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


OBJECTIVE
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.


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.


CONCLUSIONS
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.
Lüdtke
Angelika
A
Department of Medicine, College of Physicians and Surgeons, Columbia University, P&S Building 10-508, New York, NY 10032, USA.
Buettner
Janine
J
Wu
Wei
W
Muchir
Antoine
A
Schroeter
Andreas
A
Zinn-Justin
Sophie
S
Spuler
Simone
S
Schmidt
Hartmut H-J
HH
Worman
Howard J
HJ
D000328:Adult; D000595:Amino Acid Sequence; D050218:Body Fat Distribution; D002460:Cell Line; D005192:Family Health; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D052496:Lipodystrophy, Familial Partial / Q000235:genetics* / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D047495:PPAR gamma / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation; D014158:Transcription, Genetic
D047495:PPAR gamma