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Novel P450c17 Mutation H373D Causing Combined 17-Hydroxylase/17,20-Lyase Deficiency

Division of Endocrinology (T.S., M.K.T., W.L.M.), Department of Pediatrics, University of California San Francisco, San Francisco, California 94143-0978; and Division of Pediatric Endocrinology (P.W.S.), Schneider Children’s Hospital, New York University, New Hyde Park, New York 11040

Address all correspondence and requests for reprints to: Walter L. Miller, M.D., Professor of Pediatrics and Chief of Endocrinology, HSE 1427, University of California–San Francisco, San Francisco, California 94143-0978. E-mail: wlmlab{at}ucsf.edu.

Context: Combined 17-hydroxylase/17,20-lyase deficiency is a rare autosomal recessive form of congenital adrenal hyperplasia presenting with hypertension and sexual infantilism. This disorder is caused by defects in P450c17, encoded by the CYP17A1 gene.

Objective: We describe a 14-yr-old female with clinical and hormonal features of 17-hydroxylase/17,20-lyase deficiency and identify and characterize the activities of her CYP17A1 mutations.

Methods: The coding regions of the CYP17A1 gene were amplified by PCR and sequenced. Mutations were recreated in P450c17 cDNA expression vectors; activities in transfected COS-1 cells were assayed by conversion of radiolabeled precursor steroids. One mutant was also expressed in Escherichia coli, and the reduced adsorption spectrum was measured.

Results: The patient carried the previously described mutation R96W and the novel missense mutation H373D. Neither mutant had detectable activity when expressed in COS-1 cells. Membrane preparations from E. coli expressing the H373D mutant vector produced an absorption peak at 420 nm, whereas the wild-type produced a peak at 450 nm, suggesting that the H373D mutation interferes with protein folding.

Conclusion: The novel P450c17 mutation H373D abolished enzyme activity because of protein misfolding. These data indicate an important role for this residue in P450c17 activity.