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Lookup NU author(s): Dr Surinder Papiha
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Peroxisome proliferator-activated receptor (PPAR)α-null mice have a defect in fatty acid metabolism but reproduce normally. The lack of a detrimental effect of the null phenotype in development and reproduction opens up the possibility for null or variant PPARα gene (PPARA) alleles in humans. To search the coding region and splice junctions for mutant and variant PPARα alleles, the human PPARα gene was cloned and characterized, and sequencing by polymerase chain reaction was carried out. Two point mutations in the human gene were found in the DNA binding domain at codons for amino acids 131 and 162. The allele containing the mutation in codon 162 (CTT to GTT, L162V) designated PPARA*3, was found at a high frequency in a Northern Indian population. Transfection assays of this mutant showed that the non-ligand dependent transactivation activity was less than one-half as active as the wild-type receptor. PPARA*3 was also unresponsive to low concentrations of ligand as compared to the wild-type PPARA*1 receptor. However, the difference is ligand concentration-dependent; at concentrations of the peroxisome proliferator Wy-14 643 > 25 μM, induction activity was restored in this variant's transactivation activity to a level five-fold greater as compared with wild-type PPARA*1 with no ligand. The mutation in codon 131 (CGA to CAA, R131Q), designated PPARA*2 is less frequent than PPARA*3, and the constitutive ligand independent activity was slightly higher than PPARA*1. Increasing concentrations of Wy-14 643 activated PPARA*2 similar to that observed with PPARA*1. The biological significance of these novel PPARα alleles remains to be established. It will be of great interest to determine whether these alleles are associated with differential response to fibrate therapy. (C) 2000 Lippincott Williams and Wilkins.
Author(s): Sapone A, Peters JM, Sakai S, Tomita S, Papiha SS, Dai R, Friedman FK, Gonzalez FJ
Publication type: Article
Publication status: Published
Journal: Pharmacogenetics
Year: 2000
Volume: 10
Issue: 4
Pages: 321-333
Print publication date: 01/01/2000
ISSN (print): 1744-6872
ISSN (electronic): 1744-6880
Publisher: Lippincott Williams & Wilkins
URL: http://dx.doi.org/10.1097/00008571-200006000-00006
DOI: 10.1097/00008571-200006000-00006
PubMed id: 10862523
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