Compound heterozygous mutations in the cholesterol side-chain cleavage enzyme gene (CYP11A) cause congenital adrenal insufficiency in humans.

Cholesterol side-chain cleavage enzyme (P450scc) catalyzes the conversion of cholesterol to pregnenolone in mitochondria, which is the first step in the biosynthesis of all steroid hormones. Until now, no homozygous or compound heterozygous mutations in CYP11A have been described in humans. Here we describe novel compound heterozygous mutations in CYP11A in a patient with congenital adrenal insufficiency born to healthy parents. One mutation, a maternally inherited R353W mutation, resulted in markedly reduced P450scc activity by the single amino acid substitution, indicating that Arg(353) is a crucial amino acid residue for P450scc activity. The other mutation, a de novo A189V mutation in the paternal allele, did not affect the P450scc activity by the single amino acid substitution and turned out to be a splicing mutation, which created a novel alternative splice-donor site. It resulted in a deletion of 61 nucleotides in the open reading frame and thus partially inactivated CYP11A. These experimental data are consistent with the clinical findings indicating that the patient had partially preserved ability to synthesize adrenal steroid hormones. This is the first report of the compound heterozygote for the CYP11A mutations with congenital adrenal insufficiency and the phenotypically normal heterozygote in humans.