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) designatedPPARA*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*3was also unresponsive to low concentrations of ligand as compared to the wild-typePPARA*1receptor. 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-typePPARA*1with no ligand. The mutation in codon 131 (CGA to CAA, R131Q), designatedPPARA*2is less frequent thanPPARA*3,and the constitutive ligand independent activity was slightly higher thanPPARA*1.Increasing concentrations of Wy-14 643 activatedPPARA*2similar to that observed withPPARA*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.