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- Title
Differential Inhibition of 17α-Hydroxylase and 17,20-Lyase Activities by Three Novel Missense CYP17 Mutations Identified in Patients with P450c17 Deficiency.
- Authors
VAN DEN AKKER, ERICA L. T.; KOPER, JAN W.; BOEHMER, ANNEMIE L. M.; THEMMEN, AXEL P. N.; VERHOEF-POST, MIRIAM; TIMMERMAN, MARIANNA A.; OTTEN, BARTO J.; DROP, STENVERT L. S.; DE JONG, FRANK H.
- Abstract
he microsomal enzyme cytochrome P450c17 is an important regulator of steroidogenesis. The enzyme has two functions: 17α-hydroxylase and 17,20-lyase activities. These functions determine the ability of adrenal glands and gonads to synthesize 17α-hydroxylated glucocorticoids (17α-hydroxylase activity) and/or sex steroids (17,20-lyase activity). Both enzyme functions depend on correct steroid binding, but it was recently shown that isolated lyase deficiency can also be caused by mutations located in the redox partner interaction domain. In this article we present the clinical history and molecular analysis of two patients with combined 17α-hydroxylase/17,20-lyase deficiency and four patients with isolated 17,20-lyase deficiency. In these six patients, four missense CYP17 mutations were identified. Two mutations were located in the steroid-binding domain (F114V and D116V), and the other two mutations were found in the redox partner interaction domain (R347C and R347H). We investigated the activity of these mutated proteins by transfection experiments in COS-1 cells using pregnenolone, progesterone, or their hydroxylated products as a substrate and measuring 17α-hydroxylase- and 17,20-lyase-dependent metabolites in the medium. The mutations in the steroid-binding domain (F114V and D116V) of P450c17 caused combined, complete (F114V), or partial (D116V) 17α-hydroxylase and 17,20-lyase deficiencies, whereas mutations in the redox partner interaction domain (R347C and R347H) displayed less severe 17α-hydroxylase deficiency, but complete 17,20-lyase deficiency. These findings are consistent with the clinical data and support the observation that the redox partner interaction domain is essential for normal 17,20-lyase function of P450c17.
- Publication
Journal of Clinical Endocrinology & Metabolism, 2002, Vol 87, Issue 12, p5714
- ISSN
0021-972X
- Publication type
journal article
- DOI
10.1210/jc.2001-011880