Analysis of the duplicated human C4/P450c21/X gene cluster

Gene duplications, deletions and rearrangements occur with an unusually high frequency in the region of the P450c21 genes encoding 21-hydroxylase. In the human genome, the locus contains at least 6 genes, oriented 5' C4A, P450c21A, XA, C4B, P450c21B, XB 3'. Sequence analysis of the XA gene, of the 5' flanking DNA of the C4A gene, and of part of the XB gene revealed that this gene cluster was duplicated by nonhomologous recombination at a CAAG tetranucleotide. The location of this duplication suggests that it may have occurred after mammalian speciation. The XA gene is abundantly expressed in the human adrenal as a stable 2.6 kb RNA, but it is not known if that RNA serves a biological function. Knowledge of the anatomy of the XA gene facilitates genetic analysis of disease-causing lesions in the P450c21B gene. Southern blotting data show that about 76% of disordered P450c21B alleles bear gene microconversions that resemble point mutations; the remaining alleles are equally distributed between gene deletions and large gene conversions.