Steroid 21-hydroxylase (21-OHase) deficiency is an HLA-linked recessive disorder of cortisol biosynthesis that can occur in several forms which differ in severity. Because they are in genetic linkage disequilibrium with different HLA antigens, the inheritance of these forms is consistent with the existence of several alleles at a single locus. When severe 21-OHase deficiency occurs in association with the HLA haplotype A3;Bw47:DR7, there is a simulataneous null allelle at one of the C4 loci. This was hypothesized to result from a single deletion or rearrangement affecting the 21-OHase and C4 loci and perhaps the HLA-B gene as well. To test this hypothesis and identify the 21-OHase gene, a cDNA clone was isolated that encoded the cytochrome P450 specific for steroid 21-hydroxylation in the bovine adrenal gland. This clone hybridized to two genese in normal human DNA, but to only one gene in DNA from an individual homozygous for A3;Bw47;DR7. All individuals heterozygous for A3;Bw47;DR7 carry a heterozygous deletion of a cytochrome P450 gene. Cosmid clones have been used to locate the 21-OHase genes both in man and mouse. It both species, there are two 21-OHase genes, each located immediately 3′ of one of the two C4 genes, and oriented in the same direction as the C4 genes. In man, the gene located 3′ of the C4B gene is deleted in 21-OHase deficiency on the Bw47 haplotype, but the gene 3′ of the C4A gene is deleted in hormonally normal individuals on the A1;B8;C4AQ0, C4B1;DR3 haplotype. Thus the 21-OHase B gene is normally active in man, but the 21-OHase A gene is not.
ASJC Scopus subject areas
- Immunology and Allergy