Steroid 21-hydroxylase deficiency is the most frequent cause of congenital adrenal hyperplasia, an inherited inability to synthesize cortisol. Mutations causing this disorder have been characterized by hybridization analysis of patient DNA samples using cDNA and oligonucleotide probes, and by cloning and sequencing of mutant 21-hydroxylase (CYP21B) genes. About 20% of mutant alleles carry a 30 kilobasepair deletion that includes the 3' end of the CYP21A pseudogene, the C4B complement gene, and the 5' end of CYP21B, leaving behind a single CYP21A-like gene that is not functional. Non-deletional mutations include a nonsense mutation at codon 318 that is associated with severe disease and missense mutations at codons 172 (isoleucine to asparagine) and 281 (valine to leucine) that are respectively associated with intermediate and mild deficiency states. All of these alleles have apparently resulted from gene conversion events that have transferred deleterious mutations from the CYP21A pseudogene to CYP21B. Thus, recombinations between CYP21A and CYP21B probably account for the majority of 21-hydroxylase deficiency alleles.
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