A review of the literature on common CYP17A1 mutations in adults with 17-hydroxylase/17,20-lyase deficiency, a case series of such mutations among Koreans and functional characteristics of a novel mutation.

OBJECTIVE: 17α-hydroxylase/17,20-lyase deficiency is a rare form of congenital adrenal hyperplasia, characterized by hypertension and sexual infantilism and caused by loss-of-function mutations in CYP17A1. This study investigated the clinical and molecular characteristics of six adults with 17α-hydroxylase/17,20-lyase deficiency and the functional consequences of a novel CYP17A1 mutation.

MATERIALS AND METHODS: Six phenotypic females, three with 46,XY and three with 46,XX karyotypes, presented with primary amenorrhea and hypertension. All had elevated levels of plasma adrenocorticotropic hormone, serum gonadotropin, progesterone, and 11-deoxycorticosterone, and reduced testosterone and dehydroepiandrosterone sulfate (DHEA-S). All coding exons and flanking intronic sequences of CYP17A1 were directly sequenced using genomic DNA. Wild-type and mutant CYP17A1 cDNAs were inserted into the pcDNA3.1/V5-His-P450c17 vector, and transiently expressed in COS-7 cells. This was followed by an assessment of 17α-hydroxylase and 17,20-lyase activities by measuring the conversions of progesterone to 17-hydroxyprogesterone and 17-hydroxypregnenolone to DHEA.

RESULTS: The mutation analysis identified one patient with compound heterozygosity for p.H373L and p.W406L, one with compound heterozygosity for p.H373L and p.A174E, three with compound heterozygosity for p.Y329fs and p.H373L, and one with homozygosity for p.H373L. An in vitro functional analysis of the novel p.W406L mutation revealed a complete loss of 17α-hydroxylase/17, 20-lyase activities.

CONCLUSIONS: p.H373L was the most common mutation among these Korean patients, consistent with the high allele frequency of p.H373L in Chinese and Japanese populations, suggesting possible founder effects in Asian countries. The novel p.W406L mutation caused a complete loss of both catalytic activities, indicating that this amino acid is critical for P450c17 function.