Heterozygous mutation in the cholesterol side chain cleavage enzyme (P450scc) gene in a patient with 46,XY sex reversal and adrenal insufficiency

Cytochrome P450scc, the mitochondrial cholesterol side chain cleavage enzym e, is the only enzyme that catalyzes the conversion of cholesterol to pregn enolone and, thus, is required for the biosynthesis of all steroid hormones . Congenital lipoid adrenal hyperplasia is a severe disorder of steroidogen esis in which cholesterol accumulates within steroidogenic cells and the sy nthesis of all adrenal and gonadal steroids is impaired, hormonally suggest ing a disorder in P450scc. However, congenital lipoid adrenal hyperplasia i s caused by mutations in the steroidogenic acute regulatory protein StAR; i t has been thought that P450scc mutations are incompatible with human term gestation, because P450scc is needed for placental biosynthesis of progeste rone, which is required to maintain pregnancy. In studying patients with co ngenital lipoid adrenal hyperplasia, we identified an individual with norma l StAR and SF-1 genes and a heterozygous mutation in P450scc. The mutation was found in multiple cell types, but neither parent carried the mutation, suggesting it arose de novo during meiosis, before fertilization. The patie nt was atypical for congenital lipoid adrenal hyperplasia, having survived for 4 yr without hormonal replacement before experiencing life-threatening adrenal insufficiency. The P450scc mutation, an in-frame insertion of Gly a nd Asp between Asp271 and Val272, was inserted into a catalytically active fusion protein of the P450scc system (H2N-P450sceAdrenodoxin Reductase-Adre nodoxin-COOH), completely inactivating enzymatic activity. Cotransfection o f wild-type and mutant vectors showed that the mutation did not exert a dom inant negative effect. Because P450scc is normally a slow and inefficient e nzyme, we propose that P450scc haploinsufficiency results in subnormal resp onses to ACTH, so that recurrent ACTH stimulation leads to a slow accumulat ion of adrenal cholesterol, eventually causing cellular damage. Thus, altho ugh homozygous absence of P450scc should be incompatible with term gestatio n, haploinsufficiency of P450scc causes a late-onset form of congenital lip oid adrenal hyperplasia that can be explained by the same two-hit model tha t has been validated for congenital lipoid adrenal hyperplasia caused by St AR deficiency.