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Endocrinol."],"abstract":"<jats:sec><jats:title>Objectives<\/jats:title><jats:p><jats:italic>PPAR\u03b3<\/jats:italic> variants cause lipodystrophy, insulin resistance, and diabetes. This study aimed to determine the relationship between <jats:italic>PPAR\u03b3<\/jats:italic> genotypes and phenotypes and to explore the pathogenesis of diabetes beyond this relationship.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p><jats:italic>PPAR\u03b32<\/jats:italic> exons in 1,002 Chinese patients with early-onset type 2 diabetes (diagnosed before 40\u00a0years of age) were sequenced. The functions of variants were evaluated by <jats:italic>in vitro<\/jats:italic> assays. Additionally, a review of the literature was performed to obtain all reported cases with rare <jats:italic>PPAR\u03b32<\/jats:italic> variants to evaluate the characteristics of variants in different functional domains.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Six (0.6%) patients had <jats:italic>PPAR\u03b32<\/jats:italic> variant-induced diabetes (PPARG-DM) in the early-onset type 2 diabetes group, including three with the p.Tyr95Cys variant in activation function 1 domain (AF1), of which five patients (83%) had diabetic kidney disease (DKD). Functional experiments showed that p.Tyr95Cys suppresses 3T3-L1 preadipocyte differentiation. A total of 64 cases with damaging rare variants were reported previously. Patients with rare <jats:italic>PPAR\u03b32<\/jats:italic> variants in AF1 of <jats:italic>PPAR\u03b32<\/jats:italic> had a lower risk of lipodystrophy and a higher rate of obesity than those with variants in other domains, as confirmed in patients identified in this study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The prevalence of PPARG-DM is similar in Caucasian and Chinese populations, and DKD was often observed in these patients. Patients with variants in the AF1 of <jats:italic>PPAR\u03b32<\/jats:italic> had milder clinical phenotypes and lack typical lipodystrophy features than those with variants in other domains. Our findings emphasize the importance of screening such patients <jats:italic>via<\/jats:italic> genetic testing and suggest that thiazolidinediones might be a good choice for these patients.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2021.677130","type":"journal-article","created":{"date-parts":[[2021,10,26]],"date-time":"2021-10-26T06:35:20Z","timestamp":1635230120000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Genetics and Clinical Characteristics of PPAR\u03b3 Variant-Induced Diabetes in a Chinese Han Population"],"prefix":"10.3389","volume":"12","author":[{"given":"Siqian","family":"Gong","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xueyao","family":"Han","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meng","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoling","family":"Cai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingying","family":"Luo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Si-min","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lingli","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yumin","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiuting","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yufeng","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xianghai","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiuping","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian","family":"Ren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ping","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linong","family":"Ji","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,10,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e66947","DOI":"10.1371\/journal.pone.0066947","article-title":"Ligand Binding Reduces SUMOylation of the Peroxisome Proliferator-Activated Receptor \u03b3 (Ppar\u03b3) Activation Function 1 (AF1) Domain","volume":"8","author":"Diezko","year":"2013","journal-title":"PloS One"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.2337\/db17-1236","article-title":"Savage DB. 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