Format

Send to

Choose Destination
Diabetes. 2018 Jun;67(6):1086-1092. doi: 10.2337/db17-1236. Epub 2018 Apr 5.

A Pharmacogenetic Approach to the Treatment of Patients With PPARG Mutations.

Author information

1
The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, U.K.
2
The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, U.K.
3
Greenlane Diabetes Centre, Auckland Hospital, Auckland, New Zealand.
4
Leicester Institute of Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicester, Leicester, U.K.
5
Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
6
Division of Chemical Pathology, Department of Pathology, University of Cape Town and National Health Laboratory Service, Cape Town, South Africa.
7
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
8
Leicester Institute of Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicester, Leicester, U.K. dbs23@medschl.cam.ac.uk kkc1@medschl.cam.ac.uk r.murphy@auckland.ac.nz dirk.blom@uct.ac.za js336@leicester.ac.uk.
9
Department of Medicine, University of Cape Town Health Science Faculty, Cape Town, South Africa dbs23@medschl.cam.ac.uk kkc1@medschl.cam.ac.uk r.murphy@auckland.ac.nz dirk.blom@uct.ac.za js336@leicester.ac.uk.
10
Greenlane Diabetes Centre, Auckland Hospital, Auckland, New Zealand dbs23@medschl.cam.ac.uk kkc1@medschl.cam.ac.uk r.murphy@auckland.ac.nz dirk.blom@uct.ac.za js336@leicester.ac.uk.
11
Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
12
The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, U.K. dbs23@medschl.cam.ac.uk kkc1@medschl.cam.ac.uk r.murphy@auckland.ac.nz dirk.blom@uct.ac.za js336@leicester.ac.uk.

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-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.

PMID:
29622583
PMCID:
PMC5967605
DOI:
10.2337/db17-1236
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center