posted on 2019-05-21, 13:32authored byM Agostini, E Schoenmakers, J Beig, L Fairall, I Szatmari, O Rajanayagam, FW Muskett, C Adams, AD Marais, S O'Rahilly, RK Semple, L Nagy, AR Majithia, JWR Schwabe, DJ Blom, R Murphy, K Chatterjee, DB Savage
Loss-of-function mutations in PPARG cause familial partial lipodystrophy type 3 (FPLD3) and severe metabolic disease in many patients. Missense mutations in PPARG are present in ∼1 in 500 people. Although mutations are often binarily classified as benign or deleterious, prospective functional classification of all missense PPARG variants suggests that their impact is graded. Furthermore, in testing novel mutations with both prototypic endogenous (e.g., prostaglandin J2 [PGJ2]) and synthetic ligands (thiazolidinediones, tyrosine agonists), we observed that synthetic agonists selectively rescue function of some peroxisome proliferator-activated receptor-γ (PPARγ) mutants. We report on patients with FPLD3 who harbor two such PPARγ mutations (R308P and A261E). Both PPARγ mutants exhibit negligible constitutive or PGJ2-induced transcriptional activity but respond readily to synthetic agonists in vitro, with structural modeling providing a basis for such differential ligand-dependent responsiveness. Concordant with this finding, dramatic clinical improvement was seen after pioglitazone treatment of a patient with R308P mutant PPARγ. A patient with A261E mutant PPARγ also responded beneficially to rosiglitazone, although cardiomyopathy precluded prolonged thiazolidinedione use. These observations indicate that detailed structural and functional classification can be used to inform therapeutic decisions in patients with PPARG mutations.
Funding
J.W.R.S., K.C., and D.B.S. are supported by the Wellcome Trust (grants WT100237, WT095564, and WT107064, respectively), the MRC Metabolic Disease Unit, the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, and the NIHR Rare Disease Translational Research Collaboration. J.W.R.S. holds a Royal Society Wolfson Research Merit Award.
History
Citation
Diabetes, 2018, 67 (6), pp. 1086-1092
Author affiliation
/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Molecular & Cell Biology