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This version published online on June 17, 2008
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2008-0051
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Submitted on January 8, 2008
Accepted on June 6, 2008

Homozygous mutation G539R in the gene for P450 oxidoreductase in a family previously diagnosed as having 17,20 lyase deficiency

Eli Hershkovitz*, Ruthi Parvari, Stefan A. Wudy, Michaela F. Hartmann, Larissa G. Gomes, Neta Loewental, and Walter L. Miller

Pediatric Endocrinology and Metabolic Unit, Soroka Medical Center, Beer Sheva, Israel (E.H, N.L); Department of Developmental Genetics and Virology, Faculty of Health Sciences and the National Institute of Biotechnology Negev, Ben Gurion University of the Negev (R.P), Steroid Research Unit, Center of Child and Adolescent Medicine, Justus Liebig University, Giessen, Germany (S.A.W., M.H.); and Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143 (L.G.G., W.L.M.)

* To whom correspondence should be addressed. E-mail: elih{at}bgu.ac.il.

Context: Very few patients have been described with isolated 17,20 lyase deficiency who have had their mutations in P450c17 (17{alpha}-hydroxylase/17,20 lyase) proven by DNA sequencing and in vitro characterization of the mutations. Most patients with 17,20 lyase deficiency have mutations in the domain of P450c17 that interacts with the electron-donating redox partner, P450 oxidoreductase (POR).

Objective: To clarify the genetic and functional basis of isolated 17,20 lyase deficiency in familial cases who were previously reported as having 17,20 lyase deficiency.

Patients: Four undervirilized males of an extended Bedouin family were investigated. One of these has previously been reported to carry mutations in the CYP17A1 gene encoding P450c17 causing isolated 17,20 lyase deficiency.

Methods: Serum hormones were evaluated before and after stimulation with ACTH. Urinary steroid metabolites were profiled by gas chromatography-mass spectrometry (GC-MS). Exons 1 and 8 of CYP17A1 previously reported to harbor mutations in one of these patients and all 15 coding exons of POR were sequenced.

Results: GC-MS urinary steroid profiling and serum steroid measurements showed combined deficiencies of 17,20 lyase and 21-hydroxylase. Sequencing of exons 1 and 8 of CYP17A1 in two different laboratories showed no mutations. Sequencing of POR showed that all four patients were homozygous for G539R, a previously studied mutation that retains 46% of normal capacity to support the 17{alpha}-hydroxylase activity, but only 8% of the 17,20 lyase activity of P450c17.

Conclusion: POR deficiency can masquerade clinically as isolated 17,20-lyase deficiency.
Key words: P450 oxidoreductase • P450c17 (17{alpha}-hydroxylase/17,20 lyase) • hypogonadism






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