Genetic polymorphism of the human cytochrome P450 CYP4B1: evidence for a non-functional allelic variant

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Abstract

In the present study, we report the first systematic investigation of polymorphism in the humanCYP4B1gene. Using a strategy based on single-strand conformation polymorphism analysis of PCR products (PCR–SSCP), we analyzed the twelve exons of the gene, as well as their 5'- and 3'- proximal flanking sequences, in DNA samples from 190 French Caucasians. In addition to the wild-typeCYP4B1* allele (CYP4B1*1), four variants, namelyCYP4B1*2, *3, *4and *5, were characterized. TheCYP4B1*3, *4and *5 alleles encode missense mutations Arg173Trp, Ser322Gly and Met331Ile, respectively. The fourth variant,CYP4B1*2, harbors three missense mutations (Met331Ile, Arg340Cys and Arg375Cys) and a double nucleotide deletion (AT881-882del) that causes a frameshift and premature stop codon in the second third of the coding sequence of the gene. This latter mutation can be assumed to lead to the synthesis of a severely truncated protein and, therefore, probably contributes to interindividual variability of CYP4B1 expression and enzymatic activity. In order to investigate the extent of theCYP4B1*2allele in a large population, a rapid genotyping test, based on restriction analysis of PCR products, was developed and applied to 2082 French Caucasians. Forty-two subjects were found homozygous for the AT881-882 deletion, which suggests that about 2% of individuals should be unable to develop metabolic reactions mediated by CYP4B1. Given the relatively high frequency and the functional consequences of theCYP4B1*2allele, associations betweenCYP4B1polymorphism and certain pathological processes should be considered.

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