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Yang H, Lin SZ, Guan SH, Wang WQ, Li JY, Yang GD, Zhang SL. Two novel mutations in the VPS33B gene in a Chinese patient with arthrogryposis, renal dysfunction and cholestasis syndrome 1: A case report. World J Clin Cases 2022; 10:11016-11022. [PMID: 36338198 PMCID: PMC9631127 DOI: 10.12998/wjcc.v10.i30.11016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 07/27/2022] [Accepted: 09/14/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The VPS33B (OMIM: 608552) gene is located on chromosome 15q26.1. We found a female infant with autosomal recessive arthrogryposis, renal dysfunction and cholestasis syndrome 1 (ARCS1) caused by mutation in VPS33B. The child was diagnosed with ARCS1 (OMIM: 208085) after the whole exome sequencing revealed two heterozygous mutations (c.96+1G>C, c.242delT) in the VPS33B gene.
CASE SUMMARY We report a Chinese female infant with neonatal cholestasis disorder, who was eventually diagnosed with ARCS1 by genetic analysis. Genetic testing revealed two new mutations (c.96+1G>C and c.242delT) in VPS33B, which is the causal gene. The patient was compound heterozygous, and her parents were both heterozygous.
CONCLUSION This study extends the mutational spectrum of the VPS33B gene to provide a molecular basis for the etiological diagnosis of ARCS1 and for genetic counseling of the family.
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Affiliation(s)
- Hui Yang
- Department of Neonatology, Hainan Women and Children's Medical Center, Haikou 570100, Hainan Province, China
| | - Shuang-Zhu Lin
- Diagnosis and Treatment Center for Children, The First Affiliated Hospital to Changchun University of Chinese Medicine, Changchun 130021, Jilin Province, China
| | - Shi-Hui Guan
- Diagnosis and Treatment Center for Children, The First Affiliated Hospital to Changchun University of Chinese Medicine, Changchun 130021, Jilin Province, China
| | - Wan-Qi Wang
- Changchun University of Chinese Medicine, Changchun 130000, Jilin Province, China
| | - Jia-Yi Li
- Changchun University of Chinese Medicine, Changchun 130000, Jilin Province, China
| | - Gui-Dan Yang
- Department of Neonatology, Hainan Women and Children's Medical Center, Haikou 570100, Hainan Province, China
| | - Su-Li Zhang
- Department of Neonatology, Hainan Women and Children's Medical Center, Haikou 570100, Hainan Province, China
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Quelhas P, Jacinto J, Cerski C, Oliveira R, Oliveira J, Carvalho E, dos Santos J. Protocols of Investigation of Neonatal Cholestasis-A Critical Appraisal. Healthcare (Basel) 2022; 10:2012. [PMID: 36292464 PMCID: PMC9602084 DOI: 10.3390/healthcare10102012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/06/2022] [Accepted: 10/08/2022] [Indexed: 11/04/2022] Open
Abstract
Neonatal cholestasis (NC) starts during the first three months of life and comprises extrahepatic and intrahepatic groups of diseases, some of which have high morbimortality rates if not timely identified and treated. Prolonged jaundice, clay-colored or acholic stools, and choluria in an infant indicate the urgent need to investigate the presence of NC, and thenceforth the differential diagnosis of extra- and intrahepatic causes of NC. The differential diagnosis of NC is a laborious process demanding the accurate exclusion of a wide range of diseases, through the skillful use and interpretation of several diagnostic tests. A wise integration of clinical-laboratory, histopathological, molecular, and genetic evaluations is imperative, employing extensive knowledge about each evaluated disease as well as the pitfalls of each diagnostic test. Here, we review the difficulties involved in correctly diagnosing the cause of cholestasis in an affected infant.
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Affiliation(s)
- Patricia Quelhas
- Faculty of Health Sciences, Health Science Investigation Center of University of Beira Interior (CICS-UBI), 6200-506 Covilha, Portugal
| | - Joana Jacinto
- Medicine Department, University of Beira Interior (UBI), Faculty of Health Sciences, 6201-001 Covilha, Portugal
| | - Carlos Cerski
- Pathology Department of Universidade Federal do Rio Grande do Sul (UFRGS), Pathology Service of Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre 90035-903, Brazil
| | - Rui Oliveira
- Centro de Diagnóstico Histopatológico (CEDAP), 3000-377 Coimbra, Portugal
| | - Jorge Oliveira
- Center for Predictive and Preventive Genetics (CGPP), IBMC, UnIGENe, i3S, University of Porto, 4200-135 Porto, Portugal
| | - Elisa Carvalho
- Department of Gastroenterology and Hepatology, Hospital de Base do Distrito Federal, Hospital da Criança de Brasília, Brasília 70330-150, Brazil
| | - Jorge dos Santos
- Faculty of Health Sciences, Health Science Investigation Center of University of Beira Interior (CICS-UBI), 6200-506 Covilha, Portugal
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Adamczyk-Gruszka O, Horecka-Lewitowicz A, Zmelonek-Znamirowska A, Gruszka J, Koziel D, Lewitowicz P. A New Aberration in the VPS33B Gene Leads to Full-Symptom ARCS1. AMERICAN JOURNAL OF CASE REPORTS 2021; 22:e932769. [PMID: 34531360 PMCID: PMC8455109 DOI: 10.12659/ajcr.932769] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 08/06/2021] [Accepted: 07/02/2021] [Indexed: 11/09/2022]
Abstract
BACKGROUND ARCS1 is an acronym for arthrogryposis, renal dysfunction, and cholestasis. It is a congenital malfunction with autosomal recessive inheritance, and, unfortunately, its prognosis is still poor. It is believed that VPS33B is altered in 75% of cases and that the VIPAR gene is altered in approximately 25% of them. CASE REPORT An affected child was born from the first pregnancy of 26-year-old mother and a 30-year-old father with no previous medical history and no genetic conditions. The first clinical symptoms were observed at the end of the child's second week of life. The mother reported the child has decreasing body weight and loss of appetite. After admission to the ward, the child was apathetic and sleepy. Symptoms of conjunctivitis, pale and dry skin, and mild face and mild body dysmorphia were observed. CONCLUSIONS Laboratory tests revealed proteinuria of up to 1.36 g/l and glycosuria of up to 28 mmol/l, as well as fluctuating metabolic acidosis. The bilirubin level reached 6.62 mg/dl, along with alkaline phosphatase at 470 U/l. Moreover, hypothyroidism with TSH at 16.71 uU/ml was observed. Because of the co-occurrence of cholestasis and renal dysfunction, molecular testing was done. The 17th exon of VPS33B was sequenced by Sanger DNA sequencing method. To the best of our knowledge, this is the first report of homozygotic mutation c.1235_1236delinsG (p.Pro412ArgfsTer7) in the VPS33B gene. The risk of transfer of the mutation to future descendants was calculated as 25%. Due to the wide landscape of molecular alternation in the 17th exon of the VPS33B gene, we propose using Sanger whole-exon sequencing as a first-choice diagnostic test.
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Affiliation(s)
- Olga Adamczyk-Gruszka
- Department of Gynaecology and Obstetrics, Institute of Medical Sciences, Jan Kochanowski University, Kielce, Poland
- Department of Obstetrics and Gynecology, Province Hospital, Kielce, Poland
| | - Agata Horecka-Lewitowicz
- Department of Clinical Psychology and Psychiatry, Institute of Health Sciences, Jan Kochanowski University, Kielce, Poland
| | - Anna Zmelonek-Znamirowska
- Department of Gynaecology and Obstetrics, Institute of Medical Sciences, Jan Kochanowski University, Kielce, Poland
| | - Jakub Gruszka
- 2 Department of Obstetrics and Gynaecology, Medical University of Warsaw,Warsaw, Poland
| | - Dorota Koziel
- Institute of Health Sciences, Jan Kochanowski University, Kielce, Poland
| | - Piotr Lewitowicz
- Department of Clinical and Experimental Pathology, Institute of Medical Sciences, Jan Kochanowski University, Kielce, Poland
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Lee MJ, Suh CR, Shin JH, Lee JH, Lee Y, Eun BL, Yoo KH, Shim JO. A Novel VPS33B Variant Identified by Exome Sequencing in a Patient with Arthrogryposis-Renal Dysfunction-Cholestasis Syndrome. Pediatr Gastroenterol Hepatol Nutr 2019; 22:581-587. [PMID: 31777725 PMCID: PMC6856508 DOI: 10.5223/pghn.2019.22.6.581] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 08/31/2019] [Indexed: 11/15/2022] Open
Abstract
Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a rare autosomal recessive multisystemic disease that is associated with the liver, kidney, skin, and central nervous and musculoskeletal systems. ARC occurs as a result of mutations in the VPS33B (Vacuolar protein sorting 33 homolog B) or VIPAR (VPS33B interacting protein, apical-basolateral polarity regulator) genes. A female infant presented with neonatal cholestasis with a severe clinical outcome. She was diagnosed with ARC syndrome using targeted exome sequencing (TES). Exome sequencing revealed compound heterozygous mutations, c.707A>T and c.239+5G>A, in VPS33B, where c.707A>T was a novel variant; the resultant functional protein defects were predicted via in silico analysis. c.239+5G>A, a pathogenic mutation that affects splicing, is found in less than 0.1% of the general population. Invasive techniques, such as liver biopsies, did not contribute to a differential diagnosis of ARC syndrome; thus, early TES together with clinical presentations constituted an apparently accurate diagnostic procedure.
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Affiliation(s)
- Min Ju Lee
- Department of Pediatrics, Korea University College of Medicine, Seoul, Korea
| | - Chae Ri Suh
- Department of Pediatrics, Korea University College of Medicine, Seoul, Korea
| | - Jeong Hee Shin
- Department of Pediatrics, Korea University College of Medicine, Seoul, Korea
| | - Jee Hyun Lee
- Department of Pediatrics, Korea University College of Medicine, Seoul, Korea
| | - Yoon Lee
- Department of Pediatrics, Korea University College of Medicine, Seoul, Korea
| | - Baik-Lin Eun
- Department of Pediatrics, Korea University College of Medicine, Seoul, Korea
| | - Kee Hwan Yoo
- Department of Pediatrics, Korea University College of Medicine, Seoul, Korea
| | - Jung Ok Shim
- Department of Pediatrics, Korea University College of Medicine, Seoul, Korea
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van der Beek J, Jonker C, van der Welle R, Liv N, Klumperman J. CORVET, CHEVI and HOPS – multisubunit tethers of the endo-lysosomal system in health and disease. J Cell Sci 2019; 132:132/10/jcs189134. [DOI: 10.1242/jcs.189134] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
ABSTRACT
Multisubunit tethering complexes (MTCs) are multitasking hubs that form a link between membrane fusion, organelle motility and signaling. CORVET, CHEVI and HOPS are MTCs of the endo-lysosomal system. They regulate the major membrane flows required for endocytosis, lysosome biogenesis, autophagy and phagocytosis. In addition, individual subunits control complex-independent transport of specific cargoes and exert functions beyond tethering, such as attachment to microtubules and SNARE activation. Mutations in CHEVI subunits lead to arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome, while defects in CORVET and, particularly, HOPS are associated with neurodegeneration, pigmentation disorders, liver malfunction and various forms of cancer. Diseases and phenotypes, however, vary per affected subunit and a concise overview of MTC protein function and associated human pathologies is currently lacking. Here, we provide an integrated overview on the cellular functions and pathological defects associated with CORVET, CHEVI or HOPS proteins, both with regard to their complexes and as individual subunits. The combination of these data provides novel insights into how mutations in endo-lysosomal proteins lead to human pathologies.
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Affiliation(s)
- Jan van der Beek
- Section Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Institute for Biomembranes, Utrecht University, Utrecht 3584 CX, The Netherlands
| | - Caspar Jonker
- Section Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Institute for Biomembranes, Utrecht University, Utrecht 3584 CX, The Netherlands
| | - Reini van der Welle
- Section Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Institute for Biomembranes, Utrecht University, Utrecht 3584 CX, The Netherlands
| | - Nalan Liv
- Section Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Institute for Biomembranes, Utrecht University, Utrecht 3584 CX, The Netherlands
| | - Judith Klumperman
- Section Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Institute for Biomembranes, Utrecht University, Utrecht 3584 CX, The Netherlands
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Fu K, Wang C, Gao Y, Fan S, Zhang H, Sun J, Jiang Y, Liu C, Guan L, Liu J, Huang M, Bi H. Metabolomics and Lipidomics Reveal the Effect of Hepatic Vps33b Deficiency on Bile Acids and Lipids Metabolism. Front Pharmacol 2019; 10:276. [PMID: 30967781 PMCID: PMC6439481 DOI: 10.3389/fphar.2019.00276] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 03/04/2019] [Indexed: 12/16/2022] Open
Abstract
Vascular protein sorting-associated protein 33B (VPS33B) plays important roles in hepatic polarity, which directly maintains the functional structure of the liver. It has reported that VPS33B has close association with arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome. Unfortunately, no further studies were conducted to reveal the role of Vps33b in the homeostasis of bile acids. In the current study, hepatic Vps33b-depleted male mice were used to investigate the metabolomics and lipidomics profiles of hepatic Vps33b deficiency based on ultrahigh-performance liquid chromatography coupled with an electrospray ionization high-resolution mass spectrometry (UHPLC-ESI-HRMS) system. Hepatic Vps33b-depleted male mice displayed cholestasis and slight liver damage with increased serum levels of ALT, AST, ALP and T-Bili compared to wild-type mice. Targeted metabolomics analysis of bile acids revealed that increased taurine-conjugated bile acids accumulated in the serum of hepatic Vps33b-depleted mice, while unconjugated bile acids were prone to decrease, accompanied by the regulation of bile acid homeostasis-related genes. In addition, lipid profiles were significantly altered with the lack of Vps33b in the liver. A variety of lipids, such as triglycerides and sphingomyelins, were significantly decreased in the liver and increased in the serum of hepatic Vps33b-depleted mice compared to those in wild-type mice. Our study demonstrated that Vps33b influences the progress of liver metabolism both in bile acid circulation and lipid metabolism, which is involved in the progression of liver cholestasis in mice.
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Affiliation(s)
- Kaili Fu
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Conghui Wang
- Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yue Gao
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Shicheng Fan
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Huizhen Zhang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Jiahong Sun
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Yiming Jiang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Conghui Liu
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Lihuan Guan
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Junling Liu
- Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min Huang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Huichang Bi
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
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