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Peroxisome Proliferator-Activated Receptor- C190S Mutation Causes Partial Lipodystrophy

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; Medizinische Klinik mit Schwerpunkt Gastroenterologie, Hepatologie, and Endokrinologie (A.L., J.B., H.H.-J.S.), Charité Universitätsmedizin Berlin, Campus Mitte, 10117 Berlin, Germany; Diabetesnetz Kraichgau Nord (A.S.), 69168 Wiesloch, Germany; Département d’Ingénierie et d’Etude des Protéines (S.Z.-J.), Commissariat à l’Energie Atomique Saclay, 91191 Gif-sur-Yvette Cedex, France; Abteilung für Neurologie (S.S.), Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, 13353 Berlin, Germany; and Transplantationshepatologie (H.H.-J.S.), Universitätsklinikum Münster, 48149 Münster, Germany

Address all correspondence and requests for reprints to: Howard J. Worman, M.D., Departments of Medicine and Anatomy and Cell Biology, College of Physicians and Surgeons, Columbia University, P&S Building 10-508, 630 West 168th Street, New York, New York 10032. E-mail: hjw14{at}columbia.edu.

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)-, 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 PPAR has a significantly lower ability to activate a reporter gene than wild-type PPAR in absence and presence of rosiglitazone. A dominant-negative effect was not observed. Compared with wild-type PPAR, C190S PPAR shows a reduced capacity to bind DNA.

Conclusion: Mutation of a zinc-binding amino acid of PPAR leads to an altered protein-DNA binding pattern, resulting in a partial loss of function, which in turn is associated with partial lipodystrophy.

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