Familial partial lipodystrophy phenotype resulting from a single-base mutation in deoxyribonucleic acid-binding domain of peroxisome proliferator-activated receptor-gamma.
BACKGROUND
Familial partial lipodystrophy (FPLD) results from coding sequence mutations either in LMNA, encoding nuclear lamin A/C, or in PPARG, encoding peroxisome proliferator-activated receptor-gamma (PPARgamma). The LMNA form is called FPLD2 (MIM 151660) and the PPARG form is called FPLD3 (MIM 604367).


OBJECTIVE
Our objective was to investigate whether the clinical phenotype of this proband is due to mutation(s) in PPARgamma.


METHODS
This is a case report. Patient and Setting: A 31-yr-old female with the clinical phenotype of FPLD3, i.e. lipodystrophy and early childhood diabetes with extreme insulin resistance and hypertriglyceridemia leading to recurrent pancreatitis, was assessed at an academic medical center.


RESULTS
The proband was heterozygous for a novel C-->T mutation in the PPARG gene that led to the substitution of arginine 194 in PPARgamma2 isoform, a conserved residue located in the zinc finger structure involved in DNA binding, by tryptophan (R194W). The mutation was absent from the genomes of 100 healthy Caucasians. In vitro analysis of the mutated protein showed that R194W (and R166W in PPARgamma1 isoform) could not bind to DNA and had no transcriptional activity. Furthermore, R194W had no dominant-negative activity.


CONCLUSIONS
The R194W mutation in PPARG disrupts its DNA binding activity and through haploinsufficiency leads to clinical manifestation of FPLD3 and the associated metabolic disturbances.
Monajemi
Houshang
H
Academic Medical Center, Department of Vascular Medicine, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. H.monajemi@amc.uva.nl
Zhang
Lin
L
Li
Gang
G
Jeninga
Ellen H
EH
Cao
Henian
H
Maas
Mario
M
Brouwer
C B
CB
Kalkhoven
Eric
E
Stroes
Erik
E
Hegele
Robert A
RA
Leff
Todd
T
D000328:Adult; D000818:Animals; D001120:Arginine / Q000378:metabolism; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004247:DNA / Q000235:genetics* / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D005091:Exons / Q000235:genetics; D005260:Female; D005799:Genes, Dominant / Q000235:genetics; D006801:Humans; D052496:Lipodystrophy, Familial Partial / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D051379:Mice; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D017354:Point Mutation; D014158:Transcription, Genetic / Q000235:genetics; D014364:Tryptophan / Q000378:metabolism; D016335:Zinc Fingers / Q000235:genetics
D047495:PPAR gamma; D014364:Tryptophan; D004247:DNA; D001120:Arginine