A pharmacogenetic approach to the treatment of patients with PPARG mutations

Maura Agostini, Erik Schoenmakers, Junaid Beig, Louise Fairall, Istvan Szatmari, Odelia Rajanayagam, Frederick Muskett, Claire Adams, David Marais, Stephen O'Rahilly, Robert Semple, Laszlo Nagy, Amit Majithia, John Schwabe, Dirk J Blom, Rinki Murphy, Krishna Chatterjee, David B Savage

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Loss-of-function mutations in PPARG cause familial partial lipodystrophy type 3 (FPLD3) and severe metabolic disease in many cases. Missense mutations in PPARG are present in ~1:500 people. Whilst 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 PPARg mutants. Here, we report FPLD3 patients, harbouring two such PPARg mutations (R308P, A261E). Both PPARg mutants exhibit negligible constitutive or PGJ2-induced transcriptional activity but respond readily to synthetic agonists in vitro, with structural modelling providing a basis for such differential ligand-dependent
responsiveness. Concordant with this, dramatic clinical improvement was seen following pioglitazone treatment of the patient with R308P mutant PPARg. A patient with A261E mutant PPARg also responded beneficially to rosiglitazone, though 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.
Original languageEnglish
Publication statusPublished - 5 Apr 2018


Dive into the research topics of 'A pharmacogenetic approach to the treatment of patients with PPARG mutations'. Together they form a unique fingerprint.

Cite this