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Peroxisome proliferator-activated receptor-gamma C190S mutation causes partial lipodystrophy

Item Type:Article
Title:Peroxisome proliferator-activated receptor-gamma C190S mutation causes partial lipodystrophy
Creators Name:Luedtke, A. and Buettner, J. and Wu, W. and Muchir, A. and Schroeter, A. and Zinn-Justin, S. and Spuler, S. and Schmidt, H.H. and Worman, H.J.
Abstract: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)-gamma, plays a pivotal role in regulating lipid and glucose metabolism, the differentiation of adipocytes, and other cellular regulatory processes. 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. 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. 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 PPARgamma has a significantly lower ability to activate a reporter gene than wild-type PPARgamma in absence and presence of rosiglitazone. A dominant-negative effect was not observed. Compared with wild-type PPARgamma, C190S PPARgamma shows a reduced capacity to bind DNA. Conclusion: Mutation of a zinc-binding amino acid of PPARgamma leads to an altered protein-DNA binding pattern, resulting in a partial loss of function, which in turn is associated with partial lipodystrophy.
Keywords:Amino Acid Sequence, Body Fat Distribution, Cell Line, Family Health, Familial Partial Lipodystrophy, Genetic Transcription, Insulin Resistance, Molecular Sequence Data, PPAR gamma, Pedigree, Point Mutation, Reporter Genes
Source:Journal of Clinical Endocrinology and Metabolism
ISSN:0021-972X
Publisher:Endocrine Society (U.S.A.)
Volume:92
Number:6
Page Range:2248-2255
Date:June 2007
Official Publication:https://doi.org/10.1210/jc.2005-2624
PubMed:View item in PubMed

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