A NOVEL SPLICING JUNCTION MUTATION IN THE GENE FOR THE STEROIDOGENIC ACUTE REGULATORY PROTEIN CAUSES CONGENITAL LIPOID ADRENAL-HYPERPLASIA

Congenital lipoid adrenal hyperplasia (lipoid CAH) is a relatively com mon genetic disorder of adrenal and gonadal steroidogenesis and is the most severe form of CAH. As typical affected individuals cannot produ ce any steroid hormones or can only produce low levels of steroid horm ones in the adrenals and gonads, including glucocorticoids, mineralcor ticoids, and sex steroids, a genetic defect in the cholesterol side-ch ain cleavage enzyme, cytochrome P450scc (CYPXIA1), has been postulated to be the cause of their insufficient production to date. Recently, L in and co-workers proved a link between mutations of the steroidogenic acute regulatory protein (StAR) gene and the lipoid CAH phenotype. Th erefore, we investigated both the cytochrome P450scc and StAR genes in a Korean family with a fairly mild form of Lipoid CAH to identify the mutation(s) causing this disease. The result was that no mutations co uld be found in the two genes, except for a thymine (T) insertion into intron 2 of the StAR gene, 3 bp from the splice donor site of exon 2. PCR-amplified StAR genes from a normal subject and the patient were c loned into an expression vector and then introduced into COS-7 cells. Northern blot and reverse transcriptase-PCR analyses indicated that th e StAR messenger ribonucleic acid derived from the vector with the nor mal StAR gene spliced exons 2 and 3 correctly, whereas most, but not a ll, StAR messenger ribonucleic acid derived from the vector with the T -inserted StAR gene could not remove intron 2. We concluded from these results that the T insertion into the StAR gene accounts for the lipo id CAH phenotype in this patient.