Characterization of human CYP2G genes: widespread loss-of-function mutations and genetic polymorphism

CYP2G1 is an abundant, olfactory mucosa-specific cytochrome P450 enzyme act ive in the metabolism of sex steroids and xenobiotic substrates in mammalia n animals. Two different human CYP2G genes, CYP2GP1 and CYP2GP2, were chara cterized in the present study. Polymorphisms in these genes were also studi ed. CYP2GP1 contained a single nucleotide deletion in exon 2 (DeltaC) and a 2.4-kb deletion between exons 3 and 7 (Delta E4-6), whereas CYP2GP2 contai ned a nonsense mutation in exon 1 and another in exon 3. The coding region sequences in exons 1-3 and 7-9 of the two genes were 96.7% identical. Both genes were localized to human chromosome 19, and Southern blot analysis of human genomic DNA did not detect any additional copies of the CYP2G gene. T he occurrence of these loss-of-function mutations was analysed by polymeras e chain reaction-based genotyping in more than 200 individuals, The Delta E 4-6 deletion in CYP2GP1 was detected in 94% of subjects (either homozygous or heterozygous), and an allele which does not contain this deletion was de tected in 11.6% of individuals. The nonsense mutation in CYP2GP2 exon 3 was detected in 86% of individuals (either homozygous or heterozygous); howeve r, a potentially functional CYP2GP2 allele based on the absence of the nons ense mutation in exon 3 was also detected in 31% of individuals. These resu lts indicate that a functional CYP2G allele is rare in humans, Analysis of the allelic distribution in different ethnic groups suggested that a functi onal CYP2G allele, if present, is more likely to be found in Black and Hisp anic subjects. Pharmacogenetics 10:667-678 (C) 2000 Lippincott Williams & W ilkins.