The Novel Loss-of-function Arg212Trp Mutation in PPARG Causes Familial Partial Lipodystrophy Type 3

Abstract Background Familial partial lipodystrophy type 3 (FPLD3) is a rare genetic disorder caused by mutations in peroxisome activator receptor gamma (PPARG). Patients with familial partial lipodystrophy often have abnormal fat distribution and severe metabolic abnormalities. In this study, we identified a familial genetic defect in PPARG in a Chinese family and functionally validated this gene. Methods Three family members were screened for mutations in PPARG via direct sequencing. Physical examination and laboratory tests were performed on the affected individuals. The functions of the mutant genes were analyzed in transfected cell lines by measuring the transcriptional activity and interference with the wild-type protein and software-based prediction of the mutant protein structure. Results We identified a novel missense mutation in PPARG (i.e., PPARG2 c.634C > T; p.Arg212Trp). Bioinformatics analysis revealed that the mutation of PPARG changed the three-dimensional structure and hydrophilic properties of the protein, and that the mutation was pathogenic. In vitro experiments reveal that the transcriptional activity of the mutant receptor was significantly reduced. Family members affected by the mutation were diagnosed with diabetes and hyperlipidemia. Genetic testing was performed to further confirm the diagnosis and classification of monogenic diabetes mellitus. After the diagnosis, each patient was treated with insulin aspart injection, metformin, and Lipitor, and the symptoms of hyperglycemia and hyperlipidemia improved. Conclusions We report familial partial lipodystrophy syndrome type 3 caused by a novel mutation in PPARG. Our data extend the spectrum of known PPARG mutations responsible for FPLD3 and highlight the importance of identifying FPLD syndrome and the early classification and management of diabetes.