{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T11:15:19Z","timestamp":1790680519300,"version":"4.1.0"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2018,3,24]],"date-time":"2018-03-24T00:00:00Z","timestamp":1521849600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2018,3,24]],"date-time":"2018-03-24T00:00:00Z","timestamp":1521849600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2018,5]]},"abstract":"<jats:p>Nonalcoholic fatty liver disease (NAFLD) is becoming the major chronic liver disease in many countries. Its pathogenesis is multifactorial, but twin and familial studies indicate significant heritability, which is not fully explained by currently known genetic susceptibility loci. Notably, mutations in genes encoding nuclear lamina proteins, including lamins, cause lipodystrophy syndromes that include NAFLD. We hypothesized that variants in lamina\u2010associated proteins predispose to NAFLD and used a candidate gene\u2010sequencing approach to test for variants in 10 nuclear lamina\u2010related genes in a cohort of 37 twin and sibling pairs: 21 individuals with and 53 without NAFLD. Twelve heterozygous sequence variants were identified in four lamina\u2010related genes (<jats:italic toggle=\"yes\">ZMPSTE24<\/jats:italic>, <jats:italic toggle=\"yes\">TMPO<\/jats:italic>, <jats:italic toggle=\"yes\">SREBF1<\/jats:italic>, <jats:italic toggle=\"yes\">SREBF2<\/jats:italic>). The majority of NAFLD patients (&gt;90%) had at least one variant compared to &lt;40% of controls (<jats:italic toggle=\"yes\">P<\/jats:italic> &lt; 0.0001). When only insertions\/deletions and changes in conserved residues were considered, the difference between the groups was similarly striking (&gt;80% versus &lt;25%; <jats:italic toggle=\"yes\">P<\/jats:italic> &lt; 0.0001). Presence of a lamina variant segregated with NAFLD independently of the <jats:italic toggle=\"yes\">PNPLA3<\/jats:italic> I148M polymorphism. Several variants were found in <jats:italic toggle=\"yes\">TMPO<\/jats:italic>, which encodes the lamina\u2010associated polypeptide\u20102 (LAP2) that has not been associated with liver disease. One of these, a frameshift insertion that generates truncated LAP2, abrogated lamin\u2013LAP2 binding, caused LAP2 mislocalization, altered endogenous lamin distribution, increased lipid droplet accumulation after oleic acid treatment in transfected cells, and led to cytoplasmic association with the ubiquitin\u2010binding protein p62\/SQSTM1. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> Several variants in nuclear lamina\u2010related genes were identified in a cohort of twins and siblings with NAFLD; one such variant, which results in a truncated LAP2 protein and a dramatic phenotype in cell culture, represents an association of <jats:italic toggle=\"yes\">TMPO<\/jats:italic>\/LAP2 variants with NAFLD and underscores the potential importance of the nuclear lamina in NAFLD. (H<jats:sc>epatology<\/jats:sc> 2018;67:1710\u20101725).<\/jats:p>","DOI":"10.1002\/hep.29522","type":"journal-article","created":{"date-parts":[[2017,9,13]],"date-time":"2017-09-13T13:46:43Z","timestamp":1505310403000},"page":"1710-1725","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":28,"title":["Nuclear lamina genetic variants, including a truncated LAP2, in twins and siblings with nonalcoholic fatty liver disease"],"prefix":"10.1097","volume":"67","author":[{"given":"Graham F.","family":"Brady","sequence":"first","affiliation":[{"name":"Department of Molecular and Integrative Physiology and Department of Internal Medicine,University of Michigan,Ann Arbor,MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond","family":"Kwan","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology and Department of Internal Medicine,University of Michigan,Ann Arbor,MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Ulintz","sequence":"additional","affiliation":[{"name":"Department of Computational Medicine and Bioinformatics,University of Michigan,Ann Arbor,MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phirum","family":"Nguyen","sequence":"additional","affiliation":[{"name":"NAFLD Research Center, Division of Gastroenterology, Department of Medicine,University of California,San Diego,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shirin","family":"Bassirian","sequence":"additional","affiliation":[{"name":"NAFLD Research Center, Division of Gastroenterology, Department of Medicine,University of California,San Diego,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Venkatesha","family":"Basrur","sequence":"additional","affiliation":[{"name":"Department of Pathology,University of Michigan,Ann Arbor,MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexey I.","family":"Nesvizhskii","sequence":"additional","affiliation":[{"name":"Department of Computational Medicine and Bioinformatics,University of Michigan,Ann Arbor,MI"},{"name":"Department of Pathology,University of Michigan,Ann Arbor,MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohit","family":"Loomba","sequence":"additional","affiliation":[{"name":"NAFLD Research Center, Division of Gastroenterology, Department of Medicine,University of California,San Diego,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Bishr","family":"Omary","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology and Department of Internal Medicine,University of Michigan,Ann Arbor,MI"},{"name":"\u00c5bo Akademi University,Turku,Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2018,3,24]]},"reference":[{"key":"hep29522-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1002\/hep.25762","article-title":"The diagnosis and management of non\u2010alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association","volume":"55","year":"2012","journal-title":"Hepatology"},{"key":"hep29522-bib-0002-20241017","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1038\/nrgastro.2013.183","article-title":"NAFLD, NASH and liver 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