Two genes encoding steroid 21-hydroxylase are located near the genes encoding the fourth component of complement in man.

Abstract

Two genes encoding steroid 21-hydroxylase [21-OHase; steroid 21-monooxygenase; steroid, hydrogen-donor:oxygen oxidoreductase (21-hydroxylating); EC 1.14.99.10], a cytochrome P-450 enzyme, were located within the HLA major histocompatibiity complex. Congenital adrenal hyperplasia due to 21-OHase deficiency is a common inherited disorder of cortisol biosynthesis which is in genetic linkage disequilibrium with certain extended HLA haplotypes. These haplotypes include characteristic serum complement allotypes. A series of cosmid clones was isolated from a human genomic library by using a probe encoding part of complement C4. These clones also hybridized with a probe encoding most of human 21-OHase. Restriction mapping and hybridization analysis showed that there are 2 21-OHase genes, each located near the 3'' end of one of the 2 C4 genes. Hybridization with probes specific for the 5'' and 3'' ends of the 21-OHase gene showed that the 21-OHase and C4 genes all have the same orientation. The 21-OHase genes 3'' to C4A and C4B carry Taq I fragments of 3.2 and 3.7 kilobases (kb), respectively. Both of these fragments are found in genomic DNA of most individuals. In DNA from an individual with the severe, salt-wasting form of 21-OHase deficiency who was homozygous for HLA-A3;Bw47;C4A*1;C4B*QO(null);DR7, the 3.7-kb Taq I fragment is absent, whereas hormonally normal individuals homozygous for HLA-A1;B8;C4A* QO;C4B*1;DR3 do not carry the 3.2-kb Taq I fragment. The 21-OHase "B" gene (3.7-kb Taq I fragment) is functional, but the 21-OHase "A" gene (3.2-kb Taq I fragment) is not.