title: Genetic polymorphism of the human cytochrome P450 CYP4B1: evidence for a non-functional allelic variant.
abstract: In the present study, we report the first systematic investigation of polymorphism in the human CYP4B1 gene. 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-type CYP4B1* allele (CYP4B1*1), four variants, namely CYP4B1*2, *3, *4 and *5, were characterized. The CYP4B1*3, *4 and *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 the CYP4B1*2 allele 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 the CYP4B1*2 allele, associations between CYP4B1 polymorphism and certain pathological processes should be considered.
authors.affiliation: Equipe d'accueil 2679, Faculté de Médecine de Lille, Pôle Recherche, Lille, France. jmlo-guidice@univ.lille2.fr
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Lo-Guidice
authors.forename: Delphine
authors.initials: D
authors.lastname: Allorge
authors.forename: Christelle
authors.initials: C
authors.lastname: Cauffiez
authors.forename: Dany
authors.initials: D
authors.lastname: Chevalier
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Lafitte
authors.forename: Michel
authors.initials: M
authors.lastname: Lhermitte
authors.forename: Franck
authors.initials: F
authors.lastname: Broly
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001483:Base Sequence; D017931:DNA Primers; D005091:Exons; D014644:Genetic Variation; D006801:Humans; D020125:Mutation, Missense; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D018807:Polymorphism, Single-Stranded Conformational; D017384:Sequence Deletion
chemical_list: D017931:DNA Primers; D001189:Aryl Hydrocarbon Hydroxylases; C095029:cytochrome P-450 CYP4B1