Mutation R96W in cytochrome P450c17 gene causes combined 17 alpha-hydroxylase/17-20-lyase deficiency in two French Canadian patients.
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Laflamme N, Leblanc JF, Mailloux J, Faure N, Labrie F, Simard J
Mutation R96W in cytochrome P450c17 gene causes combined 17 alpha-hydroxylase/17-20-lyase deficiency in two French Canadian patients.
J Clin Endocrinol Metab. 1996 Jan;81(1):264-8.
- PubMed ID
- 8550762 [ View in PubMed]
- Abstract
Congenital adrenal hyperplasia (CAH) is the most frequent cause of adrenal insufficiency and ambiguous genitalia in newborn children. In contrast to CAH caused by 21 alpha-hydroxylase and 11 beta-hydroxylase deficiencies, which impairs steroid formation in the adrenal exclusively, 17 alpha-hydroxylase/17,20-lyase deficiency impairs steroid biosynthesis in the adrenals and gonads. The sequence of CYP17 gene was determined by direct sequencing of asymmetric PCR products in two French-Canadian 46,XY pseudohermaphrodite siblings suffering from combined 17 alpha-hydroxylase/17,20-lyase deficiency. The two patients are homozygous for the novel missense mutation R96W caused by a C to T transition converting codon Arg96 (CGG) into a Trp (TGG) in exon 1. The both parents are heterozygous for this missense mutation. We assessed the effect of the R96W mutation on 17 alpha-hydroxylase/17,20-lyase activity by analysis of mutant enzyme, generated by site-directed mutagenesis, expressed in COS-1 cells. The presence of R96W substitution almost completely abolished the activity of the mutant protein. The present findings provide a molecular explanation for the signs and symptoms of combined 17 alpha-hydroxylase/17,20-lyase deficiency in these two patients and provide useful information on the structure-activity relationships of the P450c17, enzyme.