PPARG F388L, a transactivation-deficient mutant, in familial partial lipodystrophy.
Autosomal dominant familial partial lipodystrophy (FPLD) due to mutant LMNA encoding nuclear lamin A/C is characterized by adipose tissue repartitioning together with multiple metabolic disturbances, including insulin resistance and dyslipidemia. There is emerging evidence that some rare mutations in peroxisome proliferator-activated receptor-gamma (PPAR-gamma), encoded by PPARG, might be associated with human lipodystrophy. We report a three-generation Canadian kindred ascertained based upon partial lipodystrophy, with a normal LMNA gene sequence. Candidate gene sequencing showed that all four affected subjects were heterozygous for a novel T-->A mutation at PPARG nucleotide 1164 in exon 5 that predicted substitution of phenylalanine at codon 388 by leucine (F388L). The mutation was absent from normal family members and normal unrelated subjects, and altered a highly conserved residue within helix 8 of the predicted ligand-binding pocket of PPAR-gamma. The mutant receptor had significantly decreased basal transcriptional activity and impaired stimulation by a synthetic ligand. The germline transmission of a transactivation-deficient mutation in PPARG suggests that autosomal dominant partial lipodystrophy is genetically heterogeneous. Our findings are consistent with the idea that mutant PPARG can underlie the partial lipodystrophy phenotype.
Hegele
Robert A
RA
Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, 406-100 Perth Drive, London, Ontario, Canada N6A 5K8. hegele@robarts.ca
Cao
Henian
H
Frankowski
Christy
C
Mathews
Suresh T
ST
Leff
Todd
T
D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D001483:Base Sequence / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006801:Humans; D008060:Lipodystrophy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics / Q000502:physiology*; D010375:Pedigree; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics*
D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors