HLA-linked congenital adrenal hyperplasia results from a defective gene encoding a cytochrome P-450 specific for steroid 21-hydroxylation.
We have determined the molecular genetic basis of congenital adrenal hyperplasia due to 21-hydroxylase (21-OHase) deficiency. This common disorder of cortisol biosynthesis is HLA-linked. The haplotype HLA-(A3);Bw47;DR7 is strongly associated with 21-OHase deficiency and always carries a null allele at the locus encoding the C4A (Rodgers) form of the fourth component (C4) of complement. It seemed likely that this haplotype carries a deletion encompassing the genes encoding both C4A and 21-OHase. We hypothesized that the HLA-linked defect involved a structural gene for the adrenal microsomal cytochrome P-450 specific for steroid 21-hydroxylation. Using a plasmid with a 520-base-pair bovine adrenal cDNA insert encoding the middle third of the cytochrome P-450 polypeptide, we compared hybridization patterns in DNA from normal and 21-OHase-deficient individuals. Normal human DNA yielded two fragments that hybridized with the probe after digestion with either restriction endonuclease EcoRI [12- and 14-kilobase (kb) fragments] or Taq I (3.7 and 3.2 kb). One of these bands (the first mentioned in each digest) was absent in DNA from a cell line derived from a patient homozygous for HLA-Bw47. DNA from six unrelated patients homozygous for 21-OHase deficiency who were heterozygous for HLA-Bw47 yielded diminished relative intensity of the 3.7-kb Taq I band in five patients, consistent with a heterozygous deletion, and complete disappearance of the 3.7-kb band in one. This deletion segregated with HLA-Bw47 in a large pedigree carrying 21-OHase deficiency and HLA-Bw47. Thus, 21-OHase deficiency sometimes results from the deletion of a specific cytochrome P-450 gene and sometimes, presumably, from smaller mutations. This gene is probably located very near the C4A gene.
D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics* / Q000276:immunology; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000172:deficiency* / Q000235:genetics; D004247:DNA / Q000302:isolation & purification; D005260:Female; D005796:Genes; D008040:Genetic Linkage; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D008297:Male; D009693:Nucleic Acid Hybridization; D010375:Pedigree; D010957:Plasmids; D013255:Steroid 21-Hydroxylase / Q000235:genetics; D013250:Steroid Hydroxylases / Q000172:deficiency*
D006680:HLA Antigens; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D013255:Steroid 21-Hydroxylase