-Ling Li
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Dan Li
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Chen Zhang
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Bing Chang
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang, China
- *Correspondence: Bing Chang,
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17
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Dieudonné T, Herrera SA, Laursen MJ, Lejeune M, Stock C, Slimani K, Jaxel C, Lyons JA, Montigny C, Pomorski TG, Nissen P, Lenoir G. Autoinhibition and regulation by phosphoinositides of ATP8B1, a human lipid flippase associated with intrahepatic cholestatic disorders. eLife 2022; 11:75272. [PMID: 35416773 PMCID: PMC9045818 DOI: 10.7554/elife.75272] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 04/12/2022] [Indexed: 11/24/2022] Open
Abstract
P4-ATPases flip lipids from the exoplasmic to the cytosolic leaflet, thus maintaining lipid asymmetry in eukaryotic cell membranes. Mutations in several human P4-ATPase genes are associated with severe diseases, for example in ATP8B1 causing progressive familial intrahepatic cholestasis, a rare inherited disorder progressing toward liver failure. ATP8B1 forms a binary complex with CDC50A and displays a broad specificity to glycerophospholipids, but regulatory mechanisms are unknown. Here, we report functional studies and the cryo-EM structure of the human lipid flippase ATP8B1-CDC50A at 3.1 Å resolution. We find that ATP8B1 is autoinhibited by its N- and C-terminal tails, which form extensive interactions with the catalytic sites and flexible domain interfaces. Consistently, ATP hydrolysis is unleashed by truncation of the C-terminus, but also requires phosphoinositides, most markedly phosphatidylinositol-3,4,5-phosphate (PI(3,4,5)P3), and removal of both N- and C-termini results in full activation. Restored inhibition of ATP8B1 truncation constructs with a synthetic peptide mimicking the C-terminal segment further suggests molecular communication between N- and C-termini in the autoinhibition and demonstrates that the regulatory mechanism can be interfered with by exogenous compounds. A recurring (G/A)(Y/F)AFS motif of the C-terminal segment suggests that this mechanism is employed widely across P4-ATPase lipid flippases in plasma membrane and endomembranes.
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Affiliation(s)
- Thibaud Dieudonné
- Institute for Integrative Biology of the Cell, Université Paris-Saclay, CEA, CNRS, Gif-sur-Yvette, France
| | - Sara Abad Herrera
- Department of Molecular Biochemistry, Ruhr University Bochum, Bochum, Germany
| | | | - Maylis Lejeune
- Institute for Integrative Biology of the Cell, Université Paris-Saclay, CEA, CNRS, Gif-sur-Yvette, France
| | - Charlott Stock
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Kahina Slimani
- Institute for Integrative Biology of the Cell, Université Paris-Saclay, CEA, CNRS, Gif-sur-Yvette, France
| | - Christine Jaxel
- Institute for Integrative Biology of the Cell, Université Paris-Saclay, CEA, CNRS, Gif-sur-Yvette, France
| | - Joseph A Lyons
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Cédric Montigny
- Institute for Integrative Biology of the Cell, Université Paris-Saclay, CEA, CNRS, Gif-sur-Yvette, France
| | | | - Poul Nissen
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Guillaume Lenoir
- Institute for Integrative Biology of the Cell, Université Paris-Saclay, CEA, CNRS, Gif-sur-Yvette, France
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18
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Bakır A, Topçu V, Çavdarlı B. The molecular landscape of progressive familial intrahepatic cholestasis in Turkey: Defining the molecular profiles and expanding the variant spectrum. Ann Hum Genet 2021; 86:119-126. [PMID: 34961929 DOI: 10.1111/ahg.12456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 12/02/2021] [Accepted: 12/08/2021] [Indexed: 11/29/2022]
Abstract
Progressive familial intrahepatic cholestasis (PFIC) is a rare genetically heterogeneous group of autosomal recessive liver disorders that manifests as intrahepatic cholestasis during the neonatal period. ATP8B1, ABCB11, and ABCB4 genes are responsible for PFIC type 1, PFIC type 2, and PFIC type 3, respectively. To determine the underlying molecular etiology of PFIC, 80 patients from 77 families were investigated. The molecular genetic diagnosis was applied by using next-generation sequencing (NGS) and revealed 29 different variants from 32 patients. In this study, we evaluated these variants according to mechanisms, clinical sub-groups, and genotype-phenotype correlation.
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Affiliation(s)
- Abdullatif Bakır
- Department of Medical Genetics, AnkaraTraining and Research Hospital, Ankara, Turkey.,Department of Medical Genetics, University of Health Sciences, Dr. Sami Ulus Maternity and Children's Education and Research Hospital, Ankara, Turkey
| | - Vehap Topçu
- Department of Medical Genetics, Ankara Numune Training and Research Hospital, Ankara, Turkey.,Department of Medical Genetics, Ankara Cıty Hospıtal, Ankara, Turkey
| | - Büşranur Çavdarlı
- Department of Medical Genetics, Ankara Numune Training and Research Hospital, Ankara, Turkey.,Department of Medical Genetics, Ankara Cıty Hospıtal, Ankara, Turkey
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19
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Rodríguez BM, Busoms CM, Sampol LM, Romero RG, Rivero GC, Martín de Carpi J. Heterozygous mutations of ATP8B1, ABCB11 and ABCB4 cause mild forms of Progressive Familial Intrahepatic Cholestasis in a pediatric cohort. GASTROENTEROLOGIA Y HEPATOLOGIA 2021; 45:585-592. [PMID: 34942279 DOI: 10.1016/j.gastrohep.2021.12.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 11/29/2021] [Accepted: 12/03/2021] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Heterozygous defects in genes implicated in Progressive Familial Intrahepatic Cholestasis have been described in milder forms of cholestatic diseases. Our aim is to describe clinical, laboratory and imaging characteristics as well as treatment and outcome of a cohort of pediatric patients with heterozygous mutations in ATP8B1, ABCB11 or ABCB4. PATIENTS AND METHODS We present a retrospective descriptive study including pediatric patients with at least one heterozygosis defect in ATP8B1, ABCB11 or ABCB4 diagnosed after a cholestatic episode. Clinical, diagnostic and outcome data were collected including gene analysis (panel of PFIC NextGeneDx®). RESULTS 7 patients showed a heterozygous mutation: 3 patients in ABCB4, 1 in ABCB11, 2 in ABCB4 and ABCB11 and 1 in ATP8B1. The median onset age was 5.5 years with a median time of follow-up of 6 years. The initial presentation was pruritus followed by asymptomatic hypertransaminasemia and persistent cholestasis. Two patients had family history of gallbladder stones and mild hepatitis. All showed elevated transaminases and bile acids, high gamma glutamyl-transferase (GGT) in 3 and conjugated bilirubin in 2 patients. Liver biopsy showed inflammatory infiltrate or mild fibrosis with normal immunohistochemistry. All patients were treated with ursodeoxycholic acid, two patients requiring the addition of resincholestyramine. During follow-up, 3 patients suffered limited relapses of pruritus. No disease progression was observed. CONCLUSION Heterozygous mutations in genes coding proteins of the hepatocellular transport system can cause cholestatic diseases with great phenotypic variability. The presence of repeated episodes of hypertransaminasemia or cholestasis after a trigger should force us to rule out the presence of these heterozygous mutations in genes involved in CIFP.
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Affiliation(s)
- Beatriz Mínguez Rodríguez
- Department of Gastroenterology, Hepatology and Nutrition. Sant Joan de Déu Hospital, Barcelona, Spain.
| | - Cristina Molera Busoms
- Department of Gastroenterology, Hepatology and Nutrition. Sant Joan de Déu Hospital, Barcelona, Spain.
| | | | - Ruth García Romero
- Unit of Paediatric Gastroenterology, Hepatology and Nutrition. Miguel Servet Hospital, Zaragoza, Spain.
| | - Gemma Colomé Rivero
- Department of Paediatric Gastroenterology. Nens Hospital of Barcelona, Barcelona, Spain.
| | - Javier Martín de Carpi
- Department of Gastroenterology, Hepatology and Nutrition. Sant Joan de Déu Hospital, Barcelona, Spain.
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20
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Namgoong JM, Hwang S, Kwon H, Ha S, Kim KM, Oh SH, Hong SM. Liver transplantation in pediatric patients with progressive familial intrahepatic cholestasis: Single center experience of seven cases. Ann Hepatobiliary Pancreat Surg 2021; 26:69-75. [PMID: 34916336 PMCID: PMC8901976 DOI: 10.14701/ahbps.21-114] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 09/24/2021] [Accepted: 09/27/2021] [Indexed: 11/17/2022] Open
Abstract
Backgrounds/Aims Progressive familial intrahepatic cholestasis (PFIC) is an autosomal recessive inherited disease requiring liver transplantation (LT). The objective of this study was to investigate the clinicopathological features and posttransplant courses of seven LT recipients with PFIC. Methods This was a retrospective single-center study of patients with PFIC who underwent LT from January 2013 to June 2020. Results Two and five patients were diagnosed with PFIC type 1 and type 2, respectively. For all seven patients, age of PFIC onset was at birth. Jaundice was present in all cases. Mean pretransplant total and direct bilirubin levels were 16.1 ± 8.1 mg/dL and 12.4 ± 6.2 mg/dL, respectively. Median patient age and body weight at LT were 10 months and 7 kg, respectively. Types of donors were mothers of patients in four and deceased donors in three. All five patients with PFIC type 2 recovered uneventfully. One patient each with PFIC type 1 underwent retransplantation due to graft failure or died due to multi-organ failure. Overall graft and patient survival rates at five years were 66.7% and 83.3%, respectively. Bile salt export pump immunohistochemical staining showed normal canalicular expression in two patients with PFIC type 1, focal loss in two patients with PFIC type 2, and total loss in three patients with PFIC type 2. Conclusions LT is currently the only effective treatment for PFIC-associated end-stage liver diseases. It is mandatory to perform regular follow-up due to the risk of complications including steatohepatitis, especially for patients with PFIC type 1.
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Affiliation(s)
- Jung-Man Namgoong
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Shin Hwang
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyunhee Kwon
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Suhyeon Ha
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyung Mo Kim
- Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Seak Hee Oh
- Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Seung-Mo Hong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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21
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Henkel SAF, Salgado CM, Reyes-Mugica M, Soltys KA, Strauss K, Mazariegos GV, Squires RH, McKiernan PJ, Zhang X, Squires JE. Long-term liver transplant outcomes for progressive familial intrahepatic cholestasis type 1: The Pittsburgh experience. Pediatr Transplant 2021; 25:e14108. [PMID: 34339082 DOI: 10.1111/petr.14108] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 05/26/2021] [Accepted: 07/23/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND Progressive familial intrahepatic cholestasis type 1 (PFIC1) arises from biallelic variants in the ATP8B1 gene that annul FIC1 activity, resulting in progressive liver disease. Liver transplant (LT) is indicated in refractory disease; however, post-LT complications including worsening diarrhea and steatohepatitis progressing to fibrosis with graft loss have been reported. We aim to describe long-term outcomes of PFIC1 LT recipients at our center, focusing on the histological changes of the allografts. METHODS We assessed 7 PFIC1 patients post-LT at the Children's Hospital of Pittsburgh (CHP). All pre-transplant, explant, and sequential post-transplant pathology samples were reviewed. Continuous data are presented as the mean ± SD. We compared the pre- and post-transplant height and weight z-scores using Wilcoxon signed-rank test. RESULTS Seven (29% male) patients with PFIC1 received a LT (n = 6) or had post-LT care (n = 1) at CHP. Six had confirmed or suspected identical genetic. At a mean follow-up of 10.9 years, both patient survival and graft survival were 100%. Diarrhea persisted (n = 3) or newly developed (n = 4) in all patients after LT contributing to ongoing growth failure, with mean z-scores -2.63 (weight) and -2.98 (height) at follow-up. Histologically, allograft steatosis was common but was not accompanied by significant inflammation, ballooning, or fibrosis. CONCLUSION We show that extrahepatic disease persists and near-universal allograft steatosis occurs. However, at a mean follow-up period of over 10 years, no patients developed steatohepatitis or significant fibrosis, and both patient survival and graft survival are excellent.
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Affiliation(s)
- Sarah A F Henkel
- Department of Pediatric Gastroenterology and Hepatology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Claudia M Salgado
- Department of Pathology, University of Pittsburgh, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Miguel Reyes-Mugica
- Department of Pathology, University of Pittsburgh, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Kyle A Soltys
- Hillman Center for Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Kevin Strauss
- Clinic for Special Children, Strasburg, PA, USA.,Department of Pediatrics, Penn Medicine-Lancaster General Hospital, Lancaster, PA, USA
| | - George V Mazariegos
- Hillman Center for Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Robert H Squires
- Department of Pediatric Gastroenterology and Hepatology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Patrick J McKiernan
- Department of Pediatric Gastroenterology and Hepatology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Xingyu Zhang
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - James E Squires
- Department of Pediatric Gastroenterology and Hepatology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
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22
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Jeyaraj R, Bounford KM, Ruth N, Lloyd C, MacDonald F, Hendriksz CJ, Baumann U, Gissen P, Kelly D. The Genetics of Inherited Cholestatic Disorders in Neonates and Infants: Evolving Challenges. Genes (Basel) 2021; 12:1837. [PMID: 34828443 PMCID: PMC8621872 DOI: 10.3390/genes12111837] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/15/2021] [Accepted: 11/16/2021] [Indexed: 12/26/2022] Open
Abstract
Many inherited conditions cause cholestasis in the neonate or infant. Next-generation sequencing methods can facilitate a prompt diagnosis in some of these cases; application of these methods in patients with liver diseases of unknown cause has also uncovered novel gene-disease associations and improved our understanding of physiological bile secretion and flow. By helping to define the molecular basis of certain cholestatic disorders, these methods have also identified new targets for therapy as well patient subgroups more likely to benefit from specific therapies. At the same time, sequencing methods have presented new diagnostic challenges, such as the interpretation of single heterozygous genetic variants. This article discusses those challenges in the context of neonatal and infantile cholestasis, focusing on difficulties in predicting variant pathogenicity, the possibility of other causal variants not identified by the genetic screen used, and phenotypic variability among patients with variants in the same genes. A prospective, observational study performed between 2010-2013, which sequenced six important genes (ATP8B1, ABCB11, ABCB4, NPC1, NPC2 and SLC25A13) in an international cohort of 222 patients with infantile liver disease, is given as an example of potential benefits and challenges that clinicians could face having received a complex genetic result. Further studies including large cohorts of patients with paediatric liver disease are needed to clarify the spectrum of phenotypes associated with, as well as appropriate clinical response to, single heterozygous variants in cholestasis-associated genes.
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Affiliation(s)
- Rebecca Jeyaraj
- National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, University College London, London WC1N 1EH, UK;
| | - Kirsten McKay Bounford
- West of Scotland Centre for Genomic Medicine, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK;
| | - Nicola Ruth
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK; (N.R.); (U.B.); (D.K.)
- Liver Unit, Birmingham Women’s and Children’s Hospital, Birmingham B4 6NH, UK;
| | - Carla Lloyd
- Liver Unit, Birmingham Women’s and Children’s Hospital, Birmingham B4 6NH, UK;
| | - Fiona MacDonald
- West Midlands Regional Genetics Service, Birmingham Women’s and Children’s Hospital, Birmingham B15 2TG, UK;
| | - Christian J. Hendriksz
- Steve Biko Academic Unit, Level D3 New Pretoria Academic Hospital, Malherbe Street, Pretoria 0002, South Africa;
| | - Ulrich Baumann
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK; (N.R.); (U.B.); (D.K.)
- Paediatric Gastroenterology and Hepatology, Hannover Medical School, 30625 Hannover, Germany
| | - Paul Gissen
- National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, University College London, London WC1N 1EH, UK
| | - Deirdre Kelly
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK; (N.R.); (U.B.); (D.K.)
- Liver Unit, Birmingham Women’s and Children’s Hospital, Birmingham B4 6NH, UK;
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23
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Yang Y, Zhang J, Li LT, Qiu YL, Gong JY, Zhang MH, Li CH, Wang JS. Whole-Genome Sequencing Reveals Large ATP8B1 Deletion/Duplications as Second Mutations Missed by Exome-Based Sequencing. J Mol Diagn 2021; 23:1491-1499. [PMID: 34543749 DOI: 10.1016/j.jmoldx.2021.07.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 07/14/2021] [Accepted: 07/28/2021] [Indexed: 11/15/2022] Open
Abstract
Progressive familial intrahepatic cholestasis type 1 (PFIC1) results from biallelic pathogenic variants in ATP8B1. This study sought second pathogenic variants in ATP8B1 by whole-genome sequencing (WGS) in four unrelated low γ-glutamyl transpeptidase cholestasis patients in whom clinical suspicion of PFIC1 was high and gene-panel or Sanger sequencing had identified only one pathogenic variant in ATP8B1. Sanger sequencing confirmed WGS findings and determined the origin of each variant. Novel nonrecurrent structural variants in three patients (patient 1 to patient 3) were identified in trans: g.55396652_55403080del (6427-bp deletion), g.55335906_55346620dup (10,715-bp duplication), and g.55362063_55364293dup (2231-bp duplication). One synonymous variant in patient 4 was recognized in trans (c.1029G>A, p. Thr343Thr) and demonstrated as deleterious. In conclusion, WGS improves genetic diagnostic yield in PFIC1. These findings expand the gene-variant spectrum associated with familiar intrahepatic cholestasis 1 (FIC1) disease and for the first time report tandem duplication in ATP8B1 associated with cholestasis.
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Affiliation(s)
- Ye Yang
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China
| | - Jing Zhang
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China
| | - Li-Ting Li
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China
| | - Yi-Ling Qiu
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China; Department of Pediatrics, Jinshan Hospital, Fudan University, Shanghai, China
| | - Jing-Yu Gong
- Department of Pediatrics, Jinshan Hospital, Fudan University, Shanghai, China
| | - Mei-Hong Zhang
- Department of Pediatrics, Jinshan Hospital, Fudan University, Shanghai, China
| | - Cai-Hua Li
- Genesky Biotechnologies, Shanghai, China
| | - Jian-She Wang
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
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van Wessel DB, Thompson RJ, Gonzales E, Jankowska I, Shneider BL, Sokal E, Grammatikopoulos T, Kadaristiana A, Jacquemin E, Spraul A, Lipiński P, Czubkowski P, Rock N, Shagrani M, Broering D, Algoufi T, Mazhar N, Nicastro E, Kelly D, Nebbia G, Arnell H, Fischler B, Hulscher JB, Serranti D, Arikan C, Debray D, Lacaille F, Goncalves C, Hierro L, Muñoz Bartolo G, Mozer‐Glassberg Y, Azaz A, Brecelj J, Dezsőfi A, Luigi Calvo P, Krebs‐Schmitt D, Hartleif S, van der Woerd WL, Wang J, Li L, Durmaz Ö, Kerkar N, Hørby Jørgensen M, Fischer R, Jimenez‐Rivera C, Alam S, Cananzi M, Laverdure N, Targa Ferreira C, Ordonez F, Wang H, Sency V, Mo Kim K, Chen H, Carvalho E, Fabre A, Quintero Bernabeu J, Alonso EM, Sokol RJ, Suchy FJ, Loomes KM, McKiernan PJ, Rosenthal P, Turmelle Y, Rao GS, Horslen S, Kamath BM, Rogalidou M, Karnsakul WW, Hansen B, Verkade HJ, Natural Course and Prognosis of PFIC and Effect of Biliary Diversion Consortium. Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency. Hepatology 2021; 74:892-906. [PMID: 33666275 PMCID: PMC8456904 DOI: 10.1002/hep.31787] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Revised: 01/17/2021] [Accepted: 01/27/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Mutations in ATPase phospholipid transporting 8B1 (ATP8B1) can lead to familial intrahepatic cholestasis type 1 (FIC1) deficiency, or progressive familial intrahepatic cholestasis type 1. The rarity of FIC1 deficiency has largely prevented a detailed analysis of its natural history, effects of predicted protein truncating mutations (PPTMs), and possible associations of serum bile acid (sBA) concentrations and surgical biliary diversion (SBD) with long-term outcome. We aimed to provide insights by using the largest genetically defined cohort of patients with FIC1 deficiency to date. APPROACH AND RESULTS This multicenter, combined retrospective and prospective study included 130 patients with compound heterozygous or homozygous predicted pathogenic ATP8B1 variants. Patients were categorized according to the number of PPTMs (i.e., splice site, frameshift due to deletion or insertion, nonsense, duplication), FIC1-A (n = 67; no PPTMs), FIC1-B (n = 29; one PPTM), or FIC1-C (n = 34; two PPTMs). Survival analysis showed an overall native liver survival (NLS) of 44% at age 18 years. NLS was comparable among FIC1-A, FIC1-B, and FIC1-C (% NLS at age 10 years: 67%, 41%, and 59%, respectively; P = 0.12), despite FIC1-C undergoing SBD less often (% SBD at age 10 years: 65%, 57%, and 45%, respectively; P = 0.03). sBAs at presentation were negatively associated with NLS (NLS at age 10 years, sBAs < 194 µmol/L: 49% vs. sBAs ≥ 194 µmol/L: 15%; P = 0.03). SBD decreased sBAs (230 [125-282] to 74 [11-177] μmol/L; P = 0.005). SBD (HR 0.55, 95% CI 0.28-1.03, P = 0.06) and post-SBD sBA concentrations < 65 μmol/L (P = 0.05) tended to be associated with improved NLS. CONCLUSIONS Less than half of patients with FIC1 deficiency reach adulthood with native liver. The number of PPTMs did not associate with the natural history or prognosis of FIC1 deficiency. sBA concentrations at initial presentation and after SBD provide limited prognostic information on long-term NLS.
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Affiliation(s)
- Daan B.E. van Wessel
- Pediatric Gastroenterology and HepatologyUniversity Medical Center GroningenUniversity of GroningenGroningenthe Netherlands
| | | | - Emmanuel Gonzales
- Pediatric Hepatology & Pediatric Liver Transplant DepartmentCentre de Référence de l’Atrésie des Voies Biliaires et des Cholestases GénétiquesFilière de Santé des Maladies Rares du Foie de l’enfant et de l’adulteEuropean Reference Network RARE‐LIVERAssistance Publique‐Hôpitaux de ParisFaculté de Médecine Paris‐SaclayCHU BicêtreParisFrance
- European Reference Network on Hepatological Diseases
| | - Irena Jankowska
- European Reference Network on Hepatological Diseases
- Gastroenterology, Hepatology, Nutritional Disorders and Pediatricsthe Children’s Memorial Health InstituteWarsawPoland
| | - Benjamin L. Shneider
- Division of Pediatric Gastroenterology, Hepatology, and NutritionDepartment of PediatricsBaylor College of MedicineHoustonTXUSA
- Childhood Liver Disease Research Network (ChiLDReN)
| | - Etienne Sokal
- European Reference Network on Hepatological Diseases
- Cliniques St. LucUniversité Catholique de LouvainBrusselsBelgium
| | | | | | - Emmanuel Jacquemin
- Pediatric Hepatology & Pediatric Liver Transplant DepartmentCentre de Référence de l’Atrésie des Voies Biliaires et des Cholestases GénétiquesFilière de Santé des Maladies Rares du Foie de l’enfant et de l’adulteEuropean Reference Network RARE‐LIVERAssistance Publique‐Hôpitaux de ParisFaculté de Médecine Paris‐SaclayCHU BicêtreParisFrance
- INSERMUMR‐S 1193Université Paris‐SaclayOrsayFrance
| | - Anne Spraul
- INSERMUMR‐S 1193Université Paris‐SaclayOrsayFrance
- Biochemistry UnitCentre de Référence de l’Atrésie des Voies Biliaires et des Cholestases GénétiquesFilière de Santé des Maladies Rares du Foie de l’enfant et de l’adulteEuropean Reference Network RARE‐LIVERAssistance Publique‐Hôpitaux de ParisFaculté de Médecine Paris‐SaclayCHU BicêtreParisFrance
| | - Patryk Lipiński
- European Reference Network on Hepatological Diseases
- Gastroenterology, Hepatology, Nutritional Disorders and Pediatricsthe Children’s Memorial Health InstituteWarsawPoland
| | - Piotr Czubkowski
- European Reference Network on Hepatological Diseases
- Gastroenterology, Hepatology, Nutritional Disorders and Pediatricsthe Children’s Memorial Health InstituteWarsawPoland
| | - Nathalie Rock
- Cliniques St. LucUniversité Catholique de LouvainBrusselsBelgium
| | - Mohammad Shagrani
- Department of Liver & SB Transplant & Hepatobiliary‐Pancreatic SurgeryKing Faisal Specialist Hospital & Research CenterRiyadhSaudi Arabia
- College of MedicineAlfaisal UniversityRiyadhSaudi Arabia
| | - Dieter Broering
- Department of Liver & SB Transplant & Hepatobiliary‐Pancreatic SurgeryKing Faisal Specialist Hospital & Research CenterRiyadhSaudi Arabia
| | - Talal Algoufi
- Department of Liver & SB Transplant & Hepatobiliary‐Pancreatic SurgeryKing Faisal Specialist Hospital & Research CenterRiyadhSaudi Arabia
| | - Nejat Mazhar
- Department of Liver & SB Transplant & Hepatobiliary‐Pancreatic SurgeryKing Faisal Specialist Hospital & Research CenterRiyadhSaudi Arabia
| | - Emanuele Nicastro
- Pediatric Hepatology, Gastroenterology and TransplantationOspedale Papa Giovanni XXIIIBergamoItaly
| | - Deirdre Kelly
- European Reference Network on Hepatological Diseases
- Liver UnitBirmingham Women’s and Children’s HospitalUniversity of BirminghamBirminghamUnited Kingdom
| | - Gabriella Nebbia
- Servizio Di Epatologia e Nutrizione PediatricaFondazione Irccs Ca’ Granda Ospedale Maggiore PoliclinicoMilanoItaly
| | - Henrik Arnell
- European Reference Network on Hepatological Diseases
- Pediatric Digestive DiseasesAstrid Lindgren Children’s HospitalCLINTECKarolinska InstitutetKarolinska University HospitalStockholmSweden
| | - Björn Fischler
- European Reference Network on Hepatological Diseases
- Pediatric Digestive DiseasesAstrid Lindgren Children’s HospitalCLINTECKarolinska InstitutetKarolinska University HospitalStockholmSweden
| | - Jan B.F. Hulscher
- European Reference Network on Hepatological Diseases
- Pediatric SurgeryUniversity Medical Center GroningenGroningenthe Netherlands
| | - Daniele Serranti
- Pediatric and Liver UnitMeyer Children’s University Hospital of FlorenceFlorenceItaly
| | - Cigdem Arikan
- Pediatric GI and Hepatology Liver Transplantation CenterKuttam System in Liver MedicineKoc University School of MedicineIstanbulTurkey
| | - Dominique Debray
- Pediatric Hepatology unit, Reference Center for Biliary Atresia and Genetic Cholestatic DiseasesFilière de Santé des Maladies Rares du Foie de l’enfant et de l’adulteEuropean Reference Network RARE‐LIVERAPHP‐Neckler Enfants Malades University HospitalFaculté de Médecine Paris‐CentreParisFrance
| | - Florence Lacaille
- Pediatric Hepatology unit, Reference Center for Biliary Atresia and Genetic Cholestatic DiseasesFilière de Santé des Maladies Rares du Foie de l’enfant et de l’adulteEuropean Reference Network RARE‐LIVERAPHP‐Neckler Enfants Malades University HospitalFaculté de Médecine Paris‐CentreParisFrance
| | - Cristina Goncalves
- European Reference Network on Hepatological Diseases
- Coimbra University Hospital CenterCoimbraPortugal
| | - Loreto Hierro
- European Reference Network on Hepatological Diseases
- Pediatric Liver ServiceLa Paz University HospitalMadridSpain
| | - Gema Muñoz Bartolo
- European Reference Network on Hepatological Diseases
- Pediatric Liver ServiceLa Paz University HospitalMadridSpain
| | - Yael Mozer‐Glassberg
- Institute of Gastroenterology, Nutrition and Liver DiseasesSchneider Children’s Medical Center of IsraelPetach TikvahIsrael
| | - Amer Azaz
- Sheikh Khalifa Medical CityAbu DhabiUnited Arab Emirates
| | - Jernej Brecelj
- Department of Gastroenterology, Hepatology and NutritionUniversity Children’s Hospital LjubljanaLjubljanaSlovenia
- Department of PediatricsFaculty of MedicineUniversity of LjubljanaLjubljanaSlovenia
| | - Antal Dezsőfi
- First Department of PediatricsSemmelweis UniversityBudapestHungary
| | - Pier Luigi Calvo
- Pediatic Gastroenterology UnitRegina Margherita Children’s HospitalAzienda Ospedaliera Città Della Salute e Della Scienza University HospitalTorinoItaly
| | | | - Steffen Hartleif
- European Reference Network on Hepatological Diseases
- University Children’s Hospital TϋbingenTϋbingenGermany
| | - Wendy L. van der Woerd
- Pediatric Gastroenterology, Hepatology and NutritionWilhelmina Children’s HospitalUniversity Medical Center UtrechtUtrechtthe Netherlands
| | - Jian‐She Wang
- Children’s Hospital of Fudan UniversityShanghaiChina
| | - Li‐ting Li
- Children’s Hospital of Fudan UniversityShanghaiChina
| | - Özlem Durmaz
- Istanbul Faculty of MedicineIstanbul UniversityIstanbulTurkey
| | - Nanda Kerkar
- Pediatric Gastroenterology, Hepatology and NutritionUniversity of Rochester Medical CenterRochesterNYUSA
| | - Marianne Hørby Jørgensen
- European Reference Network on Hepatological Diseases
- Pediatric and Adolescent DepartmentDepartment of Pediatrics and Adolescent MedicineRigshospitalet Copenhagen University HospitalCopenhagenDenmark
| | - Ryan Fischer
- Section of Hepatology and Transplant MedicineChildren’s Mercy HospitalKansas CityMOUSA
| | - Carolina Jimenez‐Rivera
- Department of PediatricsChildren’s Hospital of Eastern OntarioUniversity of OttawaOttawaCanada
| | - Seema Alam
- Pediatric HepatologyInstitute of Liver and Biliary SciencesNew DelhiIndia
| | - Mara Cananzi
- European Reference Network on Hepatological Diseases
- Pediatric Gastroenterology and HepatologyUniversity Hospital of PadovaPadovaItaly
| | - Noémie Laverdure
- European Reference Network on Hepatological Diseases
- Service de Gastroentérologie, Hépatologie et Nutrition PédiatriquesHospices Civils de LyonHôpital Femme Mère EnfantLyonFrance
| | | | - Felipe Ordonez
- Fundación Cardioinfantil Instituto de CardiologiaPediatric Gastroenterology and HepatologyBogotáColombia
| | - Heng Wang
- DDC Clinic Center for Special Needs ChildrenMiddlefieldOHUSA
| | - Valerie Sency
- DDC Clinic Center for Special Needs ChildrenMiddlefieldOHUSA
| | - Kyung Mo Kim
- Department of PediatricsAsan Medical Center Children’s HospitalSeoulSouth Korea
| | - Huey‐Ling Chen
- Division of Pediatric Gastroenterology, Hepatology and NutritionNational Taiwan University Children’s HospitalTaipeiTaiwan
| | - Elisa Carvalho
- Pediatric Gastroenterology and HepatologyBrasília Children’s HospitalBrasiliaBrazil
| | - Alexandre Fabre
- INSERMMMGAix Marseille UniversityMarseilleFrance
- Serveice de Pédiatrie MultidisciplinaireTimone EnfantMarseilleFrance
| | - Jesus Quintero Bernabeu
- European Reference Network on Hepatological Diseases
- Pediatric Hepatology and Liver Transplant UnitBarcelonaSpain
| | - Estella M. Alonso
- Childhood Liver Disease Research Network (ChiLDReN)
- Division of Pediatric Gastroenterology, Hepatology and NutritionAnn & Robert H. Lurie Children’s HospitalChicagoILUSA
| | - Ronald J. Sokol
- Childhood Liver Disease Research Network (ChiLDReN)
- Section of Pediatric Gastroenterology, Hepatology and NutritionDepartment of PediatricsChildren’s Hospital ColoradoUniversity of Colorado School of MedicineAuroraCOUSA
| | - Frederick J. Suchy
- Childhood Liver Disease Research Network (ChiLDReN)
- Icahn School of Medicine at Mount SinaiMount Sinai Kravis Children’s HospitalNew YorkNYUSA
| | - Kathleen M. Loomes
- Childhood Liver Disease Research Network (ChiLDReN)
- Division of Gastroenterology, Hepatology and NutritionChildren’s Hospital of PhiladelphiaPhiladelphiaPAUSA
| | - Patrick J. McKiernan
- Childhood Liver Disease Research Network (ChiLDReN)
- Department of Pediatric Gastroenterology and HepatologyUniversity of Pittsburgh Medical Center Children’s Hospital of PittsburghPittsburghPAUSA
| | - Philip Rosenthal
- Childhood Liver Disease Research Network (ChiLDReN)
- Department of Pediatrics and SurgeryUCSF Benioff Children’s HospitalUniversity of California San Francisco School of MedicineSan FranciscoCAUSA
| | - Yumirle Turmelle
- Childhood Liver Disease Research Network (ChiLDReN)
- Section of HepatologyDepartment of PediatricsSt. Louis Children’s HospitalWashington University School of MedicineSt. LouisMOUSA
| | - Girish S. Rao
- Childhood Liver Disease Research Network (ChiLDReN)
- Riley Hospital for ChildrenIndiana University School of MedicineIndianapolisINUSA
| | - Simon Horslen
- Childhood Liver Disease Research Network (ChiLDReN)
- Department of PediatricsSeattle Children’s HospitalUniversity of WashingtonSeattleWAUSA
| | - Binita M. Kamath
- Childhood Liver Disease Research Network (ChiLDReN)
- The Hospital for Sick ChildrenUniversity of TorontoTorontoCanada
| | - Maria Rogalidou
- Division of Pediatric Gastroenterology & HepatologyFirst Pediatrics DepartmentUniversity of AthensAgia Sofia Children’s HospitalAthensGreece
| | - Wikrom W. Karnsakul
- Division of Pediatric Gastroenterology, Nutrition, and HepatologyDepartment of PediatricsJohns Hopkins University School of MedicineBaltimoreMDUSA
| | - Bettina Hansen
- Toronto Center for Liver DiseaseUniversity Health NetworkTorontoCanada
- IHPMEUniversity of TorontoTorontoCanada
| | - Henkjan J. Verkade
- Pediatric Gastroenterology and HepatologyUniversity Medical Center GroningenUniversity of GroningenGroningenthe Netherlands
- European Reference Network on Hepatological Diseases
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Jüngst C, Justinger C, Fischer J, Berg T, Lammert F. Common ABCB4 and ABCB11 Genotypes Are Associated with Idiopathic Chronic Cholestasis in Adults. Dig Dis 2021; 40:489-496. [PMID: 34348275 DOI: 10.1159/000518203] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 06/14/2021] [Indexed: 02/02/2023]
Abstract
INTRODUCTION Pathogenic mutations in genes encoding the hepatocanalicular transporters ATP8B1, ABCB11 and ABCB4 are causative for progressive cholestatic liver disease in children. In adults, less severe variants such as the common ABCB4 c.711A>T polymorphism have been associated with intrahepatic cholestasis in pregnancy and elevated liver enzymes. Hence, our aim was to study the role of common polymorphisms in adult patients with chronic unexplained cholestasis. METHODS Screening of outpatients of two university hospitals identified a cohort of 94 patients with chronic cholestasis of unknown origin after thorough exclusion of other causes. Genotyping was performed using TaqMan assays, and frequencies for the ABCB4 rs2109505 (c.711A>T), rs1202283 (c.504T>C), ABCB11 rs2287622 (p.A444V) and rs497692 (c.3084A>G) variants of the study cohort were compared to a cohort of 254 healthy controls. RESULTS The dominating symptoms of the patients were pruritus and jaundice, though the majority of them did not report symptoms at inclusion. Advanced fibrosis or cirrhosis was present in 11 patients (11.7%) only. Genotyping revealed the presence of the ABCB4 c.711A>T risk variant in 79 patients (84%), a frequency that is significantly (p = 0.037) higher than that in controls (71%). The ABCB11 p.A444V variant was also more frequent in cholestatic patients (p = 0.042). CONCLUSION The common ABCB4 c.711A>T and ABCB11 p.A444V polymorphisms are more prevalent in adult patients with idiopathic cholestasis than in healthy controls and may therefore represent risk factors for the development of chronic cholestatic liver disease.
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Affiliation(s)
- Christoph Jüngst
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.,Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Christina Justinger
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Janett Fischer
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Thomas Berg
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.,Hannover Medical School (MHH), Hannover, Germany
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26
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Henkel AS. Genetic Disorders of Bile Acid Transport. Clin Liver Dis (Hoboken) 2021; 18:237-242. [PMID: 34840725 PMCID: PMC8605694 DOI: 10.1002/cld.1132] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 04/29/2021] [Accepted: 05/05/2021] [Indexed: 02/04/2023] Open
Affiliation(s)
- Anne S. Henkel
- Division of Gastroenterology and HepatologyDepartment of MedicineNorthwestern University Feinberg School of MedicineChicagoIL
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Aydın GA, Özgen G, Görükmez O. The role of genetic mutations in intrahepatic cholestasis of pregnancy. Taiwan J Obstet Gynecol 2021; 59:706-710. [PMID: 32917322 DOI: 10.1016/j.tjog.2020.07.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/15/2020] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder of pregnancy characterized by pruritus, elevated liver enzymes and fasting serum bile acids. Genetic predisposition has been suggested to play a role in its etiology and mutations in the ATP8B1(OMIM ∗602397) (FIC1), ABCB11(OMIM ∗603201) (BSEP), and ABCB4(OMIM ∗171060) (MDR3) genes have been implicated. In the present study, we aimed to investigate the possible role of ATP8B1, ABCB11, and ABCB4 gene mutations in the patients with ICP. MATERIALS AND METHODS A total of 25 patients who were diagnosed with ICP were included in the study. Genetic test results and mutation status of the patients as assessed by the next-generation sequencing technology were retrospectively retrieved from the hospital database. RESULTS Of all patients, significant alterations in the ATP8B1 (n = 2), ABCB11 (n = 1), and ABCB4 (n = 7) genes were observed in 10 patients using the molecular analysis testing. All these alterations were heterozygous. Of these alterations, four were reported in the literature previously, while six were not. Using the in-silico parameters, there was a pathogenic alteration in the ABCB4 gene in one patient, while there was no clinically relevant alteration in the other gene mutations in the remaining nine patients. CONCLUSION Considering the fact that the alterations were compatible with clinical presentations of the ICP patients and the incidence of these mutations is low in the general population, we believe that our study results are clinically relevant. Further molecular genetic tests in ICP patients and functional studies supporting the results would shed light into the clinical importance of these alterations.
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Affiliation(s)
- Gültekin Adanaş Aydın
- Bursa Yüksek İhtisas Training and Research Hospital, Department of Obstetrics and Gynecology, 16330, Bursa, Turkey.
| | - Gülten Özgen
- Bursa Yüksek İhtisas Training and Research Hospital, Department of Obstetrics and Gynecology, 16330, Bursa, Turkey
| | - Orhan Görükmez
- Bursa Yüksek İhtisas Training and Research Hospital, Department of Medical Genetics, 16330, Bursa, Turkey
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Vogt G, Verheyen S, Schwartzmann S, Ehmke N, Potratz C, Schwerin-Nagel A, Plecko B, Holtgrewe M, Seelow D, Blatterer J, Speicher MR, Kornak U, Horn D, Mundlos S, Fischer-Zirnsak B, Boschann F. Biallelic truncating variants in ATP9A cause a novel neurodevelopmental disorder involving postnatal microcephaly and failure to thrive. J Med Genet 2021; 59:662-668. [PMID: 34379057 PMCID: PMC9252857 DOI: 10.1136/jmedgenet-2021-107843] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 05/20/2021] [Indexed: 12/04/2022]
Abstract
Background Genes implicated in the Golgi and endosomal trafficking machinery are crucial for brain development, and mutations in them are particularly associated with postnatal microcephaly (POM). Methods Exome sequencing was performed in three affected individuals from two unrelated consanguineous families presenting with delayed neurodevelopment, intellectual disability of variable degree, POM and failure to thrive. Patient-derived fibroblasts were tested for functional effects of the variants. Results We detected homozygous truncating variants in ATP9A. While the variant in family A is predicted to result in an early premature termination codon, the variant in family B affects a canonical splice site. Both variants lead to a substantial reduction of ATP9A mRNA expression. It has been shown previously that ATP9A localises to early and recycling endosomes, whereas its depletion leads to altered gene expression of components from this compartment. Consistent with previous findings, we also observed overexpression of ARPC3 and SNX3, genes strongly interacting with ATP9A. Conclusion In aggregate, our findings show that pathogenic variants in ATP9A cause a novel autosomal recessive neurodevelopmental disorder with POM. While the physiological function of endogenous ATP9A is still largely elusive, our results underline a crucial role of this gene in endosomal transport in brain tissue.
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Affiliation(s)
- Guido Vogt
- Institute of Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Sarah Verheyen
- Institute of Human Genetics, Diagnostic and Research Center for Molecular BioMedicine, Medical University of Graz, Graz, Austria
| | - Sarina Schwartzmann
- Institute of Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Nadja Ehmke
- Institute of Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Cornelia Potratz
- Department of Pediatric Neurology, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Anette Schwerin-Nagel
- Department of Pediatrics and Adolescent Medicine, Division of General Pediatrics, Medical University of Graz, Graz, Austria
| | - Barbara Plecko
- Department of Pediatrics and Adolescent Medicine, Division of General Pediatrics, Medical University of Graz, Graz, Austria
| | - Manuel Holtgrewe
- Core Unit Bioinformatics (CUBI), Berlin Institute of Health, Berlin, Germany
| | - Dominik Seelow
- Institute of Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,Bioinformatics and Translational Genetics, Berlin Institute of Health, Berlin, Germany
| | - Jasmin Blatterer
- Institute of Human Genetics, Diagnostic and Research Center for Molecular BioMedicine, Medical University of Graz, Graz, Austria
| | - Michael R Speicher
- Institute of Human Genetics, Diagnostic and Research Center for Molecular BioMedicine, Medical University of Graz, Graz, Austria
| | - Uwe Kornak
- Institute of Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,Institute of Human Genetics, University Medical Center Göttingen, Gottingen, Germany
| | - Denise Horn
- Institute of Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Stefan Mundlos
- Institute of Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,RG Development and Disease, Max-Planck-Institute for Molecular Genetics, Berlin, Germany
| | - Björn Fischer-Zirnsak
- Institute of Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,RG Development and Disease, Max-Planck-Institute for Molecular Genetics, Berlin, Germany
| | - Felix Boschann
- Institute of Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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Bull LN, Ellmers R, Foskett P, Strautnieks S, Sambrotta M, Czubkowski P, Jankowska I, Wagner B, Deheragoda M, Thompson RJ. Cholestasis Due to USP53 Deficiency. J Pediatr Gastroenterol Nutr 2021; 72:667-673. [PMID: 33075013 PMCID: PMC8549450 DOI: 10.1097/mpg.0000000000002926] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 08/17/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Although a number of genetic forms of cholestasis have been identified, the genetic etiology of disease remains unidentified in a subset of cholestasis patients. METHODS Whole exome sequencing (WES) was performed in DNA from patients diagnosed with cholestasis, at different points on the continuum from progressive familial intrahepatic cholestasis to benign recurrent intrahepatic cholestasis, in whom no disease mutations in known cholestasis genes had been identified. Candidate genes were then assessed in a larger patient sample, by targeted next-generation sequencing (NGS). Disease features at presentation and follow-up were collected from available medical records. RESULTS By WES, we identified 3 patients with homozygous mutations in USP53. Screening of USP53 in a larger set of patients identified 4 additional patients with homozygous mutations in USP53. Six of the 7 patients had deletion mutations, and 1 had a missense mutation; 3 of the patients were siblings, all bearing a deletion that also disrupted neighboring MYOZ2. Age of onset ranged from early infancy to adolescence. Cholestasis tended to be biochemically mild and intermittent, and responsive to medication. Liver fibrosis was, however, present in all 4 patients who were biopsied, and splenomegaly was apparent in 5 of 7 at last ultrasound. CONCLUSIONS Two groups recently identified patients with liver disease and mutation in USP53. We have now identified biallelic mutation in USP53 in 7 further patients with cholestasis, from 5 families. Most individuals had evidence of chronic liver disease, and long-term follow-up is recommended.
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Affiliation(s)
- Laura N. Bull
- Liver Center Laboratory, Department of Medicine and Institute for Human Genetics, University of California San Francisco, San Francisco, CA
| | | | | | | | | | - Piotr Czubkowski
- Department of Gastroenterology, Hepatology, Nutritional Disturbances and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Irena Jankowska
- Department of Gastroenterology, Hepatology, Nutritional Disturbances and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Bart Wagner
- Histopathology Department, Royal Hallamshire Hospital, Sheffield, UK
| | | | - Richard J. Thompson
- Institute of Liver Studies, King's College Hospital
- Institute of Liver Studies, King's College London, London, UK
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Long-term Outcomes of Living-donor Liver Transplantation for Progressive Familial Intrahepatic Cholestasis Type 1. J Pediatr Gastroenterol Nutr 2021; 72:425-429. [PMID: 33264179 DOI: 10.1097/mpg.0000000000002983] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Progressive familial intrahepatic cholestasis type 1 (PFIC-1), an autosomal recessive disorder, is characterized by cholestasis, jaundice, and refractory pruritus. In some patients with PFIC-1, liver cirrhosis and end-stage liver disease develop and lead to liver transplantation (LT). In this observational study, we sought to clarify the long-term outcomes of LT for PFIC-1 and predictors of favorable outcomes. METHODS The study cohort constituted 12 patients with PFIC-1 who had undergone living donor liver transplantation (LDLT) during the previous 3 decades (1990-2019). We compared the clinical manifestations and type of ATP8B1 mutations between patients in whom LDLT had been successful and those in whom it had been unsuccessful. RESULTS LDLT failed in 5 of the 12 patients and the 25-year survival rate was 58%. Comparison of physical growth after LDLT revealed significant retardation of stature in patients in whom LDLT had been unsuccessful; these patients developed severe and persistent diarrhea. ATP8B1 genotypic analysis revealed that frameshifting, splicing, and large deletion mutations occurred more commonly in successful cases, whereas missense mutations occurred more frequently in unsuccessful cases. No mutations were identical in the 2 groups. CONCLUSIONS These results suggest an association between post-LT outcomes and extrahepatic manifestations, especially intestinal function. Further investigation of correlations between ATP8B1 genotypes and intestinal function could help to identify patients with PFIC-1 who will achieve favorable post-LT outcomes.
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Affiliation(s)
- Yilin He
- State Key Laboratory of Membrane Biology, Peking-Tsinghua Center for Life Sciences, School of Life Sciences, Peking University, Beijing, 100871, China.,Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China
| | - Jinkun Xu
- State Key Laboratory of Membrane Biology, Peking-Tsinghua Center for Life Sciences, School of Life Sciences, Peking University, Beijing, 100871, China
| | - Xiaofei Wu
- State Key Laboratory of Membrane Biology, Peking-Tsinghua Center for Life Sciences, School of Life Sciences, Peking University, Beijing, 100871, China
| | - Long Li
- State Key Laboratory of Membrane Biology, Peking-Tsinghua Center for Life Sciences, School of Life Sciences, Peking University, Beijing, 100871, China.
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Mizutani A, Sabu Y, Naoi S, Ito S, Nakano S, Minowa K, Mizuochi T, Ito K, Abukawa D, Kaji S, Sasaki M, Muroya K, Azuma Y, Watanabe S, Oya Y, Inomata Y, Fukuda A, Kasahara M, Inui A, Takikawa H, Kusuhara H, Bessho K, Suzuki M, Togawa T, Hayashi H. Assessment of Adenosine Triphosphatase Phospholipid Transporting 8B1 (ATP8B1) Function in Patients With Cholestasis With ATP8B1 Deficiency by Using Peripheral Blood Monocyte-Derived Macrophages. Hepatol Commun 2021; 5:52-62. [PMID: 33437900 PMCID: PMC7789840 DOI: 10.1002/hep4.1605] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 07/11/2020] [Accepted: 08/20/2020] [Indexed: 11/29/2022] Open
Abstract
Adenosine triphosphatase phospholipid transporting 8B1 (ATP8B1) deficiency, an ultrarare autosomal recessive liver disease, includes severe and mild clinical forms, referred to as progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis type 1 (BRIC1), respectively. There is currently no practical method for determining PFIC1 or BRIC1 at an early disease course phase. Herein, we assessed the feasibility of developing a diagnostic method for PFIC1 and BRIC1. A nationwide Japanese survey conducted since 2015 identified 25 patients with cholestasis with ATP8B1 mutations, 15 of whom agreed to participate in the study. Patients were divided for analysis into PFIC1 (n = 10) or BRIC1 (n = 5) based on their disease course. An in vitro mutagenesis assay to evaluate pathogenicity of ATP8B1 mutations suggested that residual ATP8B1 function in the patients could be used to identify clinical course. To assess their ATP8B1 function more simply, human peripheral blood monocyte-derived macrophages (HMDMs) were prepared from each patient and elicited into a subset of alternatively activated macrophages (M2c) by interleukin-10 (IL-10). This was based on our previous finding that ATP8B1 contributes to polarization of HMDMs into M2c. Flow cytometric analysis showed that expression of M2c-related surface markers cluster of differentiation (CD)14 and CD163 were 2.3-fold and 2.1-fold lower (95% confidence interval, 2.0-2.5 for CD14 and 1.7-2.4 for CD163), respectively, in patients with IL-10-treated HMDMs from PFIC1 compared with BRIC1. Conclusion: CD14 and CD163 expression levels in IL-10-treated HMDMs may facilitate diagnosis of PFIC1 or BRIC1 in patients with ATP8B1 deficiency.
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Affiliation(s)
- Ayumu Mizutani
- Laboratory of Molecular PharmacokineticsGraduate School of Pharmaceutical SciencesUniversity of TokyoTokyoJapan
| | - Yusuke Sabu
- Laboratory of Molecular PharmacokineticsGraduate School of Pharmaceutical SciencesUniversity of TokyoTokyoJapan
| | - Sotaro Naoi
- Laboratory of Molecular PharmacokineticsGraduate School of Pharmaceutical SciencesUniversity of TokyoTokyoJapan
| | - Shogo Ito
- Department of Pediatrics and NeonatologyNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Satoshi Nakano
- Department of PediatricsJuntendo University School of MedicineTokyoJapan
| | - Kei Minowa
- Department of PediatricsJuntendo University School of MedicineTokyoJapan
| | - Tatsuki Mizuochi
- Department of Pediatrics and Child HealthKurume University School of MedicineFukuokaJapan
| | - Koichi Ito
- Department of Pediatrics and NeonatologyNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Daiki Abukawa
- Department of Gastroenterology and HepatologyMiyagi Children's HospitalMiyagiJapan
| | - Shunsaku Kaji
- Department of PediatricsTsuyama‐Chuo HospitalOkayamaJapan
| | - Mika Sasaki
- Department of PediatricsSchool of MedicineIwate Medical UniversityIwateJapan
| | - Koji Muroya
- Department of Endocrinology and MetabolismKanagawa Children's Medical CenterKanagawaJapan
| | - Yoshihiro Azuma
- Department of PediatricsYamaguchi University Graduate School of MedicineYamaguchiJapan
| | - Satoshi Watanabe
- Department of PediatricsNagasaki University HospitalNagasakiJapan
| | - Yuki Oya
- Department of Transplantation/Pediatric SurgeryKumamoto UniversityKumamotoJapan
- Kumamoto UniversityKumamotoJapan
| | - Yukihiro Inomata
- Department of Transplantation/Pediatric SurgeryKumamoto UniversityKumamotoJapan
- Kumamoto UniversityKumamotoJapan
| | - Akinari Fukuda
- Organ Transplantation CenterNational Center for Child Health and DevelopmentTokyoJapan
| | - Mureo Kasahara
- Organ Transplantation CenterNational Center for Child Health and DevelopmentTokyoJapan
| | - Ayano Inui
- Department of Pediatric Hepatology and GastroenterologyEastern Yokohama HospitalKanagawaJapan
| | - Hajime Takikawa
- Department of MedicineTeikyo University School of MedicineTokyoJapan
| | - Hiroyuki Kusuhara
- Laboratory of Molecular PharmacokineticsGraduate School of Pharmaceutical SciencesUniversity of TokyoTokyoJapan
| | - Kazuhiko Bessho
- Department of PediatricsOsaka University Graduate School of MedicineOsakaJapan
| | - Mitsuyoshi Suzuki
- Department of PediatricsJuntendo University School of MedicineTokyoJapan
| | - Takao Togawa
- Department of Pediatrics and NeonatologyNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Hisamitsu Hayashi
- Laboratory of Molecular PharmacokineticsGraduate School of Pharmaceutical SciencesUniversity of TokyoTokyoJapan
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Çebi AH, Altıner Ş. Application of Chromosome Microarray Analysis in the Investigation of Developmental Disabilities and Congenital Anomalies: Single Center Experience and Review of NRXN3 and NEDD4L Deletions. Mol Syndromol 2020; 11:197-206. [PMID: 33224013 PMCID: PMC7675229 DOI: 10.1159/000509645] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 05/27/2020] [Indexed: 01/01/2023] Open
Abstract
Chromosomal microarray analysis (CMA) is a first step test used for the diagnosis of patients with developmental delay, intellectual disability, autistic spectrum disorder, and multiple congenital anomalies. Its widespread usage has allowed genome-wide identification of copy number variations (CNVs). In our study, we performed a retrospective study on clinical and microarray data of 237 patients with developmental disabilities and/or multiple congenital anomalies and investigated the clinical utility of CMA. Phenotype-associated CNVs were detected in 15.18% of patients. Besides, we detected submicroscopic losses on 14q24.3q31.1 in a patient with speech delay and on 18q21.31q21.32 in twin patients with seizures. Deletions of NRXN3 and NEDD4L were responsible for the phenotypes, respectively. This study showed that CMA is a powerful diagnostic tool in this patient group and expands the genotype-phenotype correlations on developmental disabilities.
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Affiliation(s)
- Alper Han Çebi
- Department of Medical Genetics, Karadeniz Technical University School of Medicine, Trabzon, Turkey
| | - Şule Altıner
- Department of Medical Genetics, University of Health Sciences, Trabzon Kanuni Training and Research Hospital, Trabzon, Turkey
- Department of Medical Genetics, Ankara University School of Medicine, Ankara, Turkey
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Zhang W, Lin R, Lu Z, Sheng H, Xu Y, Li X, Cheng J, Cai Y, Mao X, Liu L. Phenotypic and Molecular Characteristics of Children with Progressive Familial Intrahepatic Cholestasis in South China. Pediatr Gastroenterol Hepatol Nutr 2020; 23:558-566. [PMID: 33215027 PMCID: PMC7667226 DOI: 10.5223/pghn.2020.23.6.558] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 05/21/2020] [Accepted: 06/23/2020] [Indexed: 11/30/2022] Open
Abstract
PURPOSE Progressive familial intrahepatic cholestasis (PFIC) is a rare genetic autosomal recessive disease caused by mutations in ATP8B1, ABCB11 or ABCB4. Mutational analysis of these genes is a reliable approach to identify the disorder. METHODS We collected and analyzed relevant data related to clinical diagnosis, biological investigation, and molecular determination in nine children carrying these gene mutations, who were from unrelated families in South China. RESULTS Of the nine patients (five males, four females) with PFIC, one case of PFIC1, four cases of PFIC2, and four cases of PFIC3 were diagnosed. Except in patient no. 8, jaundice and severe pruritus were the major clinical signs in all forms. γ-glutamyl transpeptidase was low in patients with PFIC1/PFIC2, and remained mildly elevated in patients with PFIC3. We identified 15 different mutations, including nine novel mutations (p.R470HfsX8, p.Q794X and p.I1170T of ABCB11 gene mutations, p.G319R, p.A1047P, p.G1074R, p.T830NfsX11, p.A1047PfsX8 and p.N1048TfsX of ABCB4 gene mutations) and six known mutations (p.G446R and p.F529del of ATP8B1 gene mutations, p.A588V, p.G1004D and p.R1057X of ABCB11 gene mutations, p.P479L of ABCB4 gene mutations). The results showed that compared with other regions, these three types of PFIC genes had different mutational spectrum in China. CONCLUSION The study expands the genotypic spectrum of PFIC. We identified nine novel mutations of PFIC and our findings could help in the diagnosis and treatment of this disease.
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Affiliation(s)
- Wen Zhang
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou, China
| | - Ruizhu Lin
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou, China
| | - Zhikun Lu
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou, China
| | - Huiying Sheng
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou, China
| | - Yi Xu
- Department of Infectious Disease, Guangzhou Women and Children's Medical Center, Guangzhou, China
| | - Xiuzhen Li
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou, China
| | - Jing Cheng
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou, China
| | - Yanna Cai
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou, China
| | - Xiaojian Mao
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou, China
| | - Li Liu
- Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou, China
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Huynh MT, Nguyen TT, Grison S, Lascols O, Fernandez E, Barbu V. Clinical characteristics and genetic profiles of young and adult patients with cholestatic liver disease. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2020; 111:775-788. [PMID: 31538484 DOI: 10.17235/reed.2019.6168/2019] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND AND AIMS heterozygous ABCB4, ABCB11 and ATP8B1 sequence variants were previously reported to be associated with low phospholipid-associated cholelithiasis, intrahepatic cholestasis of pregnancy, benign recurrent intrahepatic cholestasis and biliary lithiasis. The present study aimed to identify the presence of sequence variations in genes responsible for Mendelian liver disorders in patients with cholestatic liver disease. METHODS targeted massive parallel sequencing of a panel of genes involved in bile acid homeostasis was performed in 105 young and adult patients with cholestatic liver disease in our laboratory for molecular diagnosis. The effects of novel variants were evaluated using bioinformatics prediction tools and the Protter and Phyre2 software programs were used to create 2D, 3D topology protein modeling. Genotype-phenotype correlation was established according to molecular analysis and clinical records. RESULTS twenty novel heterozygous ABCB4 sequence variations, one heterozygous ABCB4 large intragenic deletion and only one novel missense variant in ABCB11 and ATP8B1 were identified. Interestingly, heterozygous and homozygous SLC4A2 missense variants were detected in patients with low phospholipid-associated cholelithiasis. Two patients harbored heterozygous GPBAR1 variants. Common variants such as homozygous ABCB11 p.Val444Ala and heterozygous ABCG8 p.Asp19His were also identified in 12 cases. CONCLUSIONS forty-eight variants were identified in five genes including ABCB4, ABCB11, ATP8B1, SLC4A2 and GPBAR1, twenty-five of which were novel. This study expands the phenotypic and mutational spectrum in genes involved in bile acid homeostasis and highlights the genetic and phenotypic heterogeneity in patients with inherited liver disorders.
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Affiliation(s)
| | - Truong-Tam Nguyen
- Service de Médecine Interne, Université de Médecine Pham Ngoc Thach, Viet Nam
| | - Sophie Grison
- Hôpitaux universitaires Est Parisien, hôpital Sain, Laboratoire commun de Biologie et Génétique Moléculaires, France
| | - Olivier Lascols
- Hôpitaux universitaires Est Parisien, hôpital Sain, Laboratoire commun de Biologie et Génétique Moléculaires, France
| | - Eric Fernandez
- Hôpitaux universitaires Est Parisien, hôpital Sain, Laboratoire commun de Biologie et Génétique Moléculaires, France
| | - Véronique Barbu
- Genetics Service, Laboratoire commun de Biologie et Génétique Moléculaires, Hôpitaux universitaires Est Parisien, hôpi, France
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Disease Mutation Study Identifies Critical Residues for Phosphatidylserine Flippase ATP11A. BIOMED RESEARCH INTERNATIONAL 2020; 2020:7342817. [PMID: 32596364 PMCID: PMC7288202 DOI: 10.1155/2020/7342817] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Accepted: 04/21/2020] [Indexed: 11/17/2022]
Abstract
Phosphatidylserine flippase (P4-ATPase) transports PS from the outer to the inner leaflet of the lipid bilayer in the membrane to maintain PS asymmetry, which is important for biological activities of the cell. ATP11A is expressed in multiple tissues and plays a role in myotube formation. However, the detailed cellular function of ATP11A remains elusive. Mutation analysis revealed that I91, L308, and E897 residues in ATP8A2 are important for flippase activity. In order to investigate the roles of these corresponding amino acid residues in ATP11A protein, we assessed the expression and cellular localization of the respective ATP11A mutant proteins. ATP11A mainly localizes to the Golgi and plasma membrane when coexpressed with the β-subunit of the complex TMEM30A. Y300F mutation causes reduced ATP11A expression, and Y300F and D913K mutations affect correct localization of the Golgi and plasma membrane. In addition, Y300F and D913K mutations also affect PS flippase activity. Our data provides insight into important residues of ATP11A.
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Mitra S, Das A, Thapa B, Kumar Vasishta R. Phenotype-Genotype Correlation of North Indian Progressive Familial Intrahepatic Cholestasis type2 Children Shows p.Val444Ala and p.Asn591Ser Variants and Retained BSEP Expression. Fetal Pediatr Pathol 2020; 39:107-123. [PMID: 31335238 DOI: 10.1080/15513815.2019.1641860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Backgrounds and Aims: Progressive familial intrahepatic cholestasis type 2 (PFIC2) is caused by a defect or deficiency of bile salt export protein (BSEP) due to mutation in the ABCB11 gene. We intend to evaluate the phenotype-genotype correlation in 10 diagnosed cases of PFIC2 in a single tertiary care center in North India. Methods: The clinical, biochemical, histopathological, immunohistochemical, ultrastructural and genetic data of the 10 diagnosed cases of PFIC2 were recorded. Results: Icterus, pruritus and bleeding manifestations were the commonest clinical symptoms. Giant cell transformation was seen in 50% of the patients. Two predominant genetic variants were ABCB11 missense p.Val444Ala (c. 1331 T > C) and ABCB11 missense p.Asn591Ser (c. 1772 A > G) in their homozygous or compound heterozygous states and were associated with retained BSEP immunopositivity and reduced but retained BSEP immunopositivity respectively. Conclusion: Retention of BSEP is common in North Indian children of PFIC2 with no phenotype-genotype correlation.
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Affiliation(s)
| | - Ashim Das
- PGIMER, Histopathology, Chandigarh, India
| | - Baburam Thapa
- Post Graduate Institute of Medical Education and Research, Pediatric Gastroenterology, Nehru Hospital, Chandigarh, India
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Piazzolla M, Castellaneta N, Novelli A, Agolini E, Cocciadiferro D, Resta L, Duda L, Barone M, Ierardi E, Di Leo A. Nonsense variant of ATP8B1 gene in heterozygosis and benign recurrent intrahepatic cholestasis: A case report and review of literature. World J Hepatol 2020; 12:64-71. [PMID: 32184942 PMCID: PMC7061267 DOI: 10.4254/wjh.v12.i2.64] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 12/19/2019] [Accepted: 01/01/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Benign recurrent intrahepatic cholestasis is a genetic disorder with recurrent cholestatic jaundice due to ATP8B1 and ABCB11 gene mutations encoding for hepato-canalicular transporters. Herein, we firstly provide the evidence that a nonsense variant of ATP8B1 gene (c.1558A>T) in heterozygous form is involved in BRIC pathogenesis. CASE SUMMARY A 29-year-old male showed severe jaundice and laboratory tests consistent with intrahepatic cholestasis despite normal gamma-glutamyltranspeptidase. Acute and chronic liver diseases with viral, metabolic and autoimmune etiology were excluded. Normal intra/extra-hepatic bile ducts were demonstrated by magnetic resonance. Liver biopsy showed: Cholestasis in the centrilobular and intermediate zones with bile plugs and intra-hepatocyte pigment, Kupffer's cell activation/hyperplasia and preserved biliary ducts. Being satisfied benign recurrent intrahepatic cholestasis diagnostic criteria, ATP8B1 and ABCB11 gene analysis was performed. Surprisingly, we found a novel nonsense variant of ATP8B1 gene (c.1558A>T) in heterozygosis. The variant was confirmed by Sanger sequencing following a standard protocol and tested for familial segregation, showing a maternal inheritance. Immunohistochemistry confirmed a significant reduction of mutated gene related protein (familial intrahepatic cholestasis 1). The patient was treated with ursodeoxycholic acid 15 mg/kg per day and colestyramine 8 g daily with total bilirubin decrease and normalization at the 6th and 12th mo. CONCLUSION A genetic abnormality, different from those already known, could be involved in familial intrahepatic cholestatic disorders and/or pro-cholestatic genetic predisposition, thus encouraging further mutation detection in this field.
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Affiliation(s)
- Mariano Piazzolla
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, Bari 70124, Italy
| | - Nicola Castellaneta
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, Bari 70124, Italy
| | - Antonio Novelli
- Laboratory of Medical Genetics, Ospedale Pediatrico Bambino Gesù, Rome 00165, Italy
| | - Emanuele Agolini
- Laboratory of Medical Genetics, Ospedale Pediatrico Bambino Gesù, Rome 00165, Italy
| | - Dario Cocciadiferro
- Laboratory of Medical Genetics, Ospedale Pediatrico Bambino Gesù, Rome 00165, Italy
| | - Leonardo Resta
- Section of Pathology, Department of Emergency and Organ Transplantation, University of Bari, Bari 70124, Italy
| | - Loren Duda
- Section of Pathology, Department of Emergency and Organ Transplantation, University of Bari, Bari 70124, Italy
| | - Michele Barone
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, Bari 70124, Italy
| | - Enzo Ierardi
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, Bari 70124,
| | - Alfredo Di Leo
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, Bari 70124, Italy
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Ticho AL, Malhotra P, Dudeja PK, Gill RK, Alrefai WA. Intestinal Absorption of Bile Acids in Health and Disease. Compr Physiol 2019; 10:21-56. [PMID: 31853951 PMCID: PMC7171925 DOI: 10.1002/cphy.c190007] [Citation(s) in RCA: 139] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The intestinal reclamation of bile acids is crucial for the maintenance of their enterohepatic circulation. The majority of bile acids are actively absorbed via specific transport proteins that are highly expressed in the distal ileum. The uptake of bile acids by intestinal epithelial cells modulates the activation of cytosolic and membrane receptors such as the farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (GPBAR1), which has a profound effect on hepatic synthesis of bile acids as well as glucose and lipid metabolism. Extensive research has focused on delineating the processes of bile acid absorption and determining the contribution of dysregulated ileal signaling in the development of intestinal and hepatic disorders. For example, a decrease in the levels of the bile acid-induced ileal hormone FGF15/19 is implicated in bile acid-induced diarrhea (BAD). Conversely, the increase in bile acid absorption with subsequent overload of bile acids could be involved in the pathophysiology of liver and metabolic disorders such as fatty liver diseases and type 2 diabetes mellitus. This review article will attempt to provide a comprehensive overview of the mechanisms involved in the intestinal handling of bile acids, the pathological implications of disrupted intestinal bile acid homeostasis, and the potential therapeutic targets for the treatment of bile acid-related disorders. Published 2020. Compr Physiol 10:21-56, 2020.
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Affiliation(s)
- Alexander L. Ticho
- Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Pooja Malhotra
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Pradeep K. Dudeja
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
- jesse Brown VA Medical Center, Chicago, Illinois, USA
| | - Ravinder K. Gill
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Waddah A. Alrefai
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
- jesse Brown VA Medical Center, Chicago, Illinois, USA
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Deferm N, De Vocht T, Qi B, Van Brantegem P, Gijbels E, Vinken M, de Witte P, Bouillon T, Annaert P. Current insights in the complexities underlying drug-induced cholestasis. Crit Rev Toxicol 2019; 49:520-548. [PMID: 31589080 DOI: 10.1080/10408444.2019.1635081] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Drug-induced cholestasis (DIC) poses a major challenge to the pharmaceutical industry and regulatory agencies. It causes both drug attrition and post-approval withdrawal of drugs. DIC represents itself as an impaired secretion and flow of bile, leading to the pathological hepatic and/or systemic accumulation of bile acids (BAs) and their conjugate bile salts. Due to the high number of mechanisms underlying DIC, predicting a compound's cholestatic potential during early stages of drug development remains elusive. A profound understanding of the different molecular mechanisms of DIC is, therefore, of utmost importance. Although many knowledge gaps and caveats still exist, it is generally accepted that alterations of certain hepatobiliary membrane transporters and changes in hepatocellular morphology may cause DIC. Consequently, liver models, which represent most of these mechanisms, are valuable tools to predict human DIC. Some of these models, such as membrane-based in vitro models, are exceptionally well-suited to investigate specific mechanisms (i.e. transporter inhibition) of DIC, while others, such as liver slices, encompass all relevant biological processes and, therefore, offer a better representation of the in vivo situation. In the current review, we highlight the principal molecular mechanisms associated with DIC and offer an overview and critical appraisal of the different liver models that are currently being used to predict the cholestatic potential of drugs.
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Affiliation(s)
- Neel Deferm
- Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, KU Leuven, Leuven, Belgium
| | - Tom De Vocht
- Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, KU Leuven, Leuven, Belgium
| | - Bing Qi
- Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, KU Leuven, Leuven, Belgium
| | - Pieter Van Brantegem
- Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, KU Leuven, Leuven, Belgium
| | - Eva Gijbels
- Entity of In Vitro Toxicology and Dermato-Cosmetology, Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium
| | - Mathieu Vinken
- Entity of In Vitro Toxicology and Dermato-Cosmetology, Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium
| | - Peter de Witte
- Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
| | - Thomas Bouillon
- Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, KU Leuven, Leuven, Belgium
| | - Pieter Annaert
- Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, KU Leuven, Leuven, Belgium
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Rhee ES, Kim YB, Lee S, Oh SH, Lee BH, Kim KM, Yoo HW. Novel ATP8B1 Gene Mutations in a Child with Progressive Familial Intrahepatic Cholestasis Type 1. Pediatr Gastroenterol Hepatol Nutr 2019; 22:479-486. [PMID: 31555573 PMCID: PMC6751104 DOI: 10.5223/pghn.2019.22.5.479] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 08/31/2018] [Indexed: 01/26/2023] Open
Abstract
Progressive familial intrahepatic cholestasis (PFIC) is a group of severe genetic disorders, inherited in an autosomal recessive manner, causing cholestasis of hepatocellular origin, later progressing to biliary cirrhosis and liver failure. This is the first report of PFIC type 1 with novel compound heterozygous mutations in Korea. The patient was presented with intrahepatic cholestasis, a normal level of serum γ-glutamyl transferase, steatorrhea, and growth failure. Genetic testing of this patient revealed novel compound heterozygous mutations (p.Glu585Ter and p.Leu749Pro) in the ATP8B1 gene. After a liver transplantation at age 19 months, the patient developed severe post-transplant steatohepatitis.
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Affiliation(s)
- Eun Sang Rhee
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Yu Bin Kim
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Sunghee Lee
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Seak Hee Oh
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Beom Hee Lee
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyung Mo Kim
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Han-Wook Yoo
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
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Kang HJ, Hong SA, Oh SH, Kim KM, Yoo HW, Kim GH, Yu E. Progressive Familial Intrahepatic Cholestasis in Korea: A Clinicopathological Study of Five Patients. J Pathol Transl Med 2019; 53:253-260. [PMID: 31091858 PMCID: PMC6639708 DOI: 10.4132/jptm.2019.05.03] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 04/24/2019] [Accepted: 05/03/2019] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal recessive liver diseases that present as neonatal cholestasis. Little is known of this disease in Korea. METHODS The records of five patients histologically diagnosed with PFIC, one with PFIC1 and four with PFIC2, by liver biopsy or transplant were reviewed, and ATP8B1 and ABCB11 mutation status was analyzed by direct DNA sequencing. Clinicopathological characteristics were correlated with genetic mutations. RESULTS The first symptom in all patients was jaundice. Histologically, lobular cholestasis with bile plugs was the main finding in all patients, whereas diffuse or periportal cholestasis was identified only in patients with PFIC2. Giant cells and ballooning of hepatocytes were observed in three and three patients with PFIC2, respectively, but not in the patient with PFIC1. Immunostaining showed total loss of bile salt export pump in two patients with PFIC2 and focal loss in two. Lobular and portal based fibrosis were more advanced in PFIC2 than in PFIC1. ATP8B1 and ABCB11 mutations were identified in one PFIC1 and two PFIC2 patients, respectively. One PFIC1 and three PFIC2 patients underwent liver transplantation (LT). At age 7 months, one PFIC2 patient was diagnosed with concurrent hepatocellular carcinoma and infantile hemangioma in an explanted liver. The patient with PFIC1 developed steatohepatitis after LT. One patient showed recurrence of PFIC2 after 10 years and underwent LT. CONCLUSIONS PFIC is not rare in patients with neonatal cholestasis of unknown origin. Proper clinicopathologic correlation and genetic testing can enable early detection and management.
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Affiliation(s)
- Hyo Jeong Kang
- 1Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Soon Auck Hong
- 2Department of Pathology, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Seak Hee Oh
- Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyung Mo Kim
- Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Han-Wook Yoo
- Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Gu-Hwan Kim
- Medical Genetics Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Eunsil Yu
- 1Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
- Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Henkel SAF, Squires JH, Ayers M, Ganoza A, Mckiernan P, Squires JE. Expanding etiology of progressive familial intrahepatic cholestasis. World J Hepatol 2019; 11:450-463. [PMID: 31183005 PMCID: PMC6547292 DOI: 10.4254/wjh.v11.i5.450] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 04/19/2019] [Accepted: 04/27/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Progressive familial intrahepatic cholestasis (PFIC) refers to a disparate group of autosomal recessive disorders that are linked by the inability to appropriately form and excrete bile from hepatocytes, resulting in a hepatocellular form of cholestasis. While the diagnosis of such disorders had historically been based on pattern recognition of unremitting cholestasis without other identified molecular or anatomic cause, recent scientific advancements have uncovered multiple specific responsible proteins. The variety of identified defects has resulted in an ever-broadening phenotypic spectrum, ranging from traditional benign recurrent jaundice to progressive cholestasis and end-stage liver disease.
AIM To review current data on defects in bile acid homeostasis, explore the expanding knowledge base of genetic based diseases in this field, and report disease characteristics and management.
METHODS We conducted a systemic review according to PRISMA guidelines. We performed a Medline/PubMed search in February-March 2019 for relevant articles relating to the understanding, diagnosis, and management of bile acid homeostasis with a focus on the family of diseases collectively known as PFIC. English only articles were accessed in full. The manual search included references of retrieved articles. We extracted data on disease characteristics, associations with other diseases, and treatment. Data was summarized and presented in text, figure, and table format.
RESULTS Genetic-based liver disease resulting in the inability to properly form and secrete bile constitute an important cause of morbidity and mortality in children and increasingly in adults. A growing number of PFIC have been described based on an expanded understanding of biliary transport mechanism defects and the development of a common phenotype.
CONCLUSION We present a summary of current advances made in a number of areas relevant to both the classically described FIC1 (ATP8B1), BSEP (ABCB11), and MDR3 (ABCB4) transporter deficiencies, as well as more recently described gene mutations -- TJP2 (TJP2), FXR (NR1H4), MYO5B (MYO5B), and others which expand the etiology and understanding of PFIC-related cholestatic diseases and bile transport.
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Affiliation(s)
- Sarah AF Henkel
- Division of Gastroenterology, Hepatology, and Nutrition, Emory School of Medicine, Atlanta, GA 30322, United States
| | - Judy H Squires
- Department of Radiology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
| | - Mary Ayers
- Division of Gastroenterology, Hepatology, and Nutrition, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
| | - Armando Ganoza
- Division of Pediatric Transplantation, Department of Surgery, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
| | - Patrick Mckiernan
- Division of Gastroenterology, Hepatology, and Nutrition, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
| | - James E Squires
- Division of Gastroenterology, Hepatology, and Nutrition, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
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Takar M, Huang Y, Graham TR. The PQ-loop protein Any1 segregates Drs2 and Neo1 functions required for viability and plasma membrane phospholipid asymmetry. J Lipid Res 2019; 60:1032-1042. [PMID: 30824614 PMCID: PMC6495175 DOI: 10.1194/jlr.m093526] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Indexed: 02/06/2023] Open
Abstract
Membrane asymmetry is a key organizational feature of the plasma membrane. Type IV P-type ATPases (P4-ATPases) are phospholipid flippases that establish membrane asymmetry by translocating phospholipids, such as phosphatidylserine (PS) and phospatidylethanolamine, from the exofacial leaflet to the cytosolic leaflet. Saccharomyces cerevisiae expresses five P4-ATPases: Drs2, Neo1, Dnf1, Dnf2, and Dnf3. The inactivation of Neo1 is lethal, suggesting Neo1 mediates an essential function not exerted by the other P4-ATPases. However, the disruption of ANY1, which encodes a PQ-loop membrane protein, allows the growth of neo1Δ and reveals functional redundancy between Golgi-localized Neo1 and Drs2. Here we show Drs2 PS flippase activity is required to support neo1Δ any1Δ viability. Additionally, a Dnf1 variant with enhanced PS flipping ability can replace Drs2 and Neo1 function in any1Δ cells. any1Δ also suppresses drs2Δ growth defects but not the loss of membrane asymmetry. Any1 overexpression perturbs the growth of cells but does not disrupt membrane asymmetry. Any1 coimmunoprecipitates with Neo1, an association prevented by the Any1-inactivating mutation D84G. These results indicate a critical role for PS flippase activity in Golgi membranes to sustain viability and suggests Any1 regulates Golgi membrane remodeling through protein-protein interactions rather than a previously proposed scramblase activity.
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Affiliation(s)
- Mehmet Takar
- Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235
| | - Yannan Huang
- Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235
| | - Todd R Graham
- Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235.
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Yeap SP, Harley H, Thompson R, Williamson KD, Bate J, Sethna F, Farrell G, Hague WB. Biliary transporter gene mutations in severe intrahepatic cholestasis of pregnancy: Diagnostic and management implications. J Gastroenterol Hepatol 2019; 34:425-435. [PMID: 29992621 DOI: 10.1111/jgh.14376] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 06/19/2018] [Accepted: 06/20/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Clinical syndromes associated with biallelic mutations of bile acid (BA) transporters usually present in childhood. Subtle mutations may underlie intrahepatic cholestasis of pregnancy (ICP) and oral contraceptive steroid (OCS) induced cholestasis. In five women with identified genetic mutations of such transporters, with eight observed pregnancies complicated by ICP, we examined relationships between transporter mutations, clinical phenotypes, and treatment outcomes. METHODS Gene mutation analysis for BA transporter deficiencies was performed using Next Generation/Sanger sequencing, with analysis for gene deletions/duplications. RESULTS Intrahepatic cholestasis of pregnancy was early-onset (9-32 weeks gestation) and severe (peak BA 74-370 μmol/L), with premature delivery (28+1 -370 weeks gestation) in 7/8 pregnancies, in utero passage of meconium in 4/8, but overall good perinatal outcomes, with no stillbirths. There was generally no response to ursodeoxycholic acid and variable responses to rifampicin and chelation therapies; naso-biliary drainage appeared effective in 2/2 episodes persisting post-partum in each of the two sisters. Episodic jaundice occurring spontaneously or provoked by non-specific infections, and OCS-induced cholestasis, had previously occurred in 3/5 women. Two cases showed biallelic heterozygosity for several ABCB11 mutations, one was homozygous for an ABCB4 mutation and a fourth case was heterozygous for another ABCB4 mutation. CONCLUSIONS Early-onset or recurrent ICP, especially with previous spontaneous or OCS-induced episodes of cholestasis and/or familial cholestasis, may be attributable to transporter mutations, including biallelic mutations of one or more transporters. Response to standard therapies for ICP is often incomplete; BA sequestering therapy or naso-biliary drainage may be effective. Optimized management can produce good outcomes despite premature birth and evidence of fetal compromise.
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Affiliation(s)
- Sze Pheh Yeap
- Liver Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Hugh Harley
- Liver Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia.,Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia
| | | | | | - John Bate
- Liver Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Farah Sethna
- Department of Obstetrics and Gynaecology, Canberra Hospital, Canberra, Australian Capital Territory, Australia
| | - Geoffrey Farrell
- Liver Research Unit, Canberra Hospital, Canberra, Australian Capital Territory, Australia.,The Australian National University Medical School, Canberra, Australian Capital Territory, Australia
| | - William Bill Hague
- Obstetric Medicine, Women's and Children's Hospital, North Adelaide, South Australia, Australia.,Robinson Research Institute, University of Adelaide, North Adelaide, South Australia, Australia
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Shin HW, Takatsu H. Substrates of P4‐ATPases: beyond aminophospholipids (phosphatidylserine and phosphatidylethanolamine). FASEB J 2018; 33:3087-3096. [DOI: 10.1096/fj.201801873r] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Hye-Won Shin
- Graduate School of Pharmaceutical SciencesKyoto University Kyoto Japan
| | - Hiroyuki Takatsu
- Graduate School of Pharmaceutical SciencesKyoto University Kyoto Japan
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Junge N, Dingemann J, Petersen C, Manns MP, Richter N, Klempnauer J, Baumann U, Schneider A. [Biliary atresia and congenital cholestatic syndromes : Characteristics before, after and during transition]. Internist (Berl) 2018; 59:1146-1156. [PMID: 30264190 DOI: 10.1007/s00108-018-0506-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
BACKGROUND A growing number of patients with biliary atresia and congenital cholestatic syndromes are reaching adulthood. These patients often have a number of typical medical features, including specific characteristics of liver transplantation medicine. OBJECTIVE What are the special features in the care of adults suffering from liver diseases with manifestation in childhood and adolescence, both before and after liver transplantation (LTX). How does the progression of individual diseases differ depending on age at manifestation? What are specific aspects following pediatric LTX? PATIENTS AND METHODS Evaluation and discussion of existing guidelines and recommendations of the individual disciplines and professional societies as well as the current literature. Joint discussion of the recommendations between disciplines (gastroenterology, pediatric gastroenterology, surgery). Inclusion of center-specific experiences with transition from existing transition outpatient departments and training. RESULTS The recommendations are presented specifically for each disease. Special features in individual diseases after LTX are also discussed. Diagnosis-independent general treatment concepts for cholestasis and chronic liver disease are presented. CONCLUSION Patients with biliary atresia and congenital cholestatic syndromes have a life-long chronic liver disease with and without LTX and require specific medical care. The patients benefit from the pooling of expertise in the individual disciplines.
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Affiliation(s)
- N Junge
- Klinik für Pädiatrische Nieren‑, Leber- und Stoffwechselerkrankungen, Schwerpunkt Pädiatrische Gastroenterologie und Hepatologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Deutschland.
| | - J Dingemann
- Klinik für Kinderchirurgie, Medizinische Hochschule Hannover, Hannover, Deutschland
| | - C Petersen
- Klinik für Kinderchirurgie, Medizinische Hochschule Hannover, Hannover, Deutschland
| | - M P Manns
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Deutschland
| | - N Richter
- Klinik für Allgemein‑, Viszeral- und Transplantationschirurgie, Medizinische Hochschule Hannover, Hannover, Deutschland
| | - J Klempnauer
- Klinik für Allgemein‑, Viszeral- und Transplantationschirurgie, Medizinische Hochschule Hannover, Hannover, Deutschland
| | - U Baumann
- Klinik für Pädiatrische Nieren‑, Leber- und Stoffwechselerkrankungen, Schwerpunkt Pädiatrische Gastroenterologie und Hepatologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Deutschland
| | - A Schneider
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Deutschland
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New Insights in Genetic Cholestasis: From Molecular Mechanisms to Clinical Implications. Can J Gastroenterol Hepatol 2018; 2018:2313675. [PMID: 30148122 PMCID: PMC6083523 DOI: 10.1155/2018/2313675] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 07/10/2018] [Accepted: 07/17/2018] [Indexed: 02/06/2023] Open
Abstract
Cholestasis is characterised by impaired bile secretion and accumulation of bile salts in the organism. Hereditary cholestasis is a heterogeneous group of rare autosomal recessive liver disorders, which are characterised by intrahepatic cholestasis, pruritus, and jaundice and caused by defects in genes related to the secretion and transport of bile salts and lipids. Phenotypic manifestation is highly variable, ranging from progressive familial intrahepatic cholestasis (PFIC)-with onset in early infancy and progression to end-stage liver disease-to a milder intermittent mostly nonprogressive form known as benign recurrent intrahepatic cholestasis (BRIC). Cases have been reported of initially benign episodic cholestasis that subsequently transitions to a persistent progressive form of the disease. Therefore, BRIC and PFIC seem to represent two extremes of a continuous spectrum of phenotypes that comprise one disease. Thus far, five representatives of PFIC (named PFIC1-5) caused by pathogenic mutations present in both alleles of ATP8B1, ABCB11, ABCB4, TJP2, and NR1H4 have been described. In addition to familial intrahepatic cholestasis, partial defects in ATP8B1, ABCB11, and ABCB4 predispose patients to drug-induced cholestasis and intrahepatic cholestasis in pregnancy. This review summarises the current knowledge of the clinical manifestations, genetics, and molecular mechanisms of these diseases and briefly outlines the therapeutic options, both conservative and invasive, with an outlook for future personalised therapeutic strategies.
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Sharma A, Poddar U, Agnihotry S, Phadke SR, Yachha SK, Aggarwal R. Spectrum of genomic variations in Indian patients with progressive familial intrahepatic cholestasis. BMC Gastroenterol 2018; 18:107. [PMID: 29973134 PMCID: PMC6032793 DOI: 10.1186/s12876-018-0835-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 06/26/2018] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Progressive familial intrahepatic cholestasis (PFIC) is caused by variations in ATP8B1, ABCB11 or ABCB4 genes. Data on genetic variations in Indian patients with PFIC are lacking. METHODS Coding and splice regions of the three genes were sequenced in unrelated Indian children with PFIC phenotype. The variations identified were looked for in parents, 30 healthy persons and several variation databases, and their effect was assessed in-silico. RESULTS Among 25 children (aged 1-144 months), nine (36%) had unique major genomic variations (ATP8B1: 4, ABCB11: 3 and ABCB4: 2). Seven had homozygous variations, which were assessed as 'pathogenic' or 'likely pathogenic'. These included: (i) four amino acid substitutions (ATP8B1: c.1660G > A/p.Asp554Asn and c.2941G > A/p.Glu981Lys; ABCB11: c.548 T > C/p.Met183Thr; ABCB4: c.431G > A/p.Arg144Gln); (ii) one 3-nucleotide deletion causing an amino acid deletion (ATP8B1: c.1587_1589delCTT/p.Phe529del); (iii) one single-nucleotide deletion leading to frame-shift and premature termination (ABCB11: c.1360delG/p.Val454Ter); and (iv) a complex inversion of 4 nucleotides with a single-nucleotide insertion leading to frame-shift and premature termination (ATP8B1: c.[589_592inv;592_593insA]/p.Gly197LeufsTer10). Two variations were found in heterozygous form: (i) a splice-site variation likely to cause abnormal splicing (ABCB11: c.784 + 1G > C), and (ii) a nucleotide substitution that created a premature stop codon (ABCB4: c.475C > T/p.Arg159Ter); these were considered as variations of uncertain significance. Three of the nine variations were novel. CONCLUSIONS Nine major genomic variations, including three novel ones, were identified in nearly one-third of Indian children with PFIC. No variation was identified in nearly two-thirds of patients, who may have been related to variations in promoter or intronic regions of the three PFIC genes, or in other bile-salt transport genes.
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Affiliation(s)
- Anjali Sharma
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014 India
| | - Ujjal Poddar
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014 India
| | - Shikha Agnihotry
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014 India
| | - Shubha R. Phadke
- Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014 India
| | - Surender K. Yachha
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014 India
| | - Rakesh Aggarwal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014 India
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