{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T18:09:12Z","timestamp":1792001352832,"version":"4.4.0"},"reference-count":27,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2020,4,23]],"date-time":"2020-04-23T00:00:00Z","timestamp":1587600000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2020,7]]},"abstract":"<jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>\n                      Progressive familial intrahepatic cholestasis (PFIC) 6 has been associated with missense but not biallelic nonsense or frameshift mutations in\n                      <jats:italic toggle=\"yes\">MYO5B<\/jats:italic>\n                      , encoding the motor protein myosin Vb (myoVb). This genotype\u2010phenotype correlation and the mechanism through which\n                      <jats:italic toggle=\"yes\">MYO5B<\/jats:italic>\n                      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\u2010specific myoVb mutants can be causally related to defects in canalicular protein localization and, if so, through which mechanism.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Approach and Results<\/jats:title>\n                    <jats:p>\n                      We demonstrate that the cholestasis\u2010associated 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\n                      <jats:italic toggle=\"yes\">MYO5B<\/jats:italic>\n                      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\u2010P660L mutation. Using additional myoVb and rab11a mutants, we demonstrate that motor domain\u2010deficient 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\n                      <jats:italic toggle=\"yes\">trans<\/jats:italic>\n                      \u2010Golgi Network\/recycling endosome interface.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our results reveal a mechanism through which\n                      <jats:italic toggle=\"yes\">MYO5B<\/jats:italic>\n                      motor domain mutations can cause the mislocalization of canalicular proteins in hepatocytes which, unexpectedly, does not involve myoVb loss\u2010of\u2010function but, as we propose, a rab11a\u2010mediated gain\u2010of\u2010toxic function. The results explain why biallelic\n                      <jats:italic toggle=\"yes\">MYO5B<\/jats:italic>\n                      mutations that affect the motor domain but not those that eliminate\u00a0myoVb\u00a0expression are associated with PFIC6.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.31002","type":"journal-article","created":{"date-parts":[[2019,11,21]],"date-time":"2019-11-21T08:15:57Z","timestamp":1574324157000},"page":"213-229","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":55,"title":["A Molecular Mechanism Underlying Genotype\u2010Specific Intrahepatic Cholestasis Resulting From MYO5B Mutations"],"prefix":"10.1097","volume":"72","author":[{"given":"Arend W.","family":"Overeem","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences of Cells and Systems,Section Molecular Cell Biology,University of Groningen,University Medical Center Groningen,Groningen,the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinghong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences of Cells and Systems,Section Molecular Cell Biology,University of Groningen,University Medical Center Groningen,Groningen,the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi\u2010Ling","family":"Qiu","sequence":"additional","affiliation":[{"name":"The Center for Pediatric Liver Diseases,Children\u2019s Hospital of Fudan University,Shanghai,China"},{"name":"Department of Pediatrics,Jinshan Hospital of Fudan University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Cart\u00f3n\u2010Garc\u00eda","sequence":"additional","affiliation":[{"name":"Group of Biomedical Research in Digestive Tract Tumors,CIBBIM\u2010Nanomedicine,Vall d\u2019Hebron Research Institute (VHIR),Universitat Aut\u00f2noma de Barcelona (UAB),Barcelona,08035,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changsen","family":"Leng","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences of Cells and Systems,Section Molecular Cell Biology,University of Groningen,University Medical Center Groningen,Groningen,the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Klappe","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences of Cells and Systems,Section Molecular Cell Biology,University of Groningen,University Medical Center Groningen,Groningen,the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Just","family":"Dronkers","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences of Cells and Systems,Section Molecular Cell Biology,University of Groningen,University Medical Center Groningen,Groningen,the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nai\u2010Hua","family":"Hsiao","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences of Cells and Systems,Section Molecular Cell Biology,University of Groningen,University Medical Center Groningen,Groningen,the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian\u2010She","family":"Wang","sequence":"additional","affiliation":[{"name":"The Center for Pediatric Liver Diseases,Children\u2019s Hospital of Fudan University,Shanghai,China"},{"name":"Department of Pediatrics,Jinshan Hospital of Fudan University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Arango","sequence":"additional","affiliation":[{"name":"Group of Biomedical Research in Digestive Tract Tumors,CIBBIM\u2010Nanomedicine,Vall d\u2019Hebron Research Institute (VHIR),Universitat Aut\u00f2noma de Barcelona (UAB),Barcelona,08035,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven C.D.","family":"van Ijzendoorn","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences of Cells and Systems,Section Molecular Cell Biology,University of Groningen,University Medical Center Groningen,Groningen,the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2020,4,23]]},"reference":[{"key":"hep31002-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1016\/j.jhep.2015.06.015","article-title":"Structural and functional hepatocyte polarity and liver disease","volume":"63","year":"2015","journal-title":"J Hepatol"},{"key":"hep31002-bib-0002-20241017","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.cld.2018.06.003","article-title":"Progressive familial intrahepatic cholestasis","volume":"22","year":"2018","journal-title":"Clin Liver 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