Absence of steroid biosynthetic defects in heterozygote individuals for classic 11 beta-hydroxylase deficiency due to a R448H mutation in the CYP11B1 gene.

Abstract

Steroid 11 beta-hydroxylase deficiency (failure to convert 11-deoxy-cortisol to cortisol) is responsible for less than 5% of cases of classic congenital adrenal hyperplasia, but it is relatively frequent in Israel, among Jews of Moroccan origin. Affected individuals have a single base substitution in exon 8 of CYP11B1 gene, codon 448, from CGC (arginine) to CAC (histidine) (R448H), a mutation that abolishes enzyme activity completely. We studied the hormonal response to ACTH stimulation in individuals genotyped to have the R448H mutation in one allele only (heterozygotes), and who were therefore assumed to have 50% of 11 beta-hydroxylase activity. No demonstrable hormonal abnormalities were found in the 6 adults (3 mothers and 3 fathers) and 2 sons studied, suggesting that a quantitatively reduced 11 beta-hydroxylase is still enough for normal adrenal biosynthesis.