Genetic linkage mapping of the CYP11A1 gene encoding the cholesterol side-chain cleavage P450scc close to the CYP1A1 gene and D15S204 in the chromosome 15q22.33-q23 region

The first rate-limiting step in the biosynthesis of all mammalian steroid hormones is the conversion of cholesterol to pregnenolone by the cholesterol side-chain cleavage enzyme, P450scc. The human CYP11A1 gene, encoding the mitochondrial P450scc, has been previously assigned by in situ hybridization to 15q23-q24 region. To map the CYP11A1 gene with linkage analysis, a novel TAAAA repeat polymorphism, found in its promoter region, was genotyped in the eight largest CEPH reference families, which included 91 children, 16 parents and 26 grandparents. Two-point linkage analysis was performed between this tetra-allelic polymorphism and the chromosome 15 microsatellite markers of Genethon as well as the tetranucleotide polymorphism of the CYP19 gene and a MspI RFLP of the CYP1A1 gene. A close linkage was observed with D15S204 (Z max = 27.33; theta max = 0.009) and CYP1A1 gene (Z max = 6.62; theta max = 0.001), but not with the CYP19 gene (Z max = 4.06; theta max = 0.26). The CYP19 gene that encodes the P450arom was rather closely linked with D15S123 (Z max = 31.04; theta max = 0.001). A framework map, including Genethon markers flanking the polymorphic CYP11A1 and CYP19 genes, was built by multipoint linkage analysis. Thereafter, a high-resolution genetic map of the 15q15-q25.3 region was constructed, yielding to the following order: cen - D15S214 - [D15S123; CYP19] - D15S117 - D15S159 - - D15S153 - D15S983 - [D15S204; CYP11A1; CYP1A1] - D15S211 - D15S152 - D15S199 - - tel. Thus, the CYP11A1 gene is closely linked with the CYP1A1 gene, whereas it is located approximately 27.4 cM telomeric to the CYP19 gene. (C) 1998 Chapman & Hall Ltd.