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Differential Inhibition of 17-Hydroxylase and 17,20-Lyase Activities by Three Novel Missense CYP17 Mutations Identified in Patients with P450c17 Deficiency

Department of Pediatrics, Division of Endocrinology (E.L.T.v.d.A., A.L.M.B., S.L.S.D.), and Department of Internal Medicine, Section of Endocrinology (J.W.K., A.P.N.T., M.V.-P., M.A.T., F.H.D.J.), Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands; and Department of Pediatrics, Division of Endocrinology, Radboud University Hospital (B.J.O.), 6500 HB Nijmegen, The Netherlands

Address all correspondence and requests for reprints to: Dr. Frank H. de Jong, Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Room Bd 289, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. E-mail: dejong{at}endov.fgg.eur.nl.

Abstract

The microsomal enzyme cytochrome P450c17 is an important regulator of steroidogenesis. The enzyme has two functions: 17-hydroxylase and 17,20-lyase activities. These functions determine the ability of adrenal glands and gonads to synthesize 17-hydroxylated glucocorticoids (17-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 17-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 17-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) 17-hydroxylase and 17,20-lyase deficiencies, whereas mutations in the redox partner interaction domain (R347C and R347H) displayed less severe 17-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.

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