A pharmacogenetic approach to the treatment of patients with PPARG mutations

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

Research output: Contribution to journalArticle

Abstract

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-g (PPARg) mutants. We report on patients with FPLD3 who harbor two such PPARg mutations (R308P and A261E). Both PPARg 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 PPARg. A patient with A261E mutant PPARg 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.

Original languageEnglish (US)
Pages (from-to)1086-1092
Number of pages7
JournalDiabetes
Volume67
Issue number6
DOIs
StatePublished - Jun 1 2018
Externally publishedYes

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Peroxisomes
Pharmacogenetics
Familial Partial Lipodystrophy
Mutation
rosiglitazone
pioglitazone
Ligands
Therapeutics
Thiazolidinediones
Metabolic Diseases
Missense Mutation
Cardiomyopathies
Tyrosine

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Agostini, M., Schoenmakers, E., Beig, J., Fairall, L., Szatmari, I., Rajanayagam, O., ... Savage, D. B. (2018). A pharmacogenetic approach to the treatment of patients with PPARG mutations. Diabetes, 67(6), 1086-1092. https://doi.org/10.2337/db17-1236

A pharmacogenetic approach to the treatment of patients with PPARG mutations. / Agostini, Maura; Schoenmakers, Erik; Beig, Junaid; Fairall, Louise; Szatmari, Istvan; Rajanayagam, Odelia; Muskett, Frederick W.; Adams, Claire; Marais, A. David; O’Rahilly, Stephen; Semple, Robert K.; Nagy, Laszlo; Majithia, Amit R.; Schwabe, John W.R.; Blom, Dirk J.; Murphy, Rinki; Chatterjee, Krishna; Savage, David B.

In: Diabetes, Vol. 67, No. 6, 01.06.2018, p. 1086-1092.

Research output: Contribution to journalArticle

Agostini, M, Schoenmakers, E, Beig, J, Fairall, L, Szatmari, I, Rajanayagam, O, Muskett, FW, Adams, C, Marais, AD, O’Rahilly, S, Semple, RK, Nagy, L, Majithia, AR, Schwabe, JWR, Blom, DJ, Murphy, R, Chatterjee, K & Savage, DB 2018, 'A pharmacogenetic approach to the treatment of patients with PPARG mutations', Diabetes, vol. 67, no. 6, pp. 1086-1092. https://doi.org/10.2337/db17-1236
Agostini M, Schoenmakers E, Beig J, Fairall L, Szatmari I, Rajanayagam O et al. A pharmacogenetic approach to the treatment of patients with PPARG mutations. Diabetes. 2018 Jun 1;67(6):1086-1092. https://doi.org/10.2337/db17-1236
Agostini, Maura ; Schoenmakers, Erik ; Beig, Junaid ; Fairall, Louise ; Szatmari, Istvan ; Rajanayagam, Odelia ; Muskett, Frederick W. ; Adams, Claire ; Marais, A. David ; O’Rahilly, Stephen ; Semple, Robert K. ; Nagy, Laszlo ; Majithia, Amit R. ; Schwabe, John W.R. ; Blom, Dirk J. ; Murphy, Rinki ; Chatterjee, Krishna ; Savage, David B. / A pharmacogenetic approach to the treatment of patients with PPARG mutations. In: Diabetes. 2018 ; Vol. 67, No. 6. pp. 1086-1092.
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