{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T13:59:06Z","timestamp":1778162346070,"version":"3.51.4"},"reference-count":46,"publisher":"The Endocrine Society","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2007,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Context: Mutations in PPARG are associated with insulin resistance and familial partial lipodystrophy, a disease characterized by altered distribution of sc fat and symptoms of the metabolic syndrome. The encoded protein, peroxisome proliferator-activated receptor (PPAR)-\u03b3, plays a pivotal role in regulating lipid and glucose metabolism, the differentiation of adipocytes, and other cellular regulatory processes.<\/jats:p><jats:p>Objectives: The objective of the study was to detect a novel PPARG mutation in a kindred with partial lipodystrophy and analyze the functional characteristics of the mutant protein.<\/jats:p><jats:p>Patients and Methods: In three subjects with partial lipodystrophy, one unaffected family member, and 124 unaffected subjects, PPARG was screened for mutations by direct sequencing. Body composition, laboratory abnormalities, and hepatic steatosis were assessed in each affected subject. Transcriptional activity was determined, and EMSA was performed to investigate DNA binding capacity of the mutant protein.<\/jats:p><jats:p>Results: We identified a PPARG mutation, C190S, causing partial lipodystrophy with metabolic alterations in three affected family members. The mutation was absent in the unaffected family member and unaffected controls. The mutation is located within zinc-finger 2 of the DNA binding domain. C190S PPAR\u03b3 has a significantly lower ability to activate a reporter gene than wild-type PPAR\u03b3 in absence and presence of rosiglitazone. A dominant-negative effect was not observed. Compared with wild-type PPAR\u03b3, C190S PPAR\u03b3 shows a reduced capacity to bind DNA.<\/jats:p><jats:p>Conclusion: Mutation of a zinc-binding amino acid of PPAR\u03b3 leads to an altered protein-DNA binding pattern, resulting in a partial loss of function, which in turn is associated with partial lipodystrophy.<\/jats:p>","DOI":"10.1210\/jc.2005-2624","type":"journal-article","created":{"date-parts":[[2007,3,14]],"date-time":"2007-03-14T00:38:32Z","timestamp":1173832712000},"page":"2248-2255","source":"Crossref","is-referenced-by-count":40,"title":["Peroxisome Proliferator-Activated Receptor-\u03b3 C190S Mutation Causes Partial Lipodystrophy"],"prefix":"10.1210","volume":"92","author":[{"given":"Angelika","family":"Lu\u0308dtke","sequence":"first","affiliation":[{"name":"Departments of Medicine and Anatomy and Cell Biology (A.L., W.W., A.M., H.J.W.), College of Physicians and Surgeons, Columbia University, New York, New York 10032"},{"name":"Medizinische Klinik mit Schwerpunkt Gastroenterologie, Hepatologie, and Endokrinologie (A.L., J.B., H.H.-J.S.), Charite\u0301 Universita\u0308tsmedizin Berlin, Campus Mitte, 10117 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janine","family":"Buettner","sequence":"additional","affiliation":[{"name":"Medizinische Klinik mit Schwerpunkt Gastroenterologie, Hepatologie, and Endokrinologie (A.L., J.B., H.H.-J.S.), Charite\u0301 Universita\u0308tsmedizin Berlin, Campus Mitte, 10117 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Wu","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Anatomy and Cell Biology (A.L., W.W., A.M., H.J.W.), College of Physicians and Surgeons, Columbia University, New York, New York 10032"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antoine","family":"Muchir","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Anatomy and Cell Biology (A.L., W.W., A.M., H.J.W.), College of Physicians and Surgeons, Columbia University, New York, New York 10032"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Schroeter","sequence":"additional","affiliation":[{"name":"Diabetesnetz Kraichgau Nord (A.S.), 69168 Wiesloch, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophie","family":"Zinn-Justin","sequence":"additional","affiliation":[{"name":"De\u0301partement d\u2019Inge\u0301nierie et d\u2019Etude des Prote\u0301ines (S.Z.-J.), Commissariat a\u0300 l\u2019Energie Atomique Saclay, 91191 Gif-sur-Yvette Cedex, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simone","family":"Spuler","sequence":"additional","affiliation":[{"name":"Abteilung fu\u0308r Neurologie (S.S.), Charite\u0301 Universita\u0308tsmedizin Berlin, Campus Virchow-Klinikum, 13353 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hartmut H.-J.","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Transplantationshepatologie (H.H.-J.S.), Universita\u0308tsklinikum Mu\u0308nster, 48149 Mu\u0308nster, Germany"},{"name":"Medizinische Klinik mit Schwerpunkt Gastroenterologie, Hepatologie, and Endokrinologie (A.L., J.B., H.H.-J.S.), Charite\u0301 Universita\u0308tsmedizin Berlin, Campus Mitte, 10117 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Howard J.","family":"Worman","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Anatomy and Cell Biology (A.L., W.W., A.M., H.J.W.), College of Physicians and Surgeons, Columbia University, New York, New York 10032"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","reference":[{"key":"2020071613255744500_R1","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1093\/hmg\/9.1.109","article-title":"Nuclear lamin A\/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy.","volume":"9","author":"Cao","year":"2000","journal-title":"Hum Mol Genet"},{"key":"2020071613255744500_R2","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/72807","article-title":"LMNA, encoding lamin A\/C, is mutated in partial lipodystrophy.","volume":"24","author":"Shackleton","year":"2000","journal-title":"Nat Genet"},{"key":"2020071613255744500_R3","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1086\/302836","article-title":"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.","volume":"66","author":"Speckman","year":"2000","journal-title":"Am J Hum Genet"},{"key":"2020071613255744500_R4","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1056\/NEJMra025261","article-title":"Acquired and inherited lipodystrophies.","volume":"350","author":"Garg","year":"2004","journal-title":"N Engl J Med"},{"key":"2020071613255744500_R5","doi-asserted-by":"crossref","first-page":"2289","DOI":"10.1210\/jcem.86.5.7500","article-title":"Dyslipidemia in familial partial lipodystrophy caused by an R482W mutation in the LMNA gene.","volume":"86","author":"Schmidt","year":"2001","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071613255744500_R6","doi-asserted-by":"crossref","first-page":"2218","DOI":"10.1111\/j.1572-0241.2005.00234.x","article-title":"Hepatic steatosis in Dunnigan-type familial partial lipodystrophy.","volume":"100","author":"Ludtke","year":"2005","journal-title":"Am J Gastroenterol"},{"key":"2020071613255744500_R7","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1038\/47254","article-title":"Dominant negative mutations in human PPAR\u03b3 associated with severe insulin resistance, diabetes mellitus and hypertension.","volume":"402","author":"Barroso","year":"1999","journal-title":"Nature"},{"key":"2020071613255744500_R8","doi-asserted-by":"crossref","first-page":"3586","DOI":"10.2337\/diabetes.51.12.3586","article-title":"PPARG F388L, a transactivation-deficient mutant, in familial partial lipodystrophy.","volume":"51","author":"Hegele","year":"2002","journal-title":"Diabetes"},{"key":"2020071613255744500_R9","first-page":"408","article-title":"A novel heterozygous mutation in peroxisome proliferator-activated receptor-\u03b3 gene in a patient with familial partial lipodystrophy.","volume":"87","author":"Argawal","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071613255744500_R10","doi-asserted-by":"crossref","first-page":"5655","DOI":"10.1210\/jc.2004-0280","article-title":"A single-base mutation in the peroxisome proliferator-activated receptor \u03b34 promoter associated with altered in vitro expression and partial lipodystrophy.","volume":"89","author":"Al-Shali","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071613255744500_R11","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/1471-2350-7-3","article-title":"Peroxisomal proliferator activated receptor-\u03b3 deficiency in a Canadian kindred with familial partial lipodystrophy type 3 (FPLD3)","volume":"7","author":"Francis","year":"2006","journal-title":"BMC Med Genet"},{"key":"2020071613255744500_R12","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1111\/j.1399-0004.2006.00674.x","article-title":"A frameshift mutation in peroxisome-proliferator-activated receptor-\u03b3 in familial partial lipodystrophy subtype 3 (FPLD3; MIM 604367).","volume":"70","author":"Hegele","year":"2006","journal-title":"Clin Genet"},{"key":"2020071613255744500_R13","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1016\/0092-8674(92)90031-7","article-title":"Control of the peroxisomal \u03b2-oxidation pathway by a novel family of nuclear hormone receptors.","volume":"68","author":"Dreyer","year":"1992","journal-title":"Cell"},{"key":"2020071613255744500_R14","doi-asserted-by":"crossref","first-page":"7355","DOI":"10.1073\/pnas.91.15.7355","article-title":"Differential expression and activation of a family of murine peroxisome proliferator-activated receptors.","volume":"91","author":"Kliewer","year":"1994","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071613255744500_R15","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1146\/annurev.nutr.21.1.193","article-title":"Peroxisomal \u03b2-oxidation and peroxisome proliferator-activated receptor \u03b1: an adaptive metabolic system.","volume":"21","author":"Reddy","year":"2001","journal-title":"Annu Rev Nutr"},{"key":"2020071613255744500_R16","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/S0092-8674(03)00269-1","article-title":"Peroxisome-proliferator-activated receptor \u03b4 activates fat metabolism to prevent obesity.","volume":"113","author":"Wang","year":"2003","journal-title":"Cell"},{"key":"2020071613255744500_R17","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/S1097-2765(00)80211-7","article-title":"PPAR\u03b3 is required for the differentiation of adipose tissue in vivo and in vitro.","volume":"4","author":"Rosen","year":"1999","journal-title":"Mol Cell"},{"key":"2020071613255744500_R18","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.phrs.2004.07.012","article-title":"An overview on biological mechanisms of PPARs.","volume":"51","author":"Kota","year":"2005","journal-title":"Pharmacol Res"},{"key":"2020071613255744500_R19","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1038\/358771a0","article-title":"Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors.","volume":"358","author":"Kliewer","year":"1992","journal-title":"Nature"},{"key":"2020071613255744500_R20","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1002\/j.1460-2075.1992.tb05072.x","article-title":"The mouse peroxisome proliferator activated receptor recognizes a response element in the 5\u2032 flanking sequence of the rat acyl CoA oxidase gene.","volume":"11","author":"Tugwood","year":"1992","journal-title":"EMBO J"},{"key":"2020071613255744500_R21","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1038\/334543a0","article-title":"The function and structure of the metal coordination sites within the glucocorticoid receptor DNA binding domain.","volume":"334","author":"Freedman","year":"1988","journal-title":"Nature"},{"key":"2020071613255744500_R22","doi-asserted-by":"crossref","first-page":"3529","DOI":"10.1074\/jbc.M411422200","article-title":"An intact DNA-binding domain is not required for peroxisome proliferator-activated receptor \u03b3 (PPAR\u03b3) binding and activation on some PPAR response elements.","volume":"280","author":"Temple","year":"2005","journal-title":"J Biol Chem"},{"key":"2020071613255744500_R23","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1006\/bbrc.1996.1044","article-title":"Molecular cloning, expression and characterization of human peroxisome proliferator activated receptors \u03b31 and \u03b32.","volume":"224","author":"Elbrecht","year":"1996","journal-title":"Biochem Biophys Res Commun"},{"key":"2020071613255744500_R24","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/S0014-5793(98)01273-3","article-title":"PPAR\u03b33 mRNA: a distinct PPAR\u03b3 mRNA subtype transcribed from an independent promoter.","volume":"438","author":"Fajas","year":"1998","journal-title":"FEBS Lett"},{"key":"2020071613255744500_R25","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1006\/bbrc.2001.5602","article-title":"Identification of a novel peroxisome proliferator-activated receptor (PPAR) \u03b3 promoter in man and transactivation by the nuclear receptor ROR\u03b11.","volume":"287","author":"Sundvold","year":"2001","journal-title":"Biochem Biophys Res Commun"},{"key":"2020071613255744500_R26","doi-asserted-by":"crossref","first-page":"18779","DOI":"10.1074\/jbc.272.30.18779","article-title":"The organization, promoter analysis, and expression of the human PPAR\u03b3 gene.","volume":"272","author":"Fajas","year":"1997","journal-title":"J Biol Chem"},{"key":"2020071613255744500_R27","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1056\/NEJM199912023412302","article-title":"Missense mutations in the rod domain of the lamin A\/C gene as causes of dilated cardiomyopathy and conduction-system disease.","volume":"341","author":"Fatkin","year":"1999","journal-title":"N Engl J Med"},{"key":"2020071613255744500_R28","doi-asserted-by":"crossref","first-page":"2994","DOI":"10.1093\/nar\/29.14.2994","article-title":"Improving the accuracy of PSI-BLAST protein database searches with composition-based statistics and other refinements.","volume":"29","author":"Schaffer","year":"2001","journal-title":"Nucleic Acids Res"},{"key":"2020071613255744500_R29","author":"DeLano","year":"2002"},{"key":"2020071613255744500_R30","first-page":"1262","article-title":"Spectrum of transcriptional dimerization and dominant negative properties of twenty different mutant thyroid hormone \u03b2 receptors in thyroid hormone resistance syndrome.","volume":"8","author":"Collingwood","year":"1994","journal-title":"Mol Endocrinol"},{"key":"2020071613255744500_R31","doi-asserted-by":"crossref","first-page":"5128","DOI":"10.1074\/jbc.272.8.5128","article-title":"Transcriptional activation by peroxisome proliferator-activated receptor \u03b3 is inhibited by phosphorylation at a consensus mitogen-activated protein kinase site.","volume":"272","author":"Adams","year":"1997","journal-title":"J Biol Chem"},{"key":"2020071613255744500_R32","doi-asserted-by":"crossref","first-page":"13604","DOI":"10.1074\/jbc.274.19.13604","article-title":"Adipose expression of the phosphoenolpyruvate carboxykinase promoter requires peroxisome proliferator-activated receptor \u03b3 and 9-cis-retinoic acid receptor binding to an adipocyte-specific enhancer in vivo.","volume":"274","author":"Devine","year":"1999","journal-title":"J Biol Chem"},{"key":"2020071613255744500_R33","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1002\/jcb.240490303","article-title":"Identification of a fat cell enhancer: analysis of requirements for adipose tissue-specific gene expression.","volume":"49","author":"Graves","year":"1992","journal-title":"J Cell Biochem"},{"key":"2020071613255744500_R34","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.2337\/diabetes.52.7.1655","article-title":"Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors.","volume":"52","author":"Iwaki","year":"2003","journal-title":"Diabetes"},{"key":"2020071613255744500_R35","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1016\/S0022-2275(20)42003-6","article-title":"Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression.","volume":"37","author":"Schoonjans","year":"1996","journal-title":"J Lipid Res"},{"key":"2020071613255744500_R36","doi-asserted-by":"crossref","first-page":"7558","DOI":"10.1128\/MCB.21.22.7558-7568.2001","article-title":"Autoregulation of the human liver X receptor \u03b1 promoter.","volume":"21","author":"Laffitte","year":"2001","journal-title":"Mol Cell Biol"},{"key":"2020071613255744500_R37","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.gene.2005.10.021","article-title":"Identification of novel PPAR\u03b3 target genes in primary human adipocytes.","volume":"369","author":"Perera","year":"2006","journal-title":"Gene"},{"key":"2020071613255744500_R38","doi-asserted-by":"crossref","first-page":"2540","DOI":"10.1093\/ajcn\/34.11.2540","article-title":"New norms of upper limb fat and muscle areas for assessment of nutritional status.","volume":"34","author":"Frisancho","year":"1981","journal-title":"Am J Clin Nutr"},{"key":"2020071613255744500_R39","doi-asserted-by":"crossref","first-page":"20108","DOI":"10.1074\/jbc.272.32.20108","article-title":"Polarity and specific sequence requirements of peroxisome proliferator-activated receptor (PPAR)\/retinoid X receptor heterodimer binding to DNA. A functional analysis of the malic enzyme gene PPAR response element.","volume":"272","author":"Ijpenberg","year":"1997","journal-title":"J Biol Chem"},{"key":"2020071613255744500_R40","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1038\/348458a0","article-title":"Solution structure of the DNA-binding domain of the oestrogen receptor.","volume":"348","author":"Schwabe","year":"1990","journal-title":"Nature"},{"key":"2020071613255744500_R41","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/ng926","article-title":"Digenic inheritance of severe insulin resistance in a human pedigree.","volume":"31","author":"Savage","year":"2002","journal-title":"Nat Genet"},{"key":"2020071613255744500_R42","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/S1043-2760(00)00309-X","article-title":"Lipoatrophy revisited.","volume":"11","author":"Reitman","year":"2000","journal-title":"Trends Endocrinol Metab"},{"key":"2020071613255744500_R43","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1101\/gr.10.5.652","article-title":"Association between nuclear lamin A\/C R482Q mutation and partial lipodystrophy with hyperinsulinemia, dyslipidemia, hypertension, and diabetes.","volume":"10","author":"Hegele","year":"2000","journal-title":"Genome Res"},{"key":"2020071613255744500_R44","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1161\/01.ATV.0000047460.27435.B8","article-title":"Elevated serum C-reactive protein and free fatty acids among nondiabetic carriers of missense mutations in the gene encoding lamin A\/C (LMNA) with partial lipodystrophy.","volume":"23","author":"Hegele","year":"2003","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"2020071613255744500_R45","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.cmet.2006.09.003","article-title":"Non-DNA binding, dominant-negative, human PPAR\u03b3 mutations cause lipodystrophic insulin resistance.","volume":"4","author":"Agostini","year":"2006","journal-title":"Cell Metab"},{"key":"2020071613255744500_R46","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1210\/jc.2006-1807","article-title":"Familial partial lipodystrophy phenotype resulting from a single-base mutation in deoxyribonucleic acid-binding domain of peroxisome proliferator-activated receptor \u03b3.","volume":"92","author":"Monajemi","year":"2007","journal-title":"J Clin Endocrinol Metab"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/92\/6\/2248\/10780487\/jcem2248.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/92\/6\/2248\/10780487\/jcem2248.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,11]],"date-time":"2021-08-11T05:07:41Z","timestamp":1628658461000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/92\/6\/2248\/2597837"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,6,1]]},"references-count":46,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2007,6,1]]}},"URL":"https:\/\/doi.org\/10.1210\/jc.2005-2624","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,6,1]]}}}