The pathophysiology and genetics of congenital lipoid adrenal hyperplasia

Background Congenital lipoid adrenal hyperplasia results in severe impairment of steroid biosynthesis in the adrenal glands and gonads that is manifested both in utero and postnatally. We recently found mutations in the gene for the steroidogenic acute regulatory protein in four patients with this syndrome, but it was not clear whether all patients have such mutations or why there is substantial clinical variation in these patients. Methods We directly sequenced the gene for steroidogenic acute regulatory protein in 15 patients with congenital lipoid adrenal hyperplasia from 10 countries. Identified mutations were confirmed and recreated in expression vectors, transfected into cultured cells, and assayed for the presence and activity of steroidogenic acute regulatory protein. Results Fifteen different mutations in the gene for steroidogenic acute regulatory protein were found in 14 patients; the mutation Gln258Stop was found in 80 percent of affected alleles from Japanese and Korean patients, and the mutation Arg182Leu was found in 78 percent of affected alleles from Palestinian patients. We developed diagnostic tests for these and eight other mutations. Thirteen of the 15 mutations were in exons 5, 6, or 7, and all rendered the steroidogenic acute regulatory protein inactive in functional assays. Some mutants with amino acid replacements were capable of normal mitochondrial processing, indicating that the activity of steroidogenic acute regulatory protein is not associated with its translocation into mitochondria. Steroidogenic cells lacking the protein retained low levels of steroidogenesis. This explains the secretion of some steroid hormones by the ovaries after puberty before affected cells accumulate large amounts of cholesterol esters. Conclusions The congenital lipoid adrenal hyperplasia phenotype is the result of two separate events, an initial genetic toss of steroidogenesis that is dependent on steroidogenic acute regulatory protein and a subsequent loss of steroidogenesis that is independent of the protein due to cellular damage from accumulated cholesterol esters.