{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T04:13:26Z","timestamp":1791000806531,"version":"4.1.0"},"reference-count":16,"publisher":"American Diabetes Association","issue":"6","license":[{"start":{"date-parts":[[2018,5,21]],"date-time":"2018-05-21T00:00:00Z","timestamp":1526860800000},"content-version":"vor","delay-in-days":46,"URL":"http:\/\/www.diabetesjournals.org\/content\/license"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["WT107064"],"award-info":[{"award-number":["WT107064"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2018,6,1]]},"abstract":"<jats:p>Loss-of-function mutations in PPARG cause familial partial lipodystrophy type 3 (FPLD3) and severe metabolic disease in many patients. Missense mutations in PPARG are present in \u223c1 in 500 people. Although mutations are often binarily classified as benign or deleterious, prospective functional classification of all missense PPARG variants suggests that their impact is graded. Furthermore, in testing novel mutations with both prototypic endogenous (e.g., prostaglandin J2 [PGJ2]) and synthetic ligands (thiazolidinediones, tyrosine agonists), we observed that synthetic agonists selectively rescue function of some peroxisome proliferator\u2013activated receptor-\u03b3 (PPAR\u03b3) mutants. We report on patients with FPLD3 who harbor two such PPAR\u03b3 mutations (R308P and A261E). Both PPAR\u03b3 mutants exhibit negligible constitutive or PGJ2-induced transcriptional activity but respond readily to synthetic agonists in vitro, with structural modeling providing a basis for such differential ligand-dependent responsiveness. Concordant with this finding, dramatic clinical improvement was seen after pioglitazone treatment of a patient with R308P mutant PPAR\u03b3. A patient with A261E mutant PPAR\u03b3 also responded beneficially to rosiglitazone, although cardiomyopathy precluded prolonged thiazolidinedione use. These observations indicate that detailed structural and functional classification can be used to inform therapeutic decisions in patients with PPARG mutations.<\/jats:p>","DOI":"10.2337\/db17-1236","type":"journal-article","created":{"date-parts":[[2018,4,5]],"date-time":"2018-04-05T14:00:20Z","timestamp":1522936820000},"page":"1086-1092","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":48,"title":["A Pharmacogenetic Approach to the Treatment of Patients With <i>PPARG<\/i> Mutations"],"prefix":"10.2337","volume":"67","author":[{"given":"Maura","family":"Agostini","sequence":"first","affiliation":[{"name":"The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, U.K."},{"name":"The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Schoenmakers","sequence":"additional","affiliation":[{"name":"The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junaid","family":"Beig","sequence":"additional","affiliation":[{"name":"Greenlane Diabetes Centre, Auckland Hospital, Auckland, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Fairall","sequence":"additional","affiliation":[{"name":"Leicester Institute of Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicester, Leicester, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Istvan","family":"Szatmari","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Odelia","family":"Rajanayagam","sequence":"additional","affiliation":[{"name":"The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, U.K."},{"name":"The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick W.","family":"Muskett","sequence":"additional","affiliation":[{"name":"Leicester Institute of Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicester, Leicester, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Adams","sequence":"additional","affiliation":[{"name":"The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, U.K."},{"name":"The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. David","family":"Marais","sequence":"additional","affiliation":[{"name":"Division of Chemical Pathology, Department of Pathology, University of Cape Town and National Health Laboratory Service, Cape Town, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"O\u2019Rahilly","sequence":"additional","affiliation":[{"name":"The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, U.K."},{"name":"The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6539-3069","authenticated-orcid":false,"given":"Robert K.","family":"Semple","sequence":"additional","affiliation":[{"name":"The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, U.K."},{"name":"The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laszlo","family":"Nagy","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit R.","family":"Majithia","sequence":"additional","affiliation":[{"name":"Program in Medical and Population Genetics, Broad Institute, Cambridge, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W.R.","family":"Schwabe","sequence":"additional","affiliation":[{"name":"Leicester Institute of Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicester, Leicester, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk J.","family":"Blom","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Cape Town Health Science Faculty, Cape Town, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0043-2423","authenticated-orcid":false,"given":"Rinki","family":"Murphy","sequence":"additional","affiliation":[{"name":"Greenlane Diabetes Centre, Auckland Hospital, Auckland, New Zealand"},{"name":"Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishna","family":"Chatterjee","sequence":"additional","affiliation":[{"name":"The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, U.K."},{"name":"The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7857-7032","authenticated-orcid":false,"given":"David B.","family":"Savage","sequence":"additional","affiliation":[{"name":"The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, U.K."},{"name":"The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2018,4,5]]},"reference":[{"key":"2022031300115563100_B1","doi-asserted-by":"crossref","first-page":"507","DOI":"10.2337\/diabetes.47.4.507","article-title":"PPAR-gamma: adipogenic regulator and thiazolidinedione receptor","volume":"47","author":"Spiegelman","year":"1998","journal-title":"Diabetes"},{"key":"2022031300115563100_B2","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.biochi.2004.10.021","article-title":"PPAR gamma, 10 years later","volume":"87","author":"Lazar","year":"2005","journal-title":"Biochimie"},{"key":"2022031300115563100_B3","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.plipres.2015.11.002","article-title":"The elusive endogenous adipogenic PPAR\u03b3 agonists: lining up the suspects","volume":"61","author":"Hallenborg","year":"2016","journal-title":"Prog Lipid Res"},{"key":"2022031300115563100_B4","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1038\/47254","article-title":"Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension","volume":"402","author":"Barroso","year":"1999","journal-title":"Nature"},{"key":"2022031300115563100_B5","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1172\/JCI28003","article-title":"PPAR gamma and human metabolic disease","volume":"116","author":"Semple","year":"2006","journal-title":"J Clin Invest"},{"key":"2022031300115563100_B6","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1146\/annurev.med.57.022605.114424","article-title":"Genetic basis of lipodystrophies and management of metabolic complications","volume":"57","author":"Agarwal","year":"2006","journal-title":"Annu Rev Med"},{"key":"2022031300115563100_B7","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1038\/ng.3700","article-title":"Prospective functional classification of all possible missense variants in PPARG","volume":"48","author":"Majithia","year":"2016","journal-title":"Nat Genet"},{"key":"2022031300115563100_B8","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.molmed.2015.04.004","article-title":"The genetics of lipid storage and human lipodystrophies","volume":"21","author":"Robbins","year":"2015","journal-title":"Trends Mol Med"},{"key":"2022031300115563100_B9","doi-asserted-by":"crossref","first-page":"910","DOI":"10.2337\/diabetes.52.4.910","article-title":"Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-\u03b3","volume":"52","author":"Savage","year":"2003","journal-title":"Diabetes"},{"key":"2022031300115563100_B10","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1016\/0092-8674(95)90193-0","article-title":"15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR \u03b3","volume":"83","author":"Forman","year":"1995","journal-title":"Cell"},{"key":"2022031300115563100_B11","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/0092-8674(95)90194-9","article-title":"A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor \u03b3 and promotes adipocyte differentiation","volume":"83","author":"Kliewer","year":"1995","journal-title":"Cell"},{"key":"2022031300115563100_B12","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.cmet.2014.08.005","article-title":"Thiazolidinediones and the promise of insulin sensitization in type 2 diabetes","volume":"20","author":"Soccio","year":"2014","journal-title":"Cell Metab"},{"key":"2022031300115563100_B13","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1111\/j.1365-2265.2007.03095.x","article-title":"Leptin therapy for partial lipodystrophy linked to a PPAR-\u03b3 mutation","volume":"68","author":"Guettier","year":"2008","journal-title":"Clin Endocrinol (Oxf)"},{"key":"2022031300115563100_B14","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/1471-2350-7-3","article-title":"Peroxisomal proliferator activated receptor-gamma deficiency in a Canadian kindred with familial partial lipodystrophy type 3 (FPLD3)","volume":"7","author":"Francis","year":"2006","journal-title":"BMC Med Genet"},{"key":"2022031300115563100_B15","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1111\/dme.13061","article-title":"Familial partial lipodystrophy linked to a novel peroxisome proliferator activator receptor -\u03b3 (PPARG) mutation, H449L: a comparison of people with this mutation and those with classic codon 482 Lamin A\/C (LMNA) mutations","volume":"33","author":"Demir","year":"2016","journal-title":"Diabet Med"},{"key":"2022031300115563100_B16","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.cmet.2006.09.003","article-title":"Non-DNA binding, dominant-negative, human PPARgamma mutations cause lipodystrophic insulin resistance","volume":"4","author":"Agostini","year":"2006","journal-title":"Cell Metab"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/diabetes.diabetesjournals.org\/syndication\/doi\/10.2337\/db17-1236","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/67\/6\/1086\/538472\/db171236.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/67\/6\/1086\/538472\/db171236.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:35:23Z","timestamp":1667406923000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/67\/6\/1086\/35320\/A-Pharmacogenetic-Approach-to-the-Treatment-of"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,4,5]]},"references-count":16,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2018,4,5]]},"published-print":{"date-parts":[[2018,6,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db17-1236","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,4,5]]}}}