STEROID 21-HYDROXYLASE GENE ANALYSIS IN CONGENITAL ADRENAL HYPERPLASIA

Abstract

Congenital adrenal hyperplasia (CAH) is usually due to an autosomal recessive defect in 21-hydroxylation of steroid hormones. The human gene for 21-hydroxylation, P450c21B, is closely linked to its inactive homologue, P450c21A. We have cloned a human P450c21 cDNA and used it to determine the restriction patterns of 51 members of 10 different families, each with 2 or more CAH cases. Following digestion of genomic DNA with EcoRI or TagI, patterns reported by others to indicate P450c21B gene deletions (absent 12- or 3.7-kb fragments) were seen for 6/20 CAH and 6/20 normal P450c21B alleles. Following digestion with Bg1II, EcoRI, KpnI, TaqI, or XbaI normal P450c21B gene patterns were seen in all CAH samples with at least 2 enzymes. Linkage analysis indicates the P450c21 alleles co-segregate with CAH (no recombinants seen in 15 informative meioses). We conclude 1) P450c21B gene “deletions” detected by others using single enzyme digestions may, in some cases, represent gene conversions, polymorphisms or unequal crossover products rather than simple deletions and 2) while prenatal diagnosis of CAH is feasible by linkage analysis in 8/10 families studied to avoid errors the patterns of all family members should be studied before inferring the CAH status of the fetus from restriction patterns.