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

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dc.contributor.author Qiu, Yi-Ling
dc.contributor.author Gong, Jing-Yu
dc.contributor.author Feng, Jia-Yan
dc.contributor.author Wang, Ren-Xue
dc.contributor.author Han, Jun
dc.contributor.author Liu, Teng
dc.contributor.author Lu, Yi
dc.contributor.author Li, Li-Ting
dc.contributor.author Zhang, Mei-Hong
dc.contributor.author Sheps, Jonathan A.
dc.contributor.author Wang, Neng-Li
dc.contributor.author Yan, Yan-Yan
dc.contributor.author Li, Jia-Qi
dc.contributor.author Chen, Lian
dc.contributor.author Borchers, Christoph H.
dc.contributor.author Sipos, Bence
dc.contributor.author Knisely, A. S.
dc.contributor.author Ling, Victor
dc.contributor.author Xing, Qing-He
dc.contributor.author Wang, Jian-She
dc.date.accessioned 2019-06-27T15:30:40Z
dc.date.available 2019-06-27T15:30:40Z
dc.date.copyright 2017 en_US
dc.date.issued 2017
dc.identifier.citation Qiu, 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.29020 en_US
dc.identifier.uri https://doi.org/10.1002/hep.29020
dc.identifier.uri http://hdl.handle.net/1828/10944
dc.description.abstract Hereditary 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.sponsorship Supported 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.language.iso en en_US
dc.publisher Hepatology en_US
dc.title Defects in Myosin VB are Associated with a Spectrum of Previously Undiagnosed Low γ-Glutamyltransferase Cholestasis en_US
dc.type Article en_US
dc.description.scholarlevel Faculty en_US
dc.description.reviewstatus Reviewed en_US


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