ArticleHepatology (Baltimore, Md.)2020
A Molecular Mechanism Underlying Genotype-Specific Intrahepatic Cholestasis Resulting From MYO5B Mutations.
Article in Hepatology (Baltimore, Md.), 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers, 1 of them a synthesis that pooled it.
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Who cites it
32 citing papers in PubMed, 1 synthesis or guideline pooled it, 51 citations in OpenAlex.
- Pooled it
- Integrated Bioinformatics Analysis Reveals the Impact of SHEV ORF3-Related LncRNA Network on Bile Secretion Pathway (ko 04976) in HepG2 Cells.Veterinary sciences · 2026Article
- Myosin 5b deficiency alters liver proliferation, zonation, and bile acid composition.Hepatology communications · 2026Article
- Microvillus inclusion disease-associated MYO5B deficiency impairs endosome-to-mitochondrion iron transfer.Gastroenterology report · 2026Article
- Comparative Analysis of Meat Quality and Muscle Transcriptome between Landrace and Jeju Native Pig.Food science of animal resources · 2025Article
- Clinical characteristics and genetic causes of unexplained pediatric liver disease.World journal of hepatology · 2025Article
- Alterations in the gut microbiota in individuals with infantile cholestasis: a comparison of high- and low-γ-glutamyltransferase subtypes.Translational pediatrics · 2025Article
- Odevixibat therapy in progressive familial intrahepatic cholestasis with MYO5B variants: a retrospective case series.Orphanet journal of rare diseases · 2025Article
- Cholestasis in hepatitis E virus infection.World journal of hepatology · 2025Article
- Case Report: A rare case of familial progressive cholestasis type 10 in an adult with heterozygous MYO5B variant.Frontiers in gastroenterology (Lausanne, Switzerland) · 2025Article
- Ionizing radiation leads to exosome secretion in macrophages through MYC-mediated pathways.PloS one · 2025Article
- Challenges in pediatric inherited/metabolic liver disease: Focus on the disease spectrum, diagnosis and management of relatively common disorders.World journal of gastroenterology · 2023Review
- [Clinical and genetic analysis of cases of progressive familial intrahepatic cholestasis type 3].Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology · 2023Article
- Genetic alterations and molecular mechanisms underlying hereditary intrahepatic cholestasis.Frontiers in pharmacology · 2023Review
- Gene Therapy for Acquired and Genetic Cholestasis.Biomedicines · 2022Review
- Article
- Case Report: A rare case of young adult progressive familial intrahepatic cholestasis-type 3 with a novel heterozygous pathogenic variant ofFrontiers in pediatrics · 2022Article
- Case Report:Frontiers in genetics · 2022Article
- [Clinical features, diagnosis, and treatment strategies of progressive familial intrahepatic cholestasis].Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology · 2021Article
- Article
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Authors and funding
11 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
BACKGROUND AND
aimsProgressive familial intrahepatic cholestasis (PFIC) 6 has been associated with missense but not biallelic nonsense or frameshift mutations in MYO5B, encoding the motor protein myosin Vb (myoVb). This genotype-phenotype correlation and the mechanism through which MYO5B mutations give rise to PFIC are not understood. The aim of this study was to determine whether the loss of myoVb or expression of patient-specific myoVb mutants can be causally related to defects in canalicular protein localization and, if so, through which mechanism. APPROACH AND
resultsWe demonstrate that the cholestasis-associated substitution of the proline at amino acid position 600 in the myoVb protein to a leucine (P660L) caused the intracellular accumulation of bile canalicular proteins in vesicular compartments. Remarkably, the knockout of MYO5B in vitro and in vivo produced no canalicular localization defects. In contrast, the expression of myoVb mutants consisting of only the tail domain phenocopied the effects of the Myo5b-P660L mutation. Using additional myoVb and rab11a mutants, we demonstrate that motor domain-deficient myoVb inhibited the formation of specialized apical recycling endosomes and that its disrupting effect on the localization of canalicular proteins was dependent on its interaction with active rab11a and occurred at the trans-Golgi Network/recycling endosome interface.
conclusionsOur results reveal a mechanism through which MYO5B motor domain mutations can cause the mislocalization of canalicular proteins in hepatocytes which, unexpectedly, does not involve myoVb loss-of-function but, as we propose, a rab11a-mediated gain-of-toxic function. The results explain why biallelic MYO5B mutations that affect the motor domain but not those that eliminate myoVb expression are associated with PFIC6.
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