SFEBES2018 Poster Presentations Obesity & metabolism (24 abstracts)
Dominant-negative mutations in PPAR alpha are present in unselected human populations and have a metabolic signature
Audrey Melvin 1 , Brian Lam 1 , Claudia Langenberg 2 , Maura Agostini 1 , Erik Schoenmakers 1 , Jian’an Luan 2 , Kara Rainbow 1 , Giles S Yeo 1 , Nick Wareham 2 , David B Savage 1 , Krishna Chatterjee 1 & Stephen O’Rahilly 1
1Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK; 2MRC-Epidemiology Unit, University of Cambridge, Cambridge, UK.
The study of humans carrying dominant negative mutations in PPAR gamma has contributed significantly to our understanding of its role in human physiology. To date, comparable studies of PPAR alpha have not been reported. Using a pooled approach, we undertook exon sequencing of PPARA in 11,848 adult participants of the Fenland study, a population-based cohort study with detailed metabolic phenotyping. Twenty-nine PPARA missense variants were detected (allelic frequency 1.1×10−1 to 3.7×10−5). Bioinformatic analysis predicted four defective variants (R157Q, K292R, R341C and L426H), confirmed in functional in vitro assays with impaired constitutive and ligand-activated transcriptional activity. This was associated with impaired DNA binding (R157Q, R341C and L426H) and co-activator interaction (K292R, R341C and L426H). R341C and L426H exhibited significantly impaired dimerisation with the retinoid X receptor (RXR) which accounted for impaired DNA binding and was partially rescued at higher concentrations of synthetic ligand. Crystallographic modelling of the mutations was consistent with the functional data, providing a structural basis for the observations. All mutants exerted a dominant negative effect over wildtype PPAR alpha in co-transfection assays. Heterozygous carriers of these variants had significantly elevated median (IQR) fasting levels of free fatty acids 514(421–882) umol/l vs 303(212–423) umol/l (P=0.025), alanine transaminase 34(31–50) U/l vs 24(18–33) U/l (P=0.046) and gamma glutamyl-transferase 83.5(64–98.5) U/l vs 25(20–37) U/l (P=0.003) when compared to participants free of PPARA variants. Rare PPARA variants that are predicted to be functionally impaired were found in the Genome Aggregation database (gnomAD) at a frequency of 1 in 3000. In summary, dominant negative mutations in PPARA are found in human populations at an appreciable frequency and appear to have an impact on metabolically relevant phenotypes.
Article tools
My recent searches
My recently viewed abstracts
Authors
Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
© Bioscientifica 2024 |
Privacy policy |
Cookie settings
BiosciAbstracts
Bioscientifica Abstracts is the gateway to a series of products that provide a permanent, citable record of abstracts for biomedical and life science conferences.
Find out more