Molecular genetics and the characterization of steroid 21-hydroxylase deficiency

Classical 21-hydroxylase deficiency congenital adrenal hyperplasia is a monogenic autosomal recessive disorder that has been conclusively shown by family HLA-typing studies to be in close genetic linkage with the human major histocompatibility complex. More recently recognized is the nonclassical disorder, an attenuated form of 21-hydroxylase deficiency characterized variably by late onset or absence of symptoms. Certain of the mild 21-hydroxylase deficiency allotypes involved in the nonclassical disorder have also been shown to be genetically linked with HLA, exhibiting distinct (B and B,DR) antigen associations. The nonclassical disorder is now also known to result from different genotypes: two mild 21-hydroxylase defects in conjunction, or a mild defect occurring with a severe (classical) defect. Restriction mapping and hybridization analysis have located two highly homologous base sequences, one structural gene coding for 21-hydroxylase and one pseudogene, in the Class III region of the MHC in tandem with the A and B genes for C4, the fourth component of complement. Current work documenting and characterizing gene abnormalities, as well as elucidating the molecular genetic basis of the mutations that have arisen, is aimed at developing better cDNA probes for prenatal diagnosis by amniocentesis and chorionic villus biopsy. In addition, because of the close association of the C4 and 21-hydroxylase genes, coordination of data on C4 variants and null alleles with altered 21-hydroxylase activity is improving understanding of the genetic mechanisms generating disease alleles of this enzyme crucial for normal endocrine function.