A Pharmacogenetic Approach to the Treatment of Patients With Mutations.

Diabetes
Authors
Keywords
Abstract

Loss-of-function mutations in cause familial partial lipodystrophy type 3 (FPLD3) and severe metabolic disease in many patients. Missense mutations in are present in ∼1 in 500 people. Although mutations are often binarily classified as benign or deleterious, prospective functional classification of all missense 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 mutations.

Year of Publication
2018
Journal
Diabetes
Volume
67
Issue
6
Pages
1086-1092
Date Published
2018 06
ISSN
1939-327X
DOI
10.2337/db17-1236
PubMed ID
29622583
PubMed Central ID
PMC5967605
Links
Grant list
WT100237 / Wellcome Trust / United Kingdom
MC_UU_12012/5 / Medical Research Council / United Kingdom
WT095564 / Wellcome Trust / United Kingdom
G0600717 / Medical Research Council / United Kingdom
G0502115 / Medical Research Council / United Kingdom
Wellcome Trust / United Kingdom
WT107064 / Wellcome Trust / United Kingdom