{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T22:26:11Z","timestamp":1789943171084,"version":"4.0.1"},"reference-count":24,"publisher":"American Diabetes Association","issue":"1","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2015,1,1]]},"abstract":"<jats:p>Perilipin 1 is a lipid droplet coat protein predominantly expressed in adipocytes, where it inhibits basal and facilitates stimulated lipolysis. Loss-of-function mutations in the PLIN1 gene were recently reported in patients with a novel subtype of familial partial lipodystrophy, designated as FPLD4. We now report the identification and characterization of a novel heterozygous frameshift mutation affecting the carboxy-terminus (439fs) of perilipin 1 in two unrelated families. The mutation cosegregated with a similar phenotype including partial lipodystrophy, severe insulin resistance and type 2 diabetes, extreme hypertriglyceridemia, and nonalcoholic fatty liver disease in both families. Poor metabolic control despite maximal medical therapy prompted two patients to undergo bariatric surgery, with remarkably beneficial consequences. Functional studies indicated that expression levels of the mutant protein were lower than wild-type protein, and in stably transfected preadipocytes the mutant protein was associated with smaller lipid droplets. Interestingly, unlike the previously reported 398 and 404 frameshift mutants, this variant binds and stabilizes ABHD5 expression but still fails to inhibit basal lipolysis as effectively as wild-type perilipin 1. Collectively, these findings highlight the physiological need for exquisite regulation of neutral lipid storage within adipocyte lipid droplets, as well as the possible metabolic benefits of bariatric surgery in this serious disease.<\/jats:p>","DOI":"10.2337\/db14-0104","type":"journal-article","created":{"date-parts":[[2014,8,12]],"date-time":"2014-08-12T00:26:49Z","timestamp":1407803209000},"page":"299-310","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":75,"title":["Clinical and Molecular Characterization of a Novel PLIN1 Frameshift Mutation Identified in Patients With Familial Partial Lipodystrophy"],"prefix":"10.2337","volume":"64","author":[{"given":"Kristina","family":"Kozusko","sequence":"first","affiliation":[{"name":"University of Cambridge Metabolic Research Laboratories, Wellcome Trust\u2013Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Venessa H.M.","family":"Tsang","sequence":"additional","affiliation":[{"name":"Diabetes Centre and Department of Endocrinology, St Vincent\u2019s Hospital, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Bottomley","sequence":"additional","affiliation":[{"name":"Wellcome Trust Sanger Institute, University of Cambridge, Hinxton, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoon-Hi","family":"Cho","sequence":"additional","affiliation":[{"name":"Institute of Endocrinology and Diabetes, The Children\u2019s Hospital at Westmead, Sydney, Australia"},{"name":"Discipline of Paediatrics and Child Health, The Children\u2019s Hospital at Westmead Clinical School, University of Sydney, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheetal","family":"Gandotra","sequence":"additional","affiliation":[{"name":"Council of Scientific and Industrial Research-Institute of Genomics & Integrative Biology, New Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Mimmack","sequence":"additional","affiliation":[{"name":"University of Cambridge Metabolic Research Laboratories, Wellcome Trust\u2013Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koini","family":"Lim","sequence":"additional","affiliation":[{"name":"University of Cambridge Metabolic Research Laboratories, Wellcome Trust\u2013Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iona","family":"Isaac","sequence":"additional","affiliation":[{"name":"University of Cambridge Metabolic Research Laboratories, Wellcome Trust\u2013Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satish","family":"Patel","sequence":"additional","affiliation":[{"name":"University of Cambridge Metabolic Research Laboratories, Wellcome Trust\u2013Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir","family":"Saudek","sequence":"additional","affiliation":[{"name":"University of Cambridge Metabolic Research Laboratories, Wellcome Trust\u2013Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"O\u2019Rahilly","sequence":"additional","affiliation":[{"name":"University of Cambridge Metabolic Research Laboratories, Wellcome Trust\u2013Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shubha","family":"Srinivasan","sequence":"additional","affiliation":[{"name":"Institute of Endocrinology and Diabetes, The Children\u2019s Hospital at Westmead, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerry R.","family":"Greenfield","sequence":"additional","affiliation":[{"name":"Diabetes Centre and Department of Endocrinology, St Vincent\u2019s Hospital, Sydney, Australia"},{"name":"Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ines","family":"Barroso","sequence":"additional","affiliation":[{"name":"Wellcome Trust Sanger Institute, University of Cambridge, Hinxton, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lesley V.","family":"Campbell","sequence":"additional","affiliation":[{"name":"Diabetes Centre and Department of Endocrinology, St Vincent\u2019s Hospital, Sydney, Australia"},{"name":"Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David B.","family":"Savage","sequence":"additional","affiliation":[{"name":"University of Cambridge Metabolic Research Laboratories, Wellcome Trust\u2013Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2014,8,11]]},"reference":[{"key":"2022031223461746300_B1","first-page":"419","article-title":"PAT proteins, an ancient family of lipid droplet proteins that regulate cellular lipid stores. Biochim Biophys Acta","volume":"1791","author":"Bickel","year":"2009"},{"key":"2022031223461746300_B2","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.cmet.2011.12.018","article-title":"FAT SIGNALS\u2014lipases and lipolysis in lipid metabolism and signaling","volume":"15","author":"Zechner","year":"2012","journal-title":"Cell Metab"},{"key":"2022031223461746300_B3","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1056\/NEJMoa1007487","article-title":"Perilipin deficiency and autosomal dominant partial lipodystrophy","volume":"364","author":"Gandotra","year":"2011","journal-title":"N Engl J Med"},{"key":"2022031223461746300_B4","doi-asserted-by":"crossref","first-page":"34998","DOI":"10.1074\/jbc.M111.278853","article-title":"Human frame shift mutations affecting the carboxyl terminus of perilipin increase lipolysis by failing to sequester the adipose triglyceride lipase (ATGL) coactivator AB-hydrolase-containing 5 (ABHD5)","volume":"286","author":"Gandotra","year":"2011","journal-title":"J Biol Chem"},{"key":"2022031223461746300_B5","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/S1262-3636(07)70227-6","article-title":"Etiological investigations in apparent type 2 diabetes: when to search for lamin A\/C mutations","volume":"31","author":"Donadille","year":"2005","journal-title":"Diabetes Metab"},{"key":"2022031223461746300_B6"},{"key":"2022031223461746300_B7","doi-asserted-by":"crossref","first-page":"6494","DOI":"10.1073\/pnas.101042998","article-title":"Perilipin ablation results in a lean mouse with aberrant adipocyte lipolysis, enhanced leptin production, and resistance to diet-induced obesity","volume":"98","author":"Tansey","year":"2001","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022031223461746300_B8","first-page":"83","article-title":"Degradation of perilipin is mediated through ubiquitination-proteasome pathway. Biochim Biophys Acta","volume":"1761","author":"Xu","year":"2006"},{"key":"2022031223461746300_B9","doi-asserted-by":"crossref","first-page":"9378","DOI":"10.1074\/jbc.272.14.9378","article-title":"Post-translational regulation of perilipin expression. Stabilization by stored intracellular neutral lipids","volume":"272","author":"Brasaemle","year":"1997","journal-title":"J Biol Chem"},{"key":"2022031223461746300_B10","doi-asserted-by":"crossref","first-page":"21704","DOI":"10.1074\/jbc.M702223200","article-title":"Regulation of adipocyte lipolysis by degradation of the perilipin protein: nelfinavir enhances lysosome-mediated perilipin proteolysis","volume":"282","author":"Kovsan","year":"2007","journal-title":"J Biol Chem"},{"key":"2022031223461746300_B11","doi-asserted-by":"crossref","first-page":"8409","DOI":"10.1074\/jbc.M311198200","article-title":"The amino and carboxyl termini of perilipin a facilitate the storage of triacylglycerols","volume":"279","author":"Garcia","year":"2004","journal-title":"J Biol Chem"},{"key":"2022031223461746300_B12","doi-asserted-by":"crossref","first-page":"38486","DOI":"10.1074\/jbc.M007322200","article-title":"Perilipin A increases triacylglycerol storage by decreasing the rate of triacylglycerol hydrolysis","volume":"275","author":"Brasaemle","year":"2000","journal-title":"J Biol Chem"},{"key":"2022031223461746300_B13","doi-asserted-by":"crossref","first-page":"42062","DOI":"10.1074\/jbc.M407462200","article-title":"Perilipin A mediates the reversible binding of CGI-58 to lipid droplets in 3T3-L1 adipocytes","volume":"279","author":"Subramanian","year":"2004","journal-title":"J Biol Chem"},{"key":"2022031223461746300_B14","first-page":"507","article-title":"Lipodystrophies: disorders of adipose tissue biology. Biochim Biophys Acta","volume":"1791","author":"Garg","year":"2009"},{"key":"2022031223461746300_B15","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1152\/physrev.00024.2006","article-title":"Disordered lipid metabolism and the pathogenesis of insulin resistance","volume":"87","author":"Savage","year":"2007","journal-title":"Physiol Rev"},{"key":"2022031223461746300_B16","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1016\/j.biocel.2011.03.002","article-title":"Molecular mechanisms of human lipodystrophies: from adipocyte lipid droplet to oxidative stress and lipotoxicity","volume":"43","author":"Vigouroux","year":"2011","journal-title":"Int J Biochem Cell Biol"},{"key":"2022031223461746300_B17","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1677\/JOE-10-0272","article-title":"Lipodystrophy: metabolic insights from a rare disorder","volume":"207","author":"Huang-Doran","year":"2010","journal-title":"J Endocrinol"},{"key":"2022031223461746300_B18","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1002\/emmm.200900037","article-title":"Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC","volume":"1","author":"Rubio-Cabezas","year":"2009","journal-title":"EMBO Mol Med"},{"key":"2022031223461746300_B19","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1111\/j.1365-2265.2011.04057.x","article-title":"Successful treatment for the Dunnigan-type familial partial lipodystrophy with Roux-en-Y gastric bypass","volume":"75","author":"Ciudin","year":"2011","journal-title":"Clin Endocrinol (Oxf)"},{"key":"2022031223461746300_B20","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1381\/096089206778869988","article-title":"Gastric bypass for insulin resistance due to lipodystrophy","volume":"16","author":"McGrath","year":"2006","journal-title":"Obes Surg"},{"key":"2022031223461746300_B21","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.2337\/dc06-0130","article-title":"Effectiveness of gastric bypass surgery in a patient with familial partial lipodystrophy","volume":"29","author":"Utzschneider","year":"2006","journal-title":"Diabetes Care"},{"key":"2022031223461746300_B22","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1111\/eci.12162","article-title":"The effect of bariatric surgery on echocardiographic indices: a review of the literature","volume":"43","author":"Grapsa","year":"2013","journal-title":"Eur J Clin Invest"},{"key":"2022031223461746300_B23","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/j.jmb.2005.08.020","article-title":"Loss of protein structure stability as a major causative factor in monogenic disease","volume":"353","author":"Yue","year":"2005","journal-title":"J Mol Biol"},{"key":"2022031223461746300_B24","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1038\/82630","article-title":"Absence of perilipin results in leanness and reverses obesity in Lepr(db\/db) mice","volume":"26","author":"Martinez-Botas","year":"2000","journal-title":"Nat Genet"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/64\/1\/299\/576397\/299.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/64\/1\/299\/576397\/299.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,1]],"date-time":"2024-06-01T05:48:41Z","timestamp":1717220921000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/64\/1\/299\/34722\/Clinical-and-Molecular-Characterization-of-a-Novel"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,8,11]]},"references-count":24,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2014,8,11]]},"published-print":{"date-parts":[[2015,1,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db14-0104","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,8,11]]}}}