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Two Prevalent CYP17 Mutations and Genotype-Phenotype Correlations in 24 Brazilian Patients with 17-Hydroxylase Deficiency

Division of Endocrinology and Metabolism, Department of Medicine, Escola Paulista de Medicina, Federal University of Sao Paulo (M.C.-S., C.E.K.), Sao Paulo, Brazil 04039-034; and Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center (R.J.A.), Dallas, Texas 75390-8857

Address all correspondence and requests for reprints to: Richard J. Auchus, M.D., Ph.D., Division of Endocrinology and Metabolism, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-8857. E-mail: richard.auchus{at}utsouthwestern.edu.

We performed molecular genetic analysis of 24 subjects from 19 families with 17-hydroxylase deficiency in Brazil. Of 7 novel CYP17 mutations, 2 (W406R and R362C) account for 50% and 32% of the mutant alleles, respectively. Both mutations were completely inactive when studied in COS-7 cells and yeast microsomes; however, phenotypic features varied among subjects. Some 46,XY individuals with these genotypes had ambiguous genitalia, and other subjects had normal blood pressure and/or serum potassium. We found mutations W406R and R362C principally in families with Spanish and Portuguese ancestry, respectively, suggesting that two independent founder effects contribute to the increased prevalence of 17-hydroxylase deficiency in Brazil. Mutations Y329D and P428L retained a trace of activity, yet the two individuals with these mutations had severe hypertension and hypokalemia. The 46,XX female with mutation Y329D reached Tanner stage 5, whereas the 46,XY subject with mutation P428L remained sexually infantile. The severity of hypertension, hypokalemia, 17-deoxysteroid excess, and sex steroid deficiency varied, even among patients with completely inactive CYP17 protein(s). Spontaneous sexual development occurred only in 46,XX females with partial deficiencies. We conclude that other factors, in addition to CYP17 genotype, contribute to the phenotype of individual patients with 17-hydroxylase deficiency.

This work was supported by NIH Grants K08-DK-02387 and R03-DK-56641 (to R.J.A.) and by grants from Fundação de Amparo à Pequisa do Estado de Sâo Paulo (96/7449-6) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (0690/00-7; to C.E.K.).

Results from this work were presented in abstract form at the 83rd Annual Meeting of The Endocrine Society, Denver, CO, June 2001.

Abbreviations: CAH, Congenital adrenal hyperplasia; CPR, cytochrome P450-oxidoreductase; DOC, 11-deoxycorticosterone; 17OHD, 17-hydroxylase deficiency.

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