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Wendrich K, Gallant K, Recknagel S, Petroulia S, Kazi NH, Hane JA, Führer S, Bezstarosti K, O'Dea R, Demmers J, Gersch M. Discovery and mechanism of K63-linkage-directed deubiquitinase activity in USP53. Nat Chem Biol 2025; 21:746-757. [PMID: 39587316 PMCID: PMC12037411 DOI: 10.1038/s41589-024-01777-0] [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: 05/22/2024] [Accepted: 10/23/2024] [Indexed: 11/27/2024]
Abstract
Ubiquitin-specific proteases (USPs) represent the largest class of human deubiquitinases (DUBs) and comprise its phylogenetically most distant members USP53 and USP54, which are annotated as catalytically inactive pseudoenzymes. Conspicuously, mutations within the USP domain of USP53 cause progressive familial intrahepatic cholestasis. Here, we report the discovery that USP53 and USP54 are active DUBs with high specificity for K63-linked polyubiquitin. We demonstrate how USP53 mutations abrogate catalytic activity, implicating loss of DUB activity in USP53-mediated pathology. Depletion of USP53 increases K63-linked ubiquitination of tricellular junction components. Assays with substrate-bound polyubiquitin reveal that USP54 cleaves within K63-linked chains, whereas USP53 can en bloc deubiquitinate substrate proteins in a K63-linkage-dependent manner. Biochemical and structural analyses uncover underlying K63-specific S2 ubiquitin-binding sites within their catalytic domains. Collectively, our work revises the annotation of USP53 and USP54, provides reagents and a mechanistic framework to investigate K63-linked polyubiquitin decoding and establishes K63-linkage-directed deubiquitination as a new DUB activity.
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Affiliation(s)
- Kim Wendrich
- Chemical Genomics Centre, Max Planck Institute of Molecular Physiology, Dortmund, Germany
- Department of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany
| | - Kai Gallant
- Chemical Genomics Centre, Max Planck Institute of Molecular Physiology, Dortmund, Germany
- Department of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany
| | - Sarah Recknagel
- Chemical Genomics Centre, Max Planck Institute of Molecular Physiology, Dortmund, Germany
- Department of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany
| | - Stavroula Petroulia
- Chemical Genomics Centre, Max Planck Institute of Molecular Physiology, Dortmund, Germany
- Department of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany
| | - Nafizul Haque Kazi
- Chemical Genomics Centre, Max Planck Institute of Molecular Physiology, Dortmund, Germany
- Department of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany
| | - Jan André Hane
- Chemical Genomics Centre, Max Planck Institute of Molecular Physiology, Dortmund, Germany
- Department of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany
| | - Siska Führer
- Chemical Genomics Centre, Max Planck Institute of Molecular Physiology, Dortmund, Germany
- Department of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany
| | - Karel Bezstarosti
- Proteomics Center, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Rachel O'Dea
- Chemical Genomics Centre, Max Planck Institute of Molecular Physiology, Dortmund, Germany
- Department of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany
- Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK
| | - Jeroen Demmers
- Proteomics Center, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Malte Gersch
- Chemical Genomics Centre, Max Planck Institute of Molecular Physiology, Dortmund, Germany.
- Department of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany.
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Gürcan Kaya N, Öztürk H, Sarı S, Eğritaş Gürkan Ö, Dalgıç B. Neonatal Cholestasis: Exploring Genetic Causes and Clinical Outcomes. J Paediatr Child Health 2025. [PMID: 40302296 DOI: 10.1111/jpc.70072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 03/30/2025] [Accepted: 04/22/2025] [Indexed: 05/02/2025]
Abstract
INTRODUCTION Neonatal cholestasis is a group of disorders characterised by conjugated hyperbilirubinemia in the newborns and young infants. Advances in genetic testing have facilitated the identification of specific aetiology. This study examines the genetic and clinical profiles of neonates with cholestasis, focusing on genotype-phenotype correlations and diagnostic outcomes. METHODS A retrospective review of children with neonatal cholestasis treated between 1997 and 2024 was conducted. Extrahepatic causes were excluded, and genetic testing, including a targeted cholestasis panel and whole exome sequencing (WES), was employed. Clinical and biochemical data, including gamma-glutamyl transferase (GGT) levels, were collected. RESULTS Genetic disorders were identified in 28.0% of 378 cases, including mutations in ATP8B1, ABCB11, ABCB4, DCDC2, DGUOK, KIF12, USP53, and genes related to bile acid synthesis (HSD3B7, PEX1). GGT levels played a significant role in diagnosis: patients with low or normal GGT were frequently diagnosed with progressive familial intrahepatic cholestasis (PFIC)1 and 2, or bile acid synthesis defects, while high GGT levels were associated with PFIC3, alpha-1 antitrypsin deficiency, and cystic fibrosis. Consanguinity was noted in 56.0% of genetically diagnosed cases. After 2010, 35.5% of patients received a genetic diagnosis, compared to 18.2% before 2010. CONCLUSION Genetic diseases are a major cause of neonatal cholestasis, and GGT levels serve as a useful diagnostic tool in differentiating subtypes. The increasing availability of genetic testing has improved early diagnosis and personalised management. Expanded genetic testing in clinical practice is critical for timely and accurate diagnosis of these rare disorders.
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Affiliation(s)
- Neslihan Gürcan Kaya
- Department of Pediatric Gastroenterology, Ankara Training and Research Hospital, Ankara, Turkey
| | - Hakan Öztürk
- Department of Pediatric Gastroenterology, Gazi University Faculty of Medicine, Ankara, Turkey
| | - Sinan Sarı
- Department of Pediatric Gastroenterology, Gazi University Faculty of Medicine, Ankara, Turkey
| | - Ödül Eğritaş Gürkan
- Department of Pediatric Gastroenterology, Gazi University Faculty of Medicine, Ankara, Turkey
| | - Buket Dalgıç
- Department of Pediatric Gastroenterology, Gazi University Faculty of Medicine, Ankara, Turkey
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Ding J, Chi H, Qiu YL, Wang RX, Yang J, She HY, Zhang J, Ling V, Xing QH, Wang JS. Loss of hepatocyte Usp53 protects mice from a form of xenobiotic-induced liver injury. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167624. [PMID: 39705897 DOI: 10.1016/j.bbadis.2024.167624] [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: 08/14/2024] [Revised: 12/03/2024] [Accepted: 12/09/2024] [Indexed: 12/23/2024]
Abstract
BACKGROUND Ubiquitin-specific protease 53 (USP53) deficiency is associated with familial intrahepatic cholestasis in which serum gamma-glutamyl transferase (GGT) activity is relatively low. However, how USP53 deficiency contributes to cholestasis is obscure. No animal model has been reported. METHODS Usp53 liver-specific knockout (Usp53 cKO) mice generated by crossing Usp53fl/fl mice with albumin-cre (Alb-cre) recombinase transgenic mice were challenged with dietary cholic acid (CA) or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). General well-being, hepatobiliary-injury biomarker values, histopathologic and ultrastructural appearances, and expression of key genes were compared with those in wild-type (WT) littermates. Interactions of USP53 and TJP2 were investigated by immunofluorescence and co-immunoprecipitation. RESULTS Usp53 cKO mice exhibited no obvious differences from WT mice when fed with either normal-chow or CA-added diet. However, after 4 weeks of DDC feeding, Usp53 cKO mice lost less weight, were less icteric, had more nearly normal biomarker values, and accumulated less intrahepatic pigment than WT mice. On normal chow, mRNA expression of critical hepatic transporters Abcb11, Ntcp, and Abcc2 was lower in Usp53 cKO liver than in WT liver; after DDC feeding, mRNA expression of Tjp2 was higher, while detoxification enzymes Cyp3a11, Cyp2b10, and Sult2a1 was lower in Usp53 cKO liver than in WT liver, and hepatocellular tight junctions were significantly longer. USP53 interacts with TJP2. CONCLUSIONS Usp53 deficiency can protect mice from DDC-induced liver injury. Liver Usp53 cKO causes upregulation of hepatobiliary Tjp2, with biochemical and histologic features that largely mimic those of liver Tjp2 cKO, implying that USP53 deficiency may share similar mechanism to TJP2 deficiency.
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Affiliation(s)
- Jian Ding
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai 201102, China; Institutes of Biomedical Sciences of Fudan University and Children's Hospital of Fudan University, Shanghai 201102, China.
| | - Hao Chi
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai 201102, China
| | - Yi-Ling Qiu
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai 201102, China
| | - Ren-Xue Wang
- BC Cancer Research Centre, Vancouver, British Columbia, Canada.
| | - Jing Yang
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai 201102, China
| | - Hui-Yu She
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai 201102, China
| | - Jing Zhang
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai 201102, China
| | - Victor Ling
- BC Cancer Research Centre, Vancouver, British Columbia, Canada.
| | - Qing-He Xing
- Institutes of Biomedical Sciences of Fudan University and Children's Hospital of Fudan University, Shanghai 201102, China.
| | - Jian-She Wang
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai 201102, China; Shanghai Key Laboratory of Birth Defect, Shanghai 201102, China.
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Ferino L, Naumann M. Dysregulation of deubiquitinylases: a linchpin of gastrointestinal diseases. Trends Mol Med 2025:S1471-4914(25)00001-2. [PMID: 39875297 DOI: 10.1016/j.molmed.2025.01.001] [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: 11/19/2024] [Revised: 12/21/2024] [Accepted: 01/06/2025] [Indexed: 01/30/2025]
Abstract
Ubiquitinylation of proteins regulates manifold processes and is reversed by deubiquitinylating enzymes (DUBs), which are therefore implicated in a plethora of cellular processes. DUBs are frequently upregulated in many diseases, while in a few cases downregulation of DUBs is associated with disease progression. This review focuses on the involvement of DUBs in the development and progression of gastrointestinal diseases with a particular emphasis on hepatic steatosis and hepatocellular, cholangio-, esophageal, gastric, colorectal, and pancreatic ductal carcinomas. In addition, pathogens that trigger the activity of several DUBs and thus suppress the immune response and cell survival are discussed. Finally, we highlight recent approaches made towards the therapeutic treatment of gastrointestinal diseases using DUB inhibitors.
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Affiliation(s)
- Lorena Ferino
- Institute of Experimental Internal Medicine, Otto von Guericke University Magdeburg, 39120 Magdeburg, Germany
| | - Michael Naumann
- Institute of Experimental Internal Medicine, Otto von Guericke University Magdeburg, 39120 Magdeburg, Germany.
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Alam S, Lal BB, Ravindranath A, Bavdekar A, Dheivamani N, Snehavardhan P, Shah A, Tripathi PR, Nagral A, Srikanth KP, Shah I, Ramakrishna SH, Suchismita A, Waikar Y, Shah V, Nalwalla Z, Kumar K, Maria A, Sibal A, Sivaramakrishnan VM, Wadhwa N, Ashritha A, Sood V, Khanna R. Natural course and outcomes of children with ubiquitin-specific protease 53 (USP53)-related genetic chronic cholestasis. J Pediatr Gastroenterol Nutr 2024. [PMID: 39440620 DOI: 10.1002/jpn3.12392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 07/05/2024] [Accepted: 09/10/2024] [Indexed: 10/25/2024]
Abstract
Ubiquitin-specific protease 53 (USP53) is essential for formation of cellular tight junctions and variations in this gene disrupt the tight junctions, resulting in cholestasis. We describe the clinical manifestations and outcomes of patients with USP53 mutations from the Indian progressive familial intrahepatic cholestasis registry. All 29 patients who harbored mutations in the USP53 gene either in the homozygous, compound heterozygous, or heterozygous state and presented with cholestasis were included. USP53 variants related to cholestasis had good outcomes, with native liver survival in 82.7%, whereas 17.3% required liver transplantation. Jaundice developed in 93% and within 3 months of age in 48.8%. Jaundice resolved in 21 (72.4%). Pruritus 76% at a median age of 7 months (severe in 10/22, 45% and refractory to medical therapy in 4, 18.1%). Majority of them (82.7%) had biallelic mutations. Protein-truncating mutations were present in 20 (69%) and missense mutations in 9 (31%). No correlation was found between the genotype and the outcome.
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Affiliation(s)
- Seema Alam
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Bikrant Bihari Lal
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Aathira Ravindranath
- Department of Pediatric Gastroenterology, Apollo BGS Hospital, Mysuru, Karnataka, India
| | - Ashish Bavdekar
- Department of Pediatrics, KEM Hospital and Research Centre, Pune, India
| | - Nirmala Dheivamani
- Department of Pediatric Gastroenterology, Institute of Child Health and Hospital for Children, Chennai, India
| | | | | | - Parijat Ram Tripathi
- Department of Pediatric Gastroenterology, Ankura Hospital for Women and Children, Hyderabad, India
| | - Aabha Nagral
- Jaslok Hospital and Research Center, Mumbai, India
- Apollo Hospital, Navi Mumbai, India
| | | | - Ira Shah
- Pediatric Infectious Diseases and Pediatric Gastroenterology, Hepatology B.J. Wadia Hospital for Children, Mumbai, India
| | | | - Arya Suchismita
- Department of Gastroenterology, Indira Gandhi Institute of Medical Sciences, Patna, India
| | | | - Vaibhav Shah
- Gujarat Superspeciality Clinic, Ahmedabad, India
| | - Zahabiya Nalwalla
- Department of Pediatrics, B.J. Wadia Hospital for Children, Mumbai, India
| | - Karunesh Kumar
- Department of Pediatric Gastroenterology & Liver Transplantation, Indraprastha Apollo Hospitals, New Delhi, India
| | - Arjun Maria
- Department of Pediatrics, Sir Gangaram Hospital, New Delhi, India
| | - Anupam Sibal
- Department of Pediatric Gastroenterology & Liver Transplantation, Indraprastha Apollo Hospitals, New Delhi, India
| | | | - Nishant Wadhwa
- Department of Pediatrics, Sir Gangaram Hospital, New Delhi, India
| | - A Ashritha
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Vikrant Sood
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Rajeev Khanna
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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Teker Düztaş D, Öztürk H, Kayhan G, Sarı S, Eğritaş Gürkan Ö, Sözen H, Dalgıç B, Dalgıç A. Progressive Familial Intrahepatic Cholestasis Associated With Ubiquitin-Specific Peptidase 53 Gene Variant Presented with Acute-on-Chronic Liver Failure in Turkish Siblings. EXP CLIN TRANSPLANT 2024; 22:149-153. [PMID: 39498937 DOI: 10.6002/ect.pedsymp2024.o25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2024]
Abstract
Progressive familial intrahepatic cholestasis represents a group of disorders characterized by defective bile excretion, which causes a multitude of clinical symptoms of variable severity and usually begins in childhood. During the past few decades, a number of gene sequence variants have been shown to be associated with progressive familial intrahepatic cholestasis, and new subtypes continue to be discovered. Sequence variants of the ubiquitinspecific peptidase 53 gene have previously been associated with a novel autosomal recessive form of cholestasis with coincident normal or low γ-glutamyl transferase, with mild phenotypes. Here, we present 2 siblings with novel homozygous sequence variants in the ubiquitin-specific peptidase 53 gene with acute-on-chronic liver failure who underwent liver transplant.
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Affiliation(s)
- Demet Teker Düztaş
- From the Department of Pediatric Gastroenterology, Gazi University Faculty of Medicine, Ankara, Turkey
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Hahn JW, Lee H, Shin M, Seong MW, Moon JS, Ko JS. Diagnostic algorithm for neonatal intrahepatic cholestasis integrating single-gene testing and next-generation sequencing in East Asia. J Gastroenterol Hepatol 2024; 39:964-974. [PMID: 38323732 DOI: 10.1111/jgh.16505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 01/04/2024] [Accepted: 01/17/2024] [Indexed: 02/08/2024]
Abstract
BACKGROUND AND AIM Advances in molecular genetics have uncovered causative genes responsible for neonatal cholestasis. Panel-based next-generation sequencing has been used clinically in infants with neonatal cholestasis. We aimed to evaluate the clinical application of single-gene testing and next-generation sequencing and to develop a diagnostic algorithm for neonatal intrahepatic cholestasis. METHODS From January 2010 to July 2021, patients suspected of having neonatal intrahepatic cholestasis were tested at the Seoul National University Hospital. If there was a clinically suspected disease, single-gene testing was performed. Alternatively, if it was clinically difficult to differentiate, a neonatal cholestasis gene panel test containing 34 genes was performed. RESULTS Of the total 148 patients examined, 49 (33.1%) were received a confirmed genetic diagnosis, including 14 with Alagille syndrome, 14 with neonatal intrahepatic cholestasis caused by citrin deficiency, 7 with Dubin-Johnson syndrome, 5 with arthrogryposis-renal dysfunction-cholestasis syndrome, 5 with progressive familial intrahepatic cholestasis type II, 1 with Rotor syndrome, 1 with Niemann-Pick disease type C, 1 with Kabuki syndrome, and 1 with Phenylalanyl-tRNA synthetase subunit alpha mutation. Sixteen novel pathogenic or likely pathogenic variants of neonatal cholestasis were observed in this study. Based on the clinical characteristics and laboratory findings, we developed a diagnostic algorithm for neonatal intrahepatic cholestasis by integrating single-gene testing and next-generation sequencing. CONCLUSIONS Alagille syndrome and neonatal intrahepatic cholestasis caused by citrin deficiency were the most common diseases associated with genetic neonatal cholestasis. Single-gene testing and next-generation sequencing are important and complementary tools for the diagnosis of genetic neonatal cholestasis.
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Affiliation(s)
- Jong Woo Hahn
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
- Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Heerah Lee
- Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - MinSoo Shin
- Department of Pediatrics, Korea University College of Medicine, Seoul, Korea
| | - Moon Woo Seong
- Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Jin Soo Moon
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Jae Sung Ko
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
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Zheng Y, Guo H, Chen L, Cheng W, Yan K, Zhang Z, Li M, Jin Y, Hu G, Wang C, Zhou C, Zhou W, Jia Z, Zheng B, Liu Z. Diagnostic yield and novel candidate genes by next generation sequencing in 166 children with intrahepatic cholestasis. Hepatol Int 2024; 18:661-672. [PMID: 37314652 DOI: 10.1007/s12072-023-10553-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 05/19/2023] [Indexed: 06/15/2023]
Abstract
BACKGROUND AND AIMS Cholestatic liver disease is a leading referral to pediatric liver transplant centers. Inherited disorders are the second most frequent cause of cholestasis in the first month of life. METHODS We retrospectively characterized the genotype and phenotype of 166 participants with intrahepatic cholestasis, and re-analyzed phenotype and whole-exome sequencing (WES) data from patients with previously undetermined genetic etiology for newly published genes and novel candidates. Functional validations of selected variants were conducted in cultured cells. RESULTS Overall, we identified disease-causing variants in 31% (52/166) of our study participants. Of the 52 individuals, 18 (35%) had metabolic liver diseases, 9 (17%) had syndromic cholestasis, 9 (17%) had progressive familial intrahepatic cholestasis, 3 (6%) had bile acid synthesis defects, 3(6%) had infantile liver failure and 10 (19%) had a phenocopy of intrahepatic cholestasis. By reverse phenotyping, we identified a de novo variant c.1883G > A in FAM111B of a case with high glutamyl transpeptidase (GGT) cholestasis. By re-analyzing WES data, two patients were newly solved, who had compound heterozygous variants in recently published genes KIF12 and USP53, respectively. Our additional search for novel candidates in unsolved WES families revealed four potential novel candidate genes (NCOA6, CCDC88B, USP24 and ATP11C), among which the patients with variants in NCOA6 and ATP11C recapitulate the cholestasis phenotype in mice models. CONCLUSIONS In a single-center pediatric cohort, we identified monogenic variants in 22 known human intrahepatic cholestasis or phenocopy genes, explaining up to 31% of the intrahepatic cholestasis patients. Our findings suggest that re-evaluating existing WES data from well-phenotyped patients on a regular basis can increase the diagnostic yield for cholestatic liver disease in children.
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Affiliation(s)
- Yucan Zheng
- Department of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Hongmei Guo
- Department of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Leilei Chen
- Department of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Weixia Cheng
- Department of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Kunlong Yan
- Department of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Zhihua Zhang
- Department of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Mei Li
- Department of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Yu Jin
- Department of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Guorui Hu
- Department of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Chunli Wang
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Chunlei Zhou
- Department of Pathology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Wei Zhou
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Zhanjun Jia
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Bixia Zheng
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China.
| | - Zhifeng Liu
- Department of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China.
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Samanta A, Parveen N, Sen Sarma M, Poddar U, Srivastava A. Cholestatic Liver Disease due to Novel USP53 Mutations: A Case Series of Three Indian Children. J Clin Exp Hepatol 2024; 14:101290. [PMID: 38544763 PMCID: PMC10964066 DOI: 10.1016/j.jceh.2023.10.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 10/01/2023] [Indexed: 10/07/2024] Open
Abstract
Cholestatic liver diseases in children often have an underlying genetic defect. Genetic testing by next-generation sequencing has become a crucial part of the diagnostic armamentarium in such clinical scenarios. Here, we report three children who presented with early-onset cholestatic jaundice and pruritus. All of them had low gamma-glutamyl transferase and high serum bile acid levels. Symptoms were alleviated with ursodeoxycholic acid and cholestyramine in all 3 children with normal LFT at follow-up. They were detected to have novel pathogenic USP53 mutations (2 homozygous, 1 compound heterozygous) on next-generation sequencing which have previously not been reported.
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Affiliation(s)
- Arghya Samanta
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, India
| | - Neha Parveen
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, India
| | - Moinak Sen Sarma
- Department of Pediatric 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
| | - Anshu Srivastava
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, India
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Zhang XY, Zhang J, Lu Y. COG6-CDG: Two Novel Variants and Milder Phenotype in a Chinese Patient. Hum Mutat 2024; 2024:9857442. [PMID: 40225945 PMCID: PMC11919040 DOI: 10.1155/2024/9857442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 01/02/2024] [Accepted: 01/29/2024] [Indexed: 04/15/2025]
Abstract
Here, we present a Han Chinese pediatric girl highly suspected of congenial disorder of glycosylation type IIL (CDG2L; OMIM#614576). Her clinical symptoms include transferase abnormal, liver cirrhosis, hemogram, coagulopathy, growth retardation, intellectual disability, frequent infections, and enamel hypoplasia. Trio-genome sequencing identified in COG6 a paternal variant c.1672C>T (p.Gln558Ter) and a maternal variant c.153+392A>G (p.?). Reverse transcription-polymerase chain reaction (RT-PCR) using mRNA isolated from peripheral blood confirmed the pathogenicity of both variants. The paternal variant resulted in nonsense-mediated mRNA decay. The maternal variant generated two aberrant COG6 transcripts with 154 bp overlap and was predicted to result in a frameshift at the same position, leading to generation of a premature termination codon. They might result in synthesis of a truncated form of COG6. Thus, the patient was genetically diagnosed.
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Affiliation(s)
- Xue-Yuan Zhang
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Department of Pediatrics, Shanghai 201102, China
- Shanghai Medical College of Fudan University, Shanghai 201102, China
| | - Jing Zhang
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Department of Pediatrics, Shanghai 201102, China
- Shanghai Medical College of Fudan University, Shanghai 201102, China
| | - Yi Lu
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Department of Pediatrics, Shanghai 201102, China
- Shanghai Medical College of Fudan University, Shanghai 201102, China
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Geladari EV, Vallianou NG, Margellou E, Kounatidis D, Sevastianos V, Alexopoulou A. Benign Recurrent Intrahepatic Cholestasis: Where Are We Now? GASTROENTEROLOGY INSIGHTS 2024; 15:156-167. [DOI: 10.3390/gastroent15010011] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2025] Open
Abstract
Benign recurrent intrahepatic cholestasis (BRIC) stands as a rare genetic contributor to cholestasis, aligning itself within the spectrum of inherited intrahepatic cholestasis syndromes, such as progressive familial intrahepatic cholestasis (PFIC) and intrahepatic cholestasis of pregnancy. Manifesting in infancy or early adulthood, BRIC is marked by recurrent episodes of jaundice accompanied by intense pruritus, enduring from weeks to years across the lifespan. Normal gamma-glutamyl transferase (GGT) levels are a characteristic laboratory finding. Initially considered unlikely to progress to chronic liver disease or cirrhosis, some reports suggest BRIC may evolve into a continuous and progressive form of cholestasis. Moreover, these recurrent cholestatic episodes significantly impact quality of life, and certain mutations elevate the risk of hepatobiliary malignancy. Between episodes, histological findings of centrilobular cholestasis and abnormal laboratory parameters revert to normal, potentially obviating the need for liver biopsy. This review focuses on the genetic aspects of BRIC, its pathophysiology, clinical presentation, and prognosis. Additionally, it outlines triggering factors and available treatment options.
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Affiliation(s)
- Eleni V. Geladari
- 3rd Department of Internal Medicine & Liver Outpatient Clinic, Evangelismos General Hospital, 45-47 Ipsilantou Str., 10676 Athens, Greece
| | - Natalia G. Vallianou
- 1st Department of Internal Medicine, Evangelismos General Hospital, 45-47 Ipsilantou Str., 10676 Athens, Greece
| | - Evangelia Margellou
- 1st Department of Internal Medicine, Evangelismos General Hospital, 45-47 Ipsilantou Str., 10676 Athens, Greece
| | - Dimitris Kounatidis
- 2nd Department of Medicine & Research Laboratory, Medical School, National & Kapodistrian University of Athens, Hippokration Hospital, 114 Vasilissis Sofias Str., 11527 Athens, Greece
| | - Vassilios Sevastianos
- 3rd Department of Internal Medicine & Liver Outpatient Clinic, Evangelismos General Hospital, 45-47 Ipsilantou Str., 10676 Athens, Greece
| | - Alexandra Alexopoulou
- 2nd Department of Medicine & Research Laboratory, Medical School, National & Kapodistrian University of Athens, Hippokration Hospital, 114 Vasilissis Sofias Str., 11527 Athens, Greece
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12
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Xia G, Guo Y, Zhang J, Han M, Meng X, Lv J. An Overview of the Deubiquitinase USP53: A Promising Diagnostic Marker and Therapeutic Target. Curr Protein Pept Sci 2024; 25:708-718. [PMID: 39300775 DOI: 10.2174/0113892037292440240518194922] [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: 12/16/2023] [Revised: 04/08/2024] [Accepted: 04/18/2024] [Indexed: 09/22/2024]
Abstract
Ubiquitination and deubiquitination are important mechanisms to maintain normal physiological activities, and their disorders or imbalances can lead to various diseases. As a subgroup of deubiquitinases (DUBs), the ubiquitin-specific peptidase (USP) family is closely related to many biological processes. USP53, one of the family members, is widely expressed in human tissues and participates in a variety of life activities, such as cell apoptosis, nerve transmission, and bone remodeling. Mutations in the USP53 gene can cause cholestasis and deafness and may also be a potential cause of schizophrenia. Knockout of USP53 can alleviate neuropathic pain induced by chronic constriction injury. Loss of USP53 up-regulates RANKL expression, promotes the cytogenesis and functional activity of osteoclasts, and triggers osteodestructive diseases. USP53 plays a tumor-suppressive role in lung cancer, renal clear cell carcinoma, colorectal cancer, liver cancer, and esophageal cancer but reduces the radiosensitivity of cervical cancer and esophageal cancer to induce radioresistance. Through the in-depth combination of literature and bioinformatics, this review suggested that USP53 may be a good potential biomarker or therapeutic target for diseases.
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Affiliation(s)
- Guangce Xia
- First College of Clinical Medicine, Hebei North University, Zhangjiakou 075000, China
- First Hospital of Qinhuangdao Affiliated to Hebei North University, Qinhuangdao 066000, P.R. China
| | - Yulin Guo
- First College of Clinical Medicine, Hebei North University, Zhangjiakou 075000, China
- First Hospital of Qinhuangdao Affiliated to Hebei North University, Qinhuangdao 066000, P.R. China
| | - Jiajia Zhang
- First College of Clinical Medicine, Hebei North University, Zhangjiakou 075000, China
| | - Meng Han
- Breast Disease Diagnosis and Treatment Center, First Hospital of Qinhuangdao, Qinhuangdao, Hebei Province 066000, P.R. China
| | - Xiangchao Meng
- Breast Disease Diagnosis and Treatment Center, First Hospital of Qinhuangdao, Qinhuangdao, Hebei Province 066000, P.R. China
| | - Ji Lv
- Breast Disease Diagnosis and Treatment Center, First Hospital of Qinhuangdao, Qinhuangdao, Hebei Province 066000, P.R. China
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13
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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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14
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Ahn S, Choi J, Jeong SH. The First Korean Adult Case of Progressive Familial Intrahepatic Cholestasis Type 7 with Novel USP53 Splicing Variants by Next Generation Sequencing. Yonsei Med J 2023; 64:745-749. [PMID: 37992747 PMCID: PMC10681827 DOI: 10.3349/ymj.2023.0161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 08/07/2023] [Accepted: 08/31/2023] [Indexed: 11/24/2023] Open
Abstract
Progressive familial intrahepatic cholestasis (PFIC) is a group of rare genetic disorders caused by defects in biliary epithelial transporters. It mostly presents as low γ-glutamyltransferase cholestasis. Recently, USP53 has been identified as one of the novel genes associated with PFIC. Herein, we report a 21-year-old Korean male patient with a late-onset PFIC. Initial work-up, including whole genome sequencing, did not find any associated gene. However, reviewing sequencing data identified novel compound heterozygous variants in splicing site of USP53 (NM_001371395.1:c.972+3_972+6del, and c.973-1G>A). The patient's bilirubin level fluctuated during the disease course. At 4.5 years after the initial presentation, the patient's symptom and high bilirubin level were normalized after administration of high-dose ursodeoxycholic acid. Recognition of this disease entity is important for prompt diagnosis and management. USP53 is recommended for the work-up of low γ-glutamyltransferase cholestasis.
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Affiliation(s)
- Soomin Ahn
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jonggi Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sook-Hyang Jeong
- Division of Gastroenterology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
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15
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Liu Y, Tang W, Yao F. USP53 Exerts Tumor-Promoting Effects in Triple-Negative Breast Cancer by Deubiquitinating CRKL. Cancers (Basel) 2023; 15:5033. [PMID: 37894400 PMCID: PMC10605207 DOI: 10.3390/cancers15205033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Revised: 10/03/2023] [Accepted: 10/12/2023] [Indexed: 10/29/2023] Open
Abstract
Breast cancer (BC) ranks in the top five malignant tumors in terms of morbidity and mortality rates. Among BC subtypes, TNBC has a high recurrence rate and metastasis rate and the worst prognosis. However, the exact mechanism by which TNBC develops is unclear. Here, we show that the deubiquitinase USP53 contributes to tumor growth and metastasis in TNBC. USP53 is overexpressed in TNBC, and this phenotype is linked to a poor prognosis. Functionally, USP53 promotes TNBC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT). More importantly, USP53 decreases the chemosensitivity of BC cells by enhancing v-crk sarcoma virus CT10 oncogene homologue (avian)-like (CRKL) expression. Mechanistically, USP53 directly binds CRKL to stabilize and deubiquitinate it, thereby preventing CRKL degradation. Overall, we discovered that USP53 deubiquitinates CRKL, encourages tumor development and metastasis, and reduces chemosensitivity in TNBC. These findings imply that USP53 might represent a new therapeutic target for the treatment of TNBC.
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Affiliation(s)
- Yi Liu
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China;
| | - Wei Tang
- Department of Pediartrics, Renmin Hospital of Wuhan University, Wuhan 430060, China;
| | - Feng Yao
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China;
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16
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Kanwal A, Sheikh SA, Aslam F, Yaseen S, Beetham Z, Pankratz N, Clabots CR, Naz S, Pardo JV. Genome Sequencing of Consanguineous Family Implicates Ubiquitin-Specific Protease 53 ( USP53) Variant in Psychosis/Schizophrenia: Wild-Type Expression in Murine Hippocampal CA 1-3 and Granular Dentate with AMPA Synapse Interactions. Genes (Basel) 2023; 14:1921. [PMID: 37895270 PMCID: PMC10606770 DOI: 10.3390/genes14101921] [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: 08/24/2023] [Revised: 09/22/2023] [Accepted: 10/02/2023] [Indexed: 10/29/2023] Open
Abstract
Psychosis is a severe mental disorder characterized by abnormal thoughts and perceptions (e.g., hallucinations) occurring quintessentially in schizophrenia and in several other neuropsychiatric disorders. Schizophrenia is widely considered as a neurodevelopmental disorder that onsets during teenage/early adulthood. A multiplex consanguineous Pakistani family was afflicted with severe psychosis and apparent autosomal recessive transmission. The first-cousin parents and five children were healthy, whereas two teenage daughters were severely affected. Structured interviews confirmed the diagnosis of DSM-V schizophrenia. Probands and father underwent next-generation sequencing. All available relatives were subjected to confirmatory Sanger sequencing. Homozygosity mapping and directed a priori filtering identified only one rare variant [MAF < 5(10)-5] at a residue conserved across vertebrates. The variant was a non-catalytic deubiquitinase, USP53 (p.Cys228Arg), predicted in silico as damaging. Genome sequencing did not identify any other potentially pathogenic single nucleotide variant or structural variant. Since the literature on USP53 lacked relevance to mental illness or CNS expression, studies were conducted which revealed USP53 localization in regions of the hippocampus (CA 1-3) and granular dentate. The staining pattern was like that seen with GRIA2/GluA2 and GRIP2 antibodies. All three proteins coimmunoprecipitated. These findings support the glutamate hypothesis of schizophrenia as part of the AMPA-R interactome. If confirmed, USP53 appears to be one of the few Mendelian variants potentially causal to a common-appearing mental disorder that is a rare genetic form of schizophrenia.
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Affiliation(s)
- Ambreen Kanwal
- School of Biological Sciences, University of the Punjab, Lahore 54590, Pakistan; (A.K.); (F.A.); (S.Y.)
- Cognitive Neuroimaging Unit, Minneapolis Veterans Health Care System, Minneapolis, MN 55417, USA
- Department of Psychiatry, University of Minnesota, Minneapolis, MN 55454, USA
| | - Sohail A. Sheikh
- Department of Psychiatry, Hawkes Bay Hospital, Hastings 4120, New Zealand;
| | - Faiza Aslam
- School of Biological Sciences, University of the Punjab, Lahore 54590, Pakistan; (A.K.); (F.A.); (S.Y.)
| | - Samina Yaseen
- School of Biological Sciences, University of the Punjab, Lahore 54590, Pakistan; (A.K.); (F.A.); (S.Y.)
| | - Zachary Beetham
- Division of Computational Pathology, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA; (Z.B.)
| | - Nathan Pankratz
- Division of Computational Pathology, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA; (Z.B.)
| | - Connie R. Clabots
- Medicine Patient Service Line, Minneapolis Veterans Health Care System, Minneapolis, MN 55417, USA;
| | - Sadaf Naz
- School of Biological Sciences, University of the Punjab, Lahore 54590, Pakistan; (A.K.); (F.A.); (S.Y.)
| | - José V. Pardo
- Cognitive Neuroimaging Unit, Minneapolis Veterans Health Care System, Minneapolis, MN 55417, USA
- Department of Psychiatry, University of Minnesota, Minneapolis, MN 55454, USA
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17
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Xie S, Wei S, Ma X, Wang R, He T, Zhang Z, Yang J, Wang J, Chang L, Jing M, Li H, Zhou X, Zhao Y. Genetic alterations and molecular mechanisms underlying hereditary intrahepatic cholestasis. Front Pharmacol 2023; 14:1173542. [PMID: 37324459 PMCID: PMC10264785 DOI: 10.3389/fphar.2023.1173542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 05/16/2023] [Indexed: 06/17/2023] Open
Abstract
Hereditary cholestatic liver disease caused by a class of autosomal gene mutations results in jaundice, which involves the abnormality of the synthesis, secretion, and other disorders of bile acids metabolism. Due to the existence of a variety of gene mutations, the clinical manifestations of children are also diverse. There is no unified standard for diagnosis and single detection method, which seriously hinders the development of clinical treatment. Therefore, the mutated genes of hereditary intrahepatic cholestasis were systematically described in this review.
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Affiliation(s)
- Shuying Xie
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Shizhang Wei
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
| | - Xiao Ma
- Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ruilin Wang
- Department of Pharmacy, 5th Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Tingting He
- Department of Pharmacy, 5th Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Zhao Zhang
- Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ju Yang
- Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jiawei Wang
- Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lei Chang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Manyi Jing
- Department of Pharmacy, Chinese PLA General Hospital, Beijing, China
| | - Haotian Li
- Department of Pharmacy, Chinese PLA General Hospital, Beijing, China
| | - Xuelin Zhou
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Yanling Zhao
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
- Department of Pharmacy, Chinese PLA General Hospital, Beijing, China
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18
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Zou YG, Wang H, Li WW, Dai DL. Challenges in pediatric inherited/metabolic liver disease: Focus on the disease spectrum, diagnosis and management of relatively common disorders. World J Gastroenterol 2023; 29:2114-2126. [PMID: 37122598 PMCID: PMC10130973 DOI: 10.3748/wjg.v29.i14.2114] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 01/09/2023] [Accepted: 03/21/2023] [Indexed: 04/13/2023] Open
Abstract
The clinical scenario of pediatric liver disease is becoming more intricate due to changes in the disease spectrum, in which an increasing number of inherited/ metabolic liver diseases are reported, while infectious diseases show a decreasing trend. The similar clinical manifestations caused by inherited/metabolic diseases might be under-recognized or misdiagnosed due to nonspecific characteristics. A delayed visit to a doctor due to a lack of symptoms or mild symptoms at an early stage will result in late diagnosis and treatment. Moreover, limited diagnostic approaches, especially liver biopsy, are not easily accepted by pediatric patients, leading to challenges in etiological diagnosis. Liver dysfunction due to inherited/metabolic diseases is often caused by a variety of metabolites, so precision treatment is difficult; symptomatic treatment is a compelling option for inherited disorders.
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Affiliation(s)
- Yi-Gui Zou
- Key Laboratory for Precision Diagnosis and Treatment of Pediatric Digestive System Diseases and Endoscopy Center, Shenzhen Children's Hospital, Shenzhen 518026, Guangdong Province, China
| | - Huan Wang
- Key Laboratory for Precision Diagnosis and Treatment of Pediatric Digestive System Diseases and Endoscopy Center, Shenzhen Children's Hospital, Shenzhen 518026, Guangdong Province, China
| | - Wen-Wen Li
- Key Laboratory for Precision Diagnosis and Treatment of Pediatric Digestive System Diseases and Endoscopy Center, Shenzhen Children's Hospital, Shenzhen 518026, Guangdong Province, China
| | - Dong-Ling Dai
- Key Laboratory for Precision Diagnosis and Treatment of Pediatric Digestive System Diseases and Endoscopy Center, Shenzhen Children's Hospital, Shenzhen 518026, Guangdong Province, China
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19
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Shen J, Lin X, Dai F, Chen G, Lin H, Fang B, Liu H. Ubiquitin-specific peptidases: Players in bone metabolism. Cell Prolif 2023:e13444. [PMID: 36883930 PMCID: PMC10392067 DOI: 10.1111/cpr.13444] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 02/22/2023] [Accepted: 02/28/2023] [Indexed: 03/09/2023] Open
Abstract
Osteoporosis is an ageing-related disease, that has become a major public health problem and its pathogenesis has not yet been fully elucidated. Substantial evidence suggests a strong link between overall age-related disease progression and epigenetic modifications throughout the life cycle. As an important epigenetic modification, ubiquitination is extensively involved in various physiological processes, and its role in bone metabolism has attracted increasing attention. Ubiquitination can be reversed by deubiquitinases, which counteract protein ubiquitination degradation. As the largest and most structurally diverse cysteinase family of deubiquitinating enzymes, ubiquitin-specific proteases (USPs), comprising the largest and most structurally diverse cysteine kinase family of deubiquitinating enzymes, have been found to be important players in maintaining the balance between bone formation and resorption. The aim of this review is to explore recent findings highlighting the regulatory functions of USPs in bone metabolism and provide insight into the molecular mechanisms governing their actions during bone loss. An in-deep understanding of USPs-mediated regulation of bone formation and bone resorption will provide a scientific rationale for the discovery and development of novel USP-targeted therapeutic strategies for osteoporosis.
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Affiliation(s)
- Jianlin Shen
- Department of Orthopaedics, Affiliated Hospital of Putian University, Putian, China
| | - Xiaoning Lin
- Department of Orthopaedics, Affiliated Hospital of Putian University, Putian, China
| | - Feifei Dai
- School of Medicine, Putian Universtiy, Putian, China
| | - Guoli Chen
- Department of Orthopaedics, Affiliated Hospital of Putian University, Putian, China
| | - Haibin Lin
- Department of Orthopaedics, Affiliated Hospital of Putian University, Putian, China
| | - Bangjiang Fang
- Department of Emergency, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Institute of Emergency and Critical Care Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Huan Liu
- Department of Orthopaedics, Affiliated Hospital of Putian University, Putian, China
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Hariri H, Kose O, Bezdjian A, Daniel SJ, St-Arnaud R. USP53 Regulates Bone Homeostasis by Controlling Rankl Expression in Osteoblasts and Bone Marrow Adipocytes. J Bone Miner Res 2023; 38:578-596. [PMID: 36726200 DOI: 10.1002/jbmr.4778] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 01/12/2023] [Accepted: 01/19/2023] [Indexed: 02/03/2023]
Abstract
In the skeleton, osteoblasts and osteoclasts synchronize their activities to maintain bone homeostasis and integrity. Investigating the molecular mechanisms governing bone remodeling is critical and helps understand the underlying biology of bone disorders. Initially, we have identified the ubiquitin-specific peptidase gene (Usp53) as a target of the parathyroid hormone in osteoblasts and a regulator of mesenchymal stem cell differentiation. Mutations in USP53 have been linked to a constellation of developmental pathologies. However, the role of Usp53 in bone has never been visited. Here we show that Usp53 null mice have a low bone mass phenotype in vivo. Usp53 null mice exhibit a pronounced decrease in trabecular bone indices including trabecular bone volume (36%) and trabecular number (26%) along with an increase in trabecular separation (13%). Cortical bone parameters are also impacted, showing a reduction in cortical bone volume (12%) and cortical bone thickness (15%). As a result, the strength and mechanical bone properties of Usp53 null mice have been compromised. At the cellular level, the ablation of Usp53 perturbs bone remodeling, augments osteoblast-dependent osteoclastogenesis, and increases osteoclast numbers. Bone marrow adipose tissue volume increased significantly with age in Usp53-deficient mice. Usp53 null mice displayed increased serum receptor activator of NF-κB ligand (RANKL) levels, and Usp53-deficient osteoblasts and bone marrow adipocytes have increased expression of Rankl. Mechanistically, USP53 regulates Rankl expression by enhancing the interaction between VDR and SMAD3. This is the first report describing the function of Usp53 during skeletal development. Our results put Usp53 in display as a novel regulator of osteoblast-osteoclast coupling and open the door for investigating the involvement of USP53 in pathologies. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Hadla Hariri
- Research Centre, Shriners Hospital for Children-Canada, Montreal, Canada.,Department of Human Genetics, Faculty of Medicine and Health Sciences, McGill University, Montreal, Canada
| | - Orhun Kose
- McGill Otolaryngology Sciences Laboratory, McGill University Health Centre-Research Institute, Montreal, Canada
| | - Aren Bezdjian
- McGill Otolaryngology Sciences Laboratory, McGill University Health Centre-Research Institute, Montreal, Canada
| | - Sam J Daniel
- McGill Otolaryngology Sciences Laboratory, McGill University Health Centre-Research Institute, Montreal, Canada.,Department of Otolaryngology-Head and Neck Surgery, McGill University, Montreal, Canada.,Department of Pediatric Surgery, McGill University, Montreal, Canada
| | - René St-Arnaud
- Research Centre, Shriners Hospital for Children-Canada, Montreal, Canada.,Department of Human Genetics, Faculty of Medicine and Health Sciences, McGill University, Montreal, Canada.,Department of Surgery, Faculty of Medicine and Health Sciences, McGill University, Montreal, Canada.,Department of Medicine, Faculty of Medicine and Health Sciences, McGill University, Montreal, Canada
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21
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Gezdirici A, Kalaycik Şengül Ö, Doğan M, Özgüven BY, Akbulut E. Biallelic Novel USP53 Splicing Variant Disrupting the Gene Function that Causes Cholestasis Phenotype and Review of the Literature. Mol Syndromol 2023; 13:471-484. [PMID: 36660033 PMCID: PMC9843568 DOI: 10.1159/000523937] [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: 08/11/2021] [Accepted: 03/02/2022] [Indexed: 01/22/2023] Open
Abstract
Introduction Hereditary cholestasis is a heterogeneous group of liver diseases that mostly show autosomal recessive inheritance. The phenotype of cholestasis is highly variable. Molecular genetic testing offers an useful approach to differentiate different types of cholestasis because some symptoms and findings overlap. Biallelic variants in USP53 have recently been reported in cholestasis phenotype. Methods In this study, we aimed to characterize clinical findings and biological insights on a novel USP53 splice variant causing cholestasis phenotype and provided a review of the literature. We performed whole-exome sequencing and then confirmed it with Sanger sequencing. In addition, as a result of in silico analyses and cDNA analysis, we showed that the USP53 protein in our patient was shortened. Results We report a novel splice variant (NM_019050.2:c.238-1G>C) in the USP53 gene via whole-exome sequencing in a patient with cholestasis phenotype. This variant was confirmed by Sanger sequencing and was a result of family segregation analysis; it was found to be in a heterozygous state in the parents and the other healthy elder brother of our patient. According to in silico analyses, the change in the splice region resulted in an increase in the length of exon 2, whereas the stop codon after the additional 3 amino acids (VTF) caused the protein to terminate prematurely. Thus, the mature USP53 protein, consisting of 1,073 amino acids, has been reduced to a small protein of 82 amino acids. Conclusion We propose a model for the tertiary structure of USP53 for the first time, and together with all these data, we support the association of biallelic variants of the USP53 gene with cholestasis phenotype. We also present a comparison of previously reported patients with USP53-associated cholestasis phenotype to contribute to the literature.
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Affiliation(s)
- Alper Gezdirici
- Department of Medical Genetics, Basaksehir Cam and Sakura City Hospital, Istanbul, Turkey,*Alper Gezdirici,
| | - Özlem Kalaycik Şengül
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey
| | - Mustafa Doğan
- Department of Medical Genetics, Basaksehir Cam and Sakura City Hospital, Istanbul, Turkey
| | - Banu Y. Özgüven
- Department of Pathology, Basaksehir Cam and Sakura City Hospital, Istanbul, Turkey
| | - Ekrem Akbulut
- Department of Bioengineering, Malatya Turgut Ozal University, Malatya, Turkey
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22
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Pouyo R, Chung K, Delacroix L, Malgrange B. The ubiquitin-proteasome system in normal hearing and deafness. Hear Res 2022; 426:108366. [PMID: 34645583 DOI: 10.1016/j.heares.2021.108366] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 09/03/2021] [Accepted: 09/23/2021] [Indexed: 12/16/2022]
Abstract
Post-translational modifications of proteins are essential for the proper development and function of many tissues and organs, including the inner ear. Ubiquitination is a highly selective post-translational modification that involves the covalent conjugation of ubiquitin to a substrate protein. The most common outcome of protein ubiquitination is degradation by the ubiquitin-proteasome system (UPS), preventing the accumulation of misfolded, damaged, and excess proteins. In addition to proteasomal degradation, ubiquitination regulates other cellular processes, such as transcription, translation, endocytosis, receptor activity, and subcellular localization. All of these processes are essential for cochlear development and maintenance, as several studies link impairment of UPS with altered cochlear development and hearing loss. In this review, we provide insight into the well-oiled machinery of UPS with a focus on its confirmed role in normal hearing and deafness and potential therapeutic strategies to prevent and treat UPS-associated hearing loss.
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Affiliation(s)
- Ronald Pouyo
- GIGA-Stem Cells, Developmental Neurobiology Unit, University of Liege, Avenue hippocrate 15, B36 1st Floor B, Liege 4000, Belgium
| | - Keshi Chung
- GIGA-Stem Cells, Developmental Neurobiology Unit, University of Liege, Avenue hippocrate 15, B36 1st Floor B, Liege 4000, Belgium
| | - Laurence Delacroix
- GIGA-Stem Cells, Developmental Neurobiology Unit, University of Liege, Avenue hippocrate 15, B36 1st Floor B, Liege 4000, Belgium
| | - Brigitte Malgrange
- GIGA-Stem Cells, Developmental Neurobiology Unit, University of Liege, Avenue hippocrate 15, B36 1st Floor B, Liege 4000, Belgium.
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23
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Lu L. Guidelines for the Management of Cholestatic Liver Diseases (2021). J Clin Transl Hepatol 2022; 10:757-769. [PMID: 36062287 PMCID: PMC9396310 DOI: 10.14218/jcth.2022.00147] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 04/17/2022] [Accepted: 04/18/2022] [Indexed: 12/04/2022] Open
Abstract
In 2015, the Chinese Society of Hepatology and the Chinese Society of Gastroenterology issued a consensus statement on the diagnosis and management of cholestatic liver diseases. More clinical data on this topic have appeared during recent years. The Autoimmune Liver Disease Group of the Chinese Society of Hepatology organized an expert group to review recent evidence and provide an update to these previous guidelines. Herein, we provide 22 recommendations as a working reference for the management of cholestatic liver diseases by clinical practitioners.
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Affiliation(s)
- Lungen Lu
- Correspondence to: Lungen Lu, Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, China. ORCID: https://orcid.org/0000-0002-1533-4068. Tel: +86-13381616206, E-mail:
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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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Vitale G, Mattiaccio A, Conti A, Turco L, Seri M, Piscaglia F, Morelli MC. Genetics in Familial Intrahepatic Cholestasis: Clinical Patterns and Development of Liver and Biliary Cancers: A Review of the Literature. Cancers (Basel) 2022; 14:cancers14143421. [PMID: 35884482 PMCID: PMC9322180 DOI: 10.3390/cancers14143421] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/10/2022] [Accepted: 07/12/2022] [Indexed: 02/06/2023] Open
Abstract
The family of inherited intrahepatic cholestasis includes autosomal recessive cholestatic rare diseases of childhood involved in bile acids secretion or bile transport defects. Specific genetic pathways potentially cause many otherwise unexplained cholestasis or hepatobiliary tumours in a healthy liver. Lately, next-generation sequencing and whole-exome sequencing have improved the diagnostic procedures of familial intrahepatic cholestasis (FIC), as well as the discovery of several genes responsible for FIC. Moreover, mutations in these genes, even in the heterozygous status, may be responsible for cryptogenic cholestasis in both young and adults. Mutations in FIC genes can influence serum and hepatic levels of bile acids. Experimental studies on the NR1H4 gene have shown that high bile acids concentrations cause excessive production of inflammatory cytokines, resistance to apoptosis, and increased cell regeneration, all risk conditions for developing hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). NR1H4 gene encodes farnesoid X-activated receptor having a pivotal role in bile salts synthesis. Moreover, HCC and CCA can emerge in patients with several FIC genes such as ABCB11, ABCB4 and TJP2. Herein, we reviewed the available data on FIC-related hepatobiliary cancers, reporting on genetics to the pathophysiology, the risk factors and the clinical presentation.
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Affiliation(s)
- Giovanni Vitale
- Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (L.T.); (M.C.M.)
- Correspondence:
| | - Alessandro Mattiaccio
- U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.M.); (A.C.); (M.S.)
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum-University di Bologna, 40138 Bologna, Italy
| | - Amalia Conti
- U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.M.); (A.C.); (M.S.)
| | - Laura Turco
- Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (L.T.); (M.C.M.)
| | - Marco Seri
- U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.M.); (A.C.); (M.S.)
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum-University di Bologna, 40138 Bologna, Italy
| | - Fabio Piscaglia
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
| | - Maria Cristina Morelli
- Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (L.T.); (M.C.M.)
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USP53 plays an antitumor role in hepatocellular carcinoma through deubiquitination of cytochrome c. Oncogenesis 2022; 11:31. [PMID: 35654790 PMCID: PMC9163188 DOI: 10.1038/s41389-022-00404-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 05/06/2022] [Accepted: 05/10/2022] [Indexed: 11/08/2022] Open
Abstract
Despite of advances in treatment options, hepatocellular carcinoma (HCC) remains nearly incurable and has been recognized as the third leading cause of cancer-related deaths worldwide. As a deubiquitinating enzyme, the antitumor effect of ubiquitin-specific peptidase 53 (USP53) has been demonstrated on few malignancies. In this study, we investigated the potential antitumor role of USP53 in HCC. The results showed that USP53 was downregulated in HCC tissues as well as in HCC cell lines using both in silico data as well as patient samples. Furthermore, the ectopic expression of USP53 inhibited the proliferation, migration and invasion, and induced the apoptosis of HCC cells. Co-immunoprecipitation (CO-IP) assay and mass spectrometry (MS) combined with the gene set enrichment analysis (GSEA) identified cytochrome c (CYCS) as an interacting partner of USP53. USP53 overexpression increased the stability of CYCS in HCC cells following cycloheximide treatment. Finally, the overexpression of CYCS compensated for the decreased apoptotic rates in cells with USP53 knocked down, suggesting that USP53 induced the apoptosis in HCC cells through the deubiquitination of CYCS. To summarize, we identified USP53 as a tumor suppressor as well as a therapeutic target in HCC, providing novel insights into its pivotal role in cell apoptosis.
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Pfister ED, Dröge C, Liebe R, Stalke A, Buhl N, Ballauff A, Cantz T, Bueltmann E, Stindt J, Luedde T, Baumann U, Keitel V. Extrahepatic manifestations of progressive familial intrahepatic cholestasis syndromes: Presentation of a case series and literature review. Liver Int 2022; 42:1084-1096. [PMID: 35184362 DOI: 10.1111/liv.15200] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 02/02/2022] [Accepted: 02/11/2022] [Indexed: 02/13/2023]
Abstract
BACKGROUND AND AIMS Progressive familial intrahepatic cholestasis (PFIC) is a collective term for a heterogenous group of rare, inherited cholestasis syndromes. The number of genes underlying the clinical PFIC phenotype is still increasing. While progressive liver disease and its sequelae such as portal hypertension, pruritus and hepatocellular carcinoma determine transplant-free survival, extrahepatic manifestations may cause relevant morbidity. METHODS We performed a literature search for extrahepatic manifestations of PFIC associated with pathogenic gene variants in ATP8B1, ABCB11, ABCB4, TJP2, NR1H4 and MYO5B. To illustrate the extrahepatic symptoms described in the literature, PFIC cases from our centres were revisited. RESULTS Extrahepatic symptoms are common in PFIC subtypes, where the affected gene is expressed at high levels in other tissues. While most liver-associated complications resolve after successful orthotopic liver transplantation (OLT), some extrahepatic symptoms show no response or even worsen after OLT. CONCLUSION The spectrum of extrahepatic manifestations in PFIC highlights essential, non-redundant roles of the affected genes in other organs. Extrahepatic features contribute towards low health-related quality of life (HRQOL) and morbidity in PFIC. While OLT is often the only remaining, curative treatment, potential extrahepatic manifestations need to be carefully monitored and addressed.
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Affiliation(s)
- Eva-Doreen Pfister
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Liver, Kidney and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Carola Dröge
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany.,Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Magdeburg, Medical Faculty of Otto von Guericke University, Magdeburg, Germany
| | - Roman Liebe
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Amelie Stalke
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Liver, Kidney and Metabolic Diseases, Hannover Medical School, Hannover, Germany.,Department of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Nicole Buhl
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Liver, Kidney and Metabolic Diseases, Hannover Medical School, Hannover, Germany.,Department of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Antje Ballauff
- Department of Paediatrics, Helios Hospital, Krefeld, Germany
| | - Tobias Cantz
- Translational Hepatology and Stem Cell Biology, Department of Gastroenterology, Hepatology and Endocrinology, REBIRTH-Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany
| | - Eva Bueltmann
- Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
| | - Jan Stindt
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Ulrich Baumann
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Liver, Kidney and Metabolic Diseases, Hannover Medical School, Hannover, Germany.,Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Verena Keitel
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany.,Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Magdeburg, Medical Faculty of Otto von Guericke University, Magdeburg, Germany
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Vij M, Sankaranarayanan S. Biallelic Mutations in Ubiquitin-Specific Peptidase 53 ( USP53) Causing Progressive Intrahepatic Cholestasis. Report of a Case With Review of Literature. Pediatr Dev Pathol 2022; 25:207-212. [PMID: 34809518 DOI: 10.1177/10935266211051175] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Whole-exome sequencing studies have recently identified novel genes implicated in normal- or low-GGT pediatric cholestasis including ubiquitin-specific peptidase 53 (USP53). We identified novel biallelic mutations in the USP53 gene in a 7-month-old infant with pruritus and progressive intrahepatic cholestasis. His liver biopsy showed portal and perivenular fibrosis with bland bilirubinostasis. His parents were asymptomatic heterozygous for the same mutation. He is currently on vitamin supplements and cholestyramine and his family has also been counseled for liver transplantation. Our report confirms that patients with biallelic mutation in USP53 develop cholestatic liver disease.
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Affiliation(s)
- Mukul Vij
- Department of Pathology, Dr Rela Institute and Medical Centre, Bharath Institute of Higher Education and Research, Chennai, India
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29
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Vinayagamoorthy V, Srivastava A, Sarma MS. Newer variants of progressive familial intrahepatic cholestasis. World J Hepatol 2021; 13:2024-2038. [PMID: 35070006 PMCID: PMC8727216 DOI: 10.4254/wjh.v13.i12.2024] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 08/19/2021] [Accepted: 11/04/2021] [Indexed: 02/06/2023] Open
Abstract
Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of disorders characterized by defects in bile secretion and presentation with intrahepatic cholestasis in infancy or childhood. The most common types include PFIC 1 (deficiency of FIC1 protein, ATP8B1 gene mutation), PFIC 2 (bile salt export pump deficiency, ABCB11 gene mutation), and PFIC 3 (multidrug resistance protein-3 deficiency, ABCB4 gene mutation). Mutational analysis of subjects with normal gamma-glutamyl transferase cholestasis of unknown etiology has led to the identification of newer variants of PFIC, known as PFIC 4, 5, and MYO5B related (sometimes known as PFIC 6). PFIC 4 is caused by the loss of function of tight junction protein 2 (TJP2) and PFIC 5 is due to NR1H4 mutation causing Farnesoid X receptor deficiency. MYO5B gene mutation causes microvillous inclusion disease (MVID) and is also associated with isolated cholestasis. Children with TJP2 related cholestasis (PFIC-4) have a variable spectrum of presentation. Some have a self-limiting disease, while others have progressive liver disease with an increased risk of hepatocellular carcinoma. Hence, frequent surveillance for hepatocellular carcinoma is recommended from infancy. PFIC-5 patients usually have rapidly progressive liver disease with early onset coagulopathy, high alpha-fetoprotein and ultimately require a liver transplant. Subjects with MYO5 B-related disease can present with isolated cholestasis or cholestasis with intractable diarrhea (MVID). These children are at risk of worsening cholestasis post intestinal transplant (IT) for MVID, hence combined intestinal and liver transplant or IT with biliary diversion is preferred. Immunohistochemistry can differentiate most of the variants of PFIC but confirmation requires genetic analysis.
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Affiliation(s)
- Vignesh Vinayagamoorthy
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Anshu Srivastava
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Moinak Sen Sarma
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
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A Two-Year Clinical Description of a Patient with a Rare Type of Low-GGT Cholestasis Caused by a Novel Variant of USP53. Genes (Basel) 2021; 12:genes12101618. [PMID: 34681012 PMCID: PMC8535307 DOI: 10.3390/genes12101618] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 10/06/2021] [Accepted: 10/12/2021] [Indexed: 12/14/2022] Open
Abstract
Here, we report a novel truncating mutation in the ubiquitin-specific peptidase gene (USP53) causing low-γ-GT (GGT) cholestasis. Genetic testing was carried out, including clinical exome sequencing for the proband and Sanger sequencing for the proband and his parents. The proband harbored a novel c.1017_1057del (p.(Cys339TrpfsTer7)) mutation in the ubiquitin carboxyl-terminal hydrolase (UCH) domain of USP53; we describe the clinical and laboratory features of the patient with a rare type of low-GGT cholestasis caused by this variant. The clinical presentation was found to be similar to that of phenotypes described in previous studies. However, there was an unusual presence of liver hemangiomas observed in our patient. Thus, our report reinforces the link between USP53 mutations and cholestasis. With this report, we confirm USP53 as the gene for low-GGT cholestasis and describe liver hemangiomas as a possible additional symptom of the phenotype spectrum. The inclusion of USP53 in the OMIM database and liver gene panels can further increase the effectiveness of molecular genetic studies.
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Tang J, Tan M, Deng Y, Tang H, Shi H, Li M, Ma W, Li J, Dai H, Li J, Zhou S, Li X, Wei F, Ma X, Luo L. Two Novel Pathogenic Variants of TJP2 Gene and the Underlying Molecular Mechanisms in Progressive Familial Intrahepatic Cholestasis Type 4 Patients. Front Cell Dev Biol 2021; 9:661599. [PMID: 34504838 PMCID: PMC8421653 DOI: 10.3389/fcell.2021.661599] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 07/09/2021] [Indexed: 12/13/2022] Open
Abstract
Progressive familial intrahepatic cholestasis (PFIC) is an autosomal recessive inherited disease that accounts for 10%-15% childhood cholestasis and could lead to infant disability or death. There are three well-established types of PFIC (1-3), caused by mutations in the ATP8B1, ABCB11, and ABCB4 genes. Biallelic pathogenic variants in the tight junction protein 2 gene (TJP2) were newly reported as a cause for PFIC type 4; however, only a limited number of patients and undisputable variants have been reported for TJP2, and the underlying mechanism for PFIC 4 remains poorly understood. To explore the diagnostic yield of TJP2 analysis in suspected PFIC patients negative for the PFIC1-3 mutation, we designed a multiplex polymerase chain reaction-based next-generation sequencing method to analyze TJP2 gene variants in 267 PFIC patients and identified biallelic rare variants in three patients, including three known pathogenic variants and two novel variants in three patients. By using CRISPR-cas9 technology, we demonstrated that TJP2 c.1202A > G was pathogenic at least partially by increasing the expression and nuclear localization of TJP2 protein. With the minigene assay, we showed that TJP2 c.2668-11A > G was a new pathogenic variant by inducing abnormal splicing of TJP2 gene and translation of prematurely truncated TJP2 protein. Furthermore, knockdown of TJP2 protein by siRNA technology led to inhibition of cell proliferation, induction of apoptosis, dispersed F-actin, and disordered microfilaments in LO2 and HepG2celles. Global gene expression profiling of TJP2 knockdown LO2 cells and HepG2 cells identified the dysregulated genes involved in the regulation of actin cytoskeleton. Microtubule cytoskeleton genes were significantly downregulated in TJP2 knockdown cells. The results of this study demonstrate that TJP2 c.1202A > G and TJP2 c.2668-11A > G are two novel pathogenic variants and the cytoskeleton-related functions and pathways might be potential molecular pathogenesis for PFIC.
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Affiliation(s)
- Jia Tang
- NHC Key Laboratory of Male Reproduction and Genetics, Guangdong Provincial Reproductive Science Institute (Guangdong Provincial Fertility Hospital), Guangzhou, China
- Department of Medical Imaging Center, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
- Medical Genetics Center, Jiangmen Maternity and Child Health Care Hospital, Jiangmen, China
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
| | - Meihua Tan
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
- BGI Genomics Co., Ltd., Shenzhen, China
| | - Yihui Deng
- Department of Medical Imaging Center, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
| | - Hui Tang
- Department of Medical Imaging Center, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
| | - Haihong Shi
- Medical Genetics Center, Jiangmen Maternity and Child Health Care Hospital, Jiangmen, China
| | - Mingzhen Li
- NHC Key Laboratory of Male Reproduction and Genetics, Guangdong Provincial Reproductive Science Institute (Guangdong Provincial Fertility Hospital), Guangzhou, China
| | - Wei Ma
- Department of Biology, School of Basic Medicine, Jiamusi University, Jiamusi, China
| | - Jia Li
- BGI Genomics Co., Ltd., Shenzhen, China
| | - Hongzheng Dai
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
| | - Jianli Li
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
| | - Shengmei Zhou
- Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, Los Angeles, CA, United States
| | - Xu Li
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China
| | - Fengxiang Wei
- Longgang District Maternity & Child Healthcare Hospital of Shenzhen City, Shenzhen, China
| | - Xiaofen Ma
- Department of Medical Imaging of Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Liangping Luo
- Department of Medical Imaging Center, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
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Hariri H, St-Arnaud R. Expression and Role of Ubiquitin-Specific Peptidases in Osteoblasts. Int J Mol Sci 2021; 22:ijms22147746. [PMID: 34299363 PMCID: PMC8304380 DOI: 10.3390/ijms22147746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/12/2021] [Accepted: 07/16/2021] [Indexed: 11/16/2022] Open
Abstract
The ubiquitin-proteasome system regulates biological processes in normal and diseased states. Recent investigations have focused on ubiquitin-dependent modifications and their impacts on cellular function, commitment, and differentiation. Ubiquitination is reversed by deubiquitinases, including ubiquitin-specific peptidases (USPs), whose roles have been widely investigated. In this review, we explore recent findings highlighting the regulatory functions of USPs in osteoblasts and providing insight into the molecular mechanisms governing their actions during bone formation. We also give a brief overview of our work on USP53, a target of PTH in osteoblasts and a regulator of mesenchymal cell lineage fate decisions. Emerging evidence addresses questions pertaining to the complex layers of regulation exerted by USPs on osteoblast signaling. We provide a short overview of our and others' understanding of how USPs modulate osteoblastogenesis. However, further studies using knockout mouse models are needed to fully understand the mechanisms underpinning USPs actions.
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Affiliation(s)
- Hadla Hariri
- Research Centre, Shriners Hospital for Children, Montreal, QC H4A 0A9, Canada;
- Department of Human Genetics, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3A 0C7, Canada
| | - René St-Arnaud
- Research Centre, Shriners Hospital for Children, Montreal, QC H4A 0A9, Canada;
- Department of Human Genetics, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3A 0C7, Canada
- Department of Surgery, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3G 1A4, Canada
- Department of Medicine, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3A 1A1, Canada
- Correspondence: ; Tel.: +514-282-7155; Fax: +514-842-5581
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33
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Pham DH, Kudira R, Xu L, Valencia CA, Ellis JL, Shi T, Evason KJ, Osuji I, Matuschek N, Pfuhler L, Mullen M, Mohanty SK, Husami A, Bull LN, Zhang K, Wali S, Yin C, Miethke A. Deleterious Variants in ABCC12 are Detected in Idiopathic Chronic Cholestasis and Cause Intrahepatic Bile Duct Loss in Model Organisms. Gastroenterology 2021; 161:287-300.e16. [PMID: 33771553 PMCID: PMC8238842 DOI: 10.1053/j.gastro.2021.03.026] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 02/25/2021] [Accepted: 03/09/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS The etiology of cholestasis remains unknown in many children. We surveyed the genome of children with chronic cholestasis for variants in genes not previously associated with liver disease and validated their biological relevance in zebrafish and murine models. METHOD Whole-exome (n = 4) and candidate gene sequencing (n = 89) was completed on 93 children with cholestasis and normal serum γ-glutamyl transferase (GGT) levels without pathogenic variants in genes known to cause low GGT cholestasis such as ABCB11 or ATP8B1. CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 genome editing was used to induce frameshift pathogenic variants in the candidate gene in zebrafish and mice. RESULTS In a 1-year-old female patient with normal GGT cholestasis and bile duct paucity, we identified a homozygous truncating pathogenic variant (c.198delA, p.Gly67Alafs∗6) in the ABCC12 gene (NM_033226). Five additional rare ABCC12 variants, including a pathogenic one, were detected in our cohort. ABCC12 encodes multidrug resistance-associated protein 9 (MRP9) that belongs to the adenosine 5'-triphosphate-binding cassette transporter C family with unknown function and no previous implication in liver disease. Immunohistochemistry and Western blotting revealed conserved MRP9 protein expression in the bile ducts in human, mouse, and zebrafish. Zebrafish abcc12-null mutants were prone to cholangiocyte apoptosis, which caused progressive bile duct loss during the juvenile stage. MRP9-deficient mice had fewer well-formed interlobular bile ducts and higher serum alkaline phosphatase levels compared with wild-type mice. They exhibited aggravated cholangiocyte apoptosis, hyperbilirubinemia, and liver fibrosis upon cholic acid challenge. CONCLUSIONS Our work connects MRP9 with bile duct homeostasis and cholestatic liver disease for the first time. It identifies a potential therapeutic target to attenuate bile acid-induced cholangiocyte injury.
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Affiliation(s)
- Duc-Hung Pham
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Ramesh Kudira
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Lingfen Xu
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Pediatric Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, China
| | - C Alexander Valencia
- Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Department of Preclinical Education, Lake Erie College of Osteopathic Medicine, Erie, Pennsylvania
| | - Jillian L Ellis
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Tiffany Shi
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Kimberley J Evason
- Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
| | - Immaculeta Osuji
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Nelson Matuschek
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Liva Pfuhler
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Mary Mullen
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Sujit K Mohanty
- Department of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Ammar Husami
- Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Laura N Bull
- Liver Center Laboratory, Department of Medicine and Institute for Human Genetics, University of California, San Francisco, San Francisco, California
| | | | - Sami Wali
- Pediatric Gastroenterology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Chunyue Yin
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
| | - Alexander Miethke
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
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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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Squires RH, Monga SP. Progressive Familial Intrahepatic Cholestasis: Is It Time to Transition to Genetic Cholestasis? J Pediatr Gastroenterol Nutr 2021; 72:641-643. [PMID: 33661247 DOI: 10.1097/mpg.0000000000003111] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Affiliation(s)
- Robert H Squires
- Division of Gastroenterology, Hepatology, and Nutrition, School of Medicine, UPMC-Children's Hospital of Pittsburgh, University of Pittsburgh
| | - Satdarshan Pal Monga
- Pittsburgh Liver Research Center (PLRC), School of Medicine, University of Pittsburgh, Pittsburgh, PA
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A Link between Intrahepatic Cholestasis and Genetic Variations in Intracellular Trafficking Regulators. BIOLOGY 2021; 10:biology10020119. [PMID: 33557414 PMCID: PMC7914782 DOI: 10.3390/biology10020119] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/27/2021] [Accepted: 02/01/2021] [Indexed: 12/20/2022]
Abstract
Simple Summary Cholestasis refers to a medical condition in which the liver is not capable of secreting bile. The consequent accumulation of toxic bile components in the liver leads to liver failure. Cholestasis can be caused by mutations in genes that code for proteins involved in bile secretion. Recently mutations in other genes have been discovered in patients with cholestasis of unknown origin. Interestingly, many of these newly discovered genes code for proteins that regulate the intracellular distribution of other proteins, including those involved in bile secretion. This group of genes thus suggests the deregulated intracellular distribution of bile-secreting proteins as an important but still poorly understood mechanism that underlies cholestasis. To expedite a better understanding of this mechanism, we have reviewed these genes and their mutations and we discuss these in the context of cholestasis. Abstract Intrahepatic cholestasis is characterized by the accumulation of compounds in the serum that are normally secreted by hepatocytes into the bile. Genes associated with familial intrahepatic cholestasis (FIC) include ATP8B1 (FIC1), ABCB11 (FIC2), ABCB4 (FIC3), TJP2 (FIC4), NR1H4 (FIC5) and MYO5B (FIC6). With advanced genome sequencing methodologies, additional mutated genes are rapidly identified in patients presenting with idiopathic FIC. Notably, several of these genes, VPS33B, VIPAS39, SCYL1, and AP1S1, together with MYO5B, are functionally associated with recycling endosomes and/or the Golgi apparatus. These are components of a complex process that controls the sorting and trafficking of proteins, including those involved in bile secretion. These gene variants therefore suggest that defects in intracellular trafficking take a prominent place in FIC. Here we review these FIC-associated trafficking genes and their variants, their contribution to biliary transporter and canalicular protein trafficking, and, when perturbed, to cholestatic liver disease. Published variants for each of these genes have been summarized in table format, providing a convenient reference for those who work in the intrahepatic cholestasis field.
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Alhebbi H, Peer-Zada AA, Al-Hussaini AA, Algubaisi S, Albassami A, AlMasri N, Alrusayni Y, Alruzug IM, Alharby E, Samman MA, Ayoub SZ, Maddirevula S, Peake RWA, Alkuraya FS, Wali S, Almontashiri NAM. New paradigms of USP53 disease: normal GGT cholestasis, BRIC, cholangiopathy, and responsiveness to rifampicin. J Hum Genet 2020; 66:151-159. [PMID: 32759993 DOI: 10.1038/s10038-020-0811-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 06/15/2020] [Accepted: 07/14/2020] [Indexed: 02/07/2023]
Abstract
Biallelic variants in the USP53 gene have recently been reported to segregate with normal gamma glutamyltransferase (GGT) cholestasis. Using whole-exome sequencing (WES), we detected two USP53 homozygous variants (c.951delT; p. Phe317fs and c.1744C>T; p. Arg582*) in five additional cases, including an unpublished cousin of a previously described family with intractable itching and normal GGT cholestasis. Three patients, a child and two adults, presented with recurrent episodes of normal GGT cholestasis, consistent with a diagnosis of benign recurrent intrahepatic cholestasis (BRIC). Cholangiopathic changes, possibly autoimmune in origin, were recognized in some patients. Additional phenotypic details in one patient included an enlarged left kidney, and speech/developmental delay. Notably, two patients exhibited a complete response to rifampicin, and one responded to ursodeoxycholic acid (UDCA). Two adult patients were suspected to have autoimmune liver disease and treated with steroids. This report describes new cases of USP53 disease presenting with normal GGT cholestasis or BRIC in three children and two adults. We also describe the novel finding of a dramatic response to rifampicin. The association of cholangiopathy with normal GGT cholestasis provides a diagnostic challenge and remains poorly understood.
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Affiliation(s)
- Hamoud Alhebbi
- Department of Pediatrics, Division of Gastroenterology and Hepatology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Abdul Ali Peer-Zada
- Molecular Pathology, Pathology and Clinical Laboratory Medicine Administration, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Abdulrahman A Al-Hussaini
- Pediatric Gastroenterology Division, Children's Specialized Hospital at King Fahad Medical City, Riyadh, Saudi Arabia.,College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Sara Algubaisi
- Department of Pediatrics, Division of Gastroenterology and Hepatology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Awad Albassami
- Department of Pediatrics, Division of Gastroenterology and Hepatology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Nasser AlMasri
- Department of Adult Gastroenterology and Hepatology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Yasir Alrusayni
- Department of Pathology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Ibrahim M Alruzug
- Department of Adult Gastroenterology and Hepatology, King Saud Medical City, Riyadh, Saudi Arabia
| | - Essa Alharby
- Center for Genetics and Inherited Diseases, Taibah University, Almadinah Almunwarah, Saudi Arabia
| | - Manar A Samman
- Molecular Pathology, Pathology and Clinical Laboratory Medicine Administration, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Syed Zubair Ayoub
- Molecular Pathology, Pathology and Clinical Laboratory Medicine Administration, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Sateesh Maddirevula
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Roy W A Peake
- Department of Laboratory Medicine, Boston Children's Hospital, 300 Longwood Ave., Boston, MA, 02115, USA
| | - Fowzan S Alkuraya
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.,Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Sami Wali
- Department of Pediatrics, Division of Gastroenterology and Hepatology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
| | - Naif A M Almontashiri
- Center for Genetics and Inherited Diseases, Taibah University, Almadinah Almunwarah, Saudi Arabia. .,Faculty of Applied Medical Sciences, Taibah University, Almadinah Almunwarah, Saudi Arabia.
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