{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:23:05Z","timestamp":1791332585581,"version":"4.3.1"},"reference-count":20,"publisher":"American Diabetes Association","issue":"12","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2002,12,1]]},"abstract":"<jats:p>Autosomal dominant familial partial lipodystrophy (FPLD) due to mutant LMNA encoding nuclear lamin A\/C is characterized by adipose tissue repartitioning together with multiple metabolic disturbances, including insulin resistance and dyslipidemia. There is emerging evidence that some rare mutations in peroxisome proliferator-activated receptor-\u03b3 (PPAR-\u03b3), encoded by PPARG, might be associated with human lipodystrophy. We report a three-generation Canadian kindred ascertained based upon partial lipodystrophy, with a normal LMNA gene sequence. Candidate gene sequencing showed that all four affected subjects were heterozygous for a novel T\u2192A mutation at PPARG nucleotide 1164 in exon 5 that predicted substitution of phenylalanine at codon 388 by leucine (F388L). The mutation was absent from normal family members and normal unrelated subjects, and altered a highly conserved residue within helix 8 of the predicted ligand-binding pocket of PPAR-\u03b3. The mutant receptor had significantly decreased basal transcriptional activity and impaired stimulation by a synthetic ligand. The germline transmission of a transactivation-deficient mutation in PPARG suggests that autosomal dominant partial lipodystrophy is genetically heterogeneous. Our findings are consistent with the idea that mutant PPARG can underlie the partial lipodystrophy phenotype.<\/jats:p>","DOI":"10.2337\/diabetes.51.12.3586","type":"journal-article","created":{"date-parts":[[2007,3,6]],"date-time":"2007-03-06T19:04:22Z","timestamp":1173207862000},"page":"3586-3590","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":238,"title":["<i>PPARG<\/i> F388L, a Transactivation-Deficient Mutant, in Familial Partial Lipodystrophy"],"prefix":"10.2337","volume":"51","author":[{"given":"Robert A.","family":"Hegele","sequence":"first","affiliation":[{"name":"Robarts Research Institute, London, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henian","family":"Cao","sequence":"additional","affiliation":[{"name":"Robarts Research Institute, London, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christy","family":"Frankowski","sequence":"additional","affiliation":[{"name":"Pfizer Global Research and Development, Ann Arbor, Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suresh T.","family":"Mathews","sequence":"additional","affiliation":[{"name":"Department of Pathology and the Center for Integrative Metabolic and Endocrine Research, Wayne State University School of Medicine, Detroit, Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todd","family":"Leff","sequence":"additional","affiliation":[{"name":"Department of Pathology and the Center for Integrative Metabolic and Endocrine Research, Wayne State University School of Medicine, Detroit, Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","reference":[{"key":"2022031223242289100_R1","doi-asserted-by":"crossref","unstructured":"Garg A: Lipodystrophies. Am J Med\u2008108:143\u2013152,2000","DOI":"10.1016\/S0002-9343(99)00414-3"},{"key":"2022031223242289100_R2","doi-asserted-by":"crossref","unstructured":"Hegele RA: Familial partial lipodystrophy: a monogenic form of the insulin resistance syndrome. Mol Genet Metab\u200871:539\u2013544,2000","DOI":"10.1006\/mgme.2000.3092"},{"key":"2022031223242289100_R3","doi-asserted-by":"crossref","unstructured":"Hegele RA: Premature atherosclerosis associated with monogenic insulin resistance. Circulation\u2008103:2225\u20132229,2001","DOI":"10.1161\/01.CIR.103.18.2225"},{"key":"2022031223242289100_R4","doi-asserted-by":"crossref","unstructured":"Cao H, Hegele RA: Nuclear lamin A\/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy. Hum Mol Gene\u20089:109\u2013112,2000","DOI":"10.1093\/hmg\/9.1.109"},{"key":"2022031223242289100_R5","doi-asserted-by":"crossref","unstructured":"Shackleton S, Lloyd DJ, Jackson SN, Evans R, Niermeijer MF, Singh BM, Schmidt H, Brabant G, Kumar S, Durrington PN, Gregory S, O\u2019Rahilly S, Trembath RG: LMNA, encoding lamin A\/C, is mutated in partial lipodystrophy. Nat Genet\u200824:153\u2013156,2000","DOI":"10.1038\/72807"},{"key":"2022031223242289100_R6","doi-asserted-by":"crossref","unstructured":"Speckman RA, Garg A, Du F, Bennett L, Veile R, Arioglu E, Taylor SI, Lovett M, Bowcock AM: Mutational and haplotype analyses of families with familial partial lipodystrophy (Dunnigan variety) reveal recurrent missense mutations in the globular C-terminal domain of lamin A\/C. Am J Hum Genet\u200866:1192\u20131198,2000","DOI":"10.1086\/302836"},{"key":"2022031223242289100_R7","doi-asserted-by":"crossref","unstructured":"Agarwal AK, Garg A: A novel heterozygous mutation in peroxisome proliferator-activated receptor-gamma gene in a patient with familial partial lipodystrophy. J Clin Endocrinol Metab\u200887:408\u2013411,2002","DOI":"10.1210\/jcem.87.1.8290"},{"key":"2022031223242289100_R8","doi-asserted-by":"crossref","unstructured":"Spiegelman BM: PPAR-\u03b3: adipogenic regulator and thiazolidinedione receptor. Diabetes\u200847:507\u2013514,1998","DOI":"10.2337\/diabetes.47.4.507"},{"key":"2022031223242289100_R9","doi-asserted-by":"crossref","unstructured":"Barroso I, Gurnell M, Crowley VE, Agostini M, Schwabe JW, Soos MA, Maslen GL, Williams TD, Lewis H, Schafer AJ, Chatterjee VL, O\u2019Rahilly S: Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature\u2008402:880\u2013883,1999","DOI":"10.1038\/47254"},{"key":"2022031223242289100_R10","doi-asserted-by":"crossref","unstructured":"Nolte RT, Wisely GB, Westin S, Cobb JE, Lambert MH, Kurokawa R, Rosenfeld MG, Willson TM, Glass CK, Milburn MV: Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature\u2008395:137\u2013143,1998","DOI":"10.1038\/25931"},{"key":"2022031223242289100_R11","doi-asserted-by":"crossref","unstructured":"Okazawa H, Mori H, Tamori Y, Araki S, Niki T, Masugi J, Kawanishi M, Kubota T, Shinoda H, Kasuga M: No coding mutations are detected in the peroxisome proliferator-activated receptor-gamma gene in Japanese patients with lipoatrophic diabetes. Diabetes\u200846:1904\u20131906,1997","DOI":"10.2337\/diab.46.11.1904"},{"key":"2022031223242289100_R12","doi-asserted-by":"crossref","unstructured":"Vigouroux C, Fajas L, Khallouf E, Meier M, Gyapay G, Lascols O, Auwerx J, Weissenbach J, Capeau J, Magre J: Human peroxisome proliferator-activated receptor-\u03b32: genetic mapping, identification of a variant in the coding sequence, and exclusion as the gene responsible for lipoatrophic diabetes. Diabetes\u200847:490\u2013492,1998","DOI":"10.2337\/diabetes.47.3.490"},{"key":"2022031223242289100_R13","doi-asserted-by":"crossref","unstructured":"Ristow M, Muller-Wieland D, Pfeiffer A, Krone W, Kahn CR: Obesity associated with a mutation in a genetic regulator of adipocyte differentiation. N Engl J Med\u2008339:953\u2013959,1998","DOI":"10.1056\/NEJM199810013391403"},{"key":"2022031223242289100_R14","doi-asserted-by":"crossref","unstructured":"Chatterjee VK: Resistance to thyroid hormone, and peroxisome-proliferator-activated receptor gamma resistance. Biochem Soc Trans\u200829:227\u2013231,2001","DOI":"10.1042\/bst0290227"},{"key":"2022031223242289100_R15","unstructured":"Savage DB, Acerine C, Jebb S, Cinti S, Dixon A, Umpleby M, Vidal-Puig A, O\u2019Rahilly S: Insights into the physiological effects of PPARg from humans with dominant negative mutations. In Proceedings of the First International Workshop on Lipoatrophic Diabetes. Bethesda, MD, Office of Rare Diseases, National Institutes of Health Publication,2001, p.53"},{"key":"2022031223242289100_R16","doi-asserted-by":"crossref","unstructured":"Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone DS, Spiegelman BM, Mortensen RM: PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell\u20084:611\u2013617,1999","DOI":"10.1016\/S1097-2765(00)80211-7"},{"key":"2022031223242289100_R17","doi-asserted-by":"crossref","unstructured":"Gurnell M, Wentworth JM, Agostini M, Adams M, Collingwood TN, Provenzano C, Browne PO, Rajanayagam O, Burris TP, Schwabe JW, Lazar MA, Chatterjee VK: A dominant-negative peroxisome proliferator-activated receptor gamma (PPARgamma) mutant is a constitutive repressor and inhibits PPARgamma-mediated adipogenesis. J Biol Chem\u2008275:5754\u20135759,2000","DOI":"10.1074\/jbc.275.8.5754"},{"key":"2022031223242289100_R18","doi-asserted-by":"crossref","unstructured":"Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J, Lane CR, Schaffner SF, Bolk S, Brewer C, Tuomi T, Gaudet D, Hudson TJ, Daly M, Groop L, Lander ES: The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet\u200826:76\u201380,2000","DOI":"10.1038\/79216"},{"key":"2022031223242289100_R19","doi-asserted-by":"crossref","unstructured":"Hegele RA, Cao H, Harris SB, Zinman B, Hanley AJ, Anderson CM: Peroxisome proliferator-activated receptor-gamma2 P12A and type 2 diabetes in Canadian Oji-Cree. J Clin Endocrinol Metab\u200885:2014\u20132019,2000","DOI":"10.1210\/jcem.85.5.6610"},{"key":"2022031223242289100_R20","doi-asserted-by":"crossref","unstructured":"Miles PD, Barak Y, He W, Evans RM, Olefsky JM: Improved insulin-sensitivity in mice heterozygous for PPAR-gamma deficiency. J Clin Invest\u2008105:287\u2013292,2000","DOI":"10.1172\/JCI8538"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/51\/12\/3586\/652871\/db1202003586.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/51\/12\/3586\/652871\/db1202003586.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:12:06Z","timestamp":1667405526000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/51\/12\/3586\/34274\/PPARG-F388L-a-Transactivation-Deficient-Mutant-in"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2002,12,1]]},"references-count":20,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2002,12,1]]}},"URL":"https:\/\/doi.org\/10.2337\/diabetes.51.12.3586","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2002,12,1]]}}}