Nonclassic steroid 21-hydroxylase deficiency is a frequent, relatively mild disorder of cortisol biosynthesis, characterized by variable signs of postnatal androgen excess. It is inherited as an allelic variant of the gene designated CYP21B, which encodes 21-hydroxylase. CYP21B is located in the HLA histocompatibility complex, and a “nonclassic” allelic variant is often associated with characteristic HLA antigens — B14,DR1. We cloned and analyzed the CYP21B gene from a patient homozygous for HLA-B14,DR1 who had nonclassic 21 -hydroxylase deficiency. Five deviations from the normal genetic sequence of CYP21B were found, but only one appeared likely to affect the functional integrity of the protein: codon 281, GTG, encoding valine, was changed to 7TG, leucine. We constructed an oligonucleotide probe corresponding to the mutant DNA sequence surrounding codon 281 and hybridized the probe with DNA samples digested with the restriction endonuclease Taql. Samples from eight patients with nonclassic 21 -hydroxylase deficiency who had the haplotype HLA-B14,DR1 contained a hybridizing fragment 3700 base pairs long, indicating the presence of the valine-281 mutation in the CYP21B gene. In contrast, unaffected subjects and one patient with nonclassic deficiency who did not have HLA-B14,DR1 had no evidence of this mutation. We conclude that the mutation in codon 281 is a consistent molecular genetic marker for nonclassic 21-hydroxylase deficiency associated with HLA-B14,DR1. (N Engl J Med 1988;319:19–23.) THE molecular genetic basis of phenotypic diversity has been examined in the hemoglobinopathies and in inborn errors of metabolism involving enzyme deficiencies. A carefully studied example of the latter class of diseases is the most common form of congenital adrenal hyperplasia, steroid 21-hydroxylase deficiency.1 Cortisol synthesis is impaired in 21-hydroxylase deficiency because 17-hydroxyprogesterone cannot be converted to 11-deoxycortisol. The consequent excess secretion of corticotropin (ACTH) by the pituitary gland leads to overstimulation of the adrenal cortex and accumulation of steroids, including androgens, that do not require 21-hydroxylation for their synthesis. Patients with this disorder have signs of androgen excess: women.
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