Defects in Myosin VB are Associated with a Spectrum of Previously Undiagnosed Low γ-Glutamyltransferase Cholestasis

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dc.contributor.authorQiu, Yi-Ling
dc.contributor.authorGong, Jing-Yu
dc.contributor.authorFeng, Jia-Yan
dc.contributor.authorWang, Ren-Xue
dc.contributor.authorHan, Jun
dc.contributor.authorLiu, Teng
dc.contributor.authorLu, Yi
dc.contributor.authorLi, Li-Ting
dc.contributor.authorZhang, Mei-Hong
dc.contributor.authorSheps, Jonathan A.
dc.contributor.authorWang, Neng-Li
dc.contributor.authorYan, Yan-Yan
dc.contributor.authorLi, Jia-Qi
dc.contributor.authorChen, Lian
dc.contributor.authorBorchers, Christoph H.
dc.contributor.authorSipos, Bence
dc.contributor.authorKnisely, A. S.
dc.contributor.authorLing, Victor
dc.contributor.authorXing, Qing-He
dc.contributor.authorWang, Jian-She
dc.date.accessioned2019-06-27T15:30:40Z
dc.date.available2019-06-27T15:30:40Z
dc.date.copyright2017en_US
dc.date.issued2017
dc.description.abstractHereditary cholestasis in childhood and infancy with normal serum gamma‐glutamyltransferase (GGT) activity is linked to several genes. Many patients, however, remain genetically undiagnosed. Defects in myosin VB (MYO5B; encoded by MYO5B) cause microvillus inclusion disease (MVID; MIM251850) with recurrent watery diarrhea. Cholestasis, reported as an atypical presentation in MVID, has been considered a side effect of parenteral alimentation. Here, however, we report on 10 patients who experienced cholestasis associated with biallelic, or suspected biallelic, mutations in MYO5B and who had neither recurrent diarrhea nor received parenteral alimentation. Seven of them are from two study cohorts, together comprising 31 undiagnosed low‐GGT cholestasis patients; 3 are sporadic. Cholestasis in 2 patients was progressive, in 3 recurrent, in 2 transient, and in 3 uncategorized because of insufficient follow‐up. Liver biopsy specimens revealed giant‐cell change of hepatocytes and intralobular cholestasis with abnormal distribution of bile salt export pump (BSEP) at canaliculi, as well as coarse granular dislocation of MYO5B. Mass spectrometry of plasma demonstrated increased total bile acids, primary bile acids, and conjugated bile acids, with decreased free bile acids, similar to changes in BSEP‐deficient patients. Literature review revealed that patients with biallelic mutations predicted to eliminate MYO5B expression were more frequent in typical MVID than in isolated‐cholestasis patients (11 of 38 vs. 0 of 13). Conclusion: MYO5B deficiency may underlie 20% of previously undiagnosed low‐GGT cholestasis. MYO5B deficiency appears to impair targeting of BSEP to the canalicular membrane with hampered bile acid excretion, resulting in a spectrum of cholestasis without diarrhea. (Hepatology 2017;65:1655‐1669).en_US
dc.description.reviewstatusRevieweden_US
dc.description.scholarlevelFacultyen_US
dc.description.sponsorshipSupported by the National Natural Science Foundation of China, grant numbers 81361128006 and 81570468 (to J.S.W.). The work was also supported by the Terry Fox Research Institute (grant to V.L.) and the Canadian Institutes of Health Research (grant to V.L. and R.W.); and by Genome Canada and Genome BC through the "Science and Technology Innovation Centre" (grant to C.H.B.).en_US
dc.identifier.citationQiu, Y.; Gong, J.; Feng, J.; Wang, R.; Han, J.; Liu, T.; … & Wang, J. (2017). Defects in myosin VB are associated with a spectrum of previously undiagnosed low γ-glutamyltransferase cholestasis. Hepatology, 65(5), 1655-1669. DOI: 10.1002/hep.29020en_US
dc.identifier.urihttps://doi.org/10.1002/hep.29020
dc.identifier.urihttp://hdl.handle.net/1828/10944
dc.language.isoenen_US
dc.publisherHepatologyen_US
dc.subject.departmentSchool of Medical Sciences
dc.subject.departmentDepartment of Biochemistry and Microbiology
dc.titleDefects in Myosin VB are Associated with a Spectrum of Previously Undiagnosed Low γ-Glutamyltransferase Cholestasisen_US
dc.typeArticleen_US

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