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Molecular Study of the 3ß-Hydroxysteroid Dehydrogenase Gene Type II in Patients with Hypospadias

Institute of Maternal and Child Research (E.C., C.O., G.I., M.A.B., M.C.J., F.C.), School of Medicine, University of Chile; and Hospital Clínico San Borja Arriarán (E.C., A.A.), National Health Service, Santiago, Chile

Address all correspondence and requests for reprints to: Fernando Cassorla, M.D., Casilla 226-3, Santiago, Chile. E-mail: fcassorl{at}machi.med.uchile.cl.

To determine whether some patients with idiopathic hypospadias have HSD3B2 mutations, we genotyped this locus in 90 patients with hypospadias (age, 6.0 ± 0.4 yr) and 101 healthy fertile male controls. We measured basal plasma renin activity and performed an ACTH test for determination of 17-OH-pregnenolone, 17-OH-progesterone, cortisol, dehydroepiandrosterone sulfate, and androstenedione and an human chorionic gonadotropin test for determination of androstenedione, testosterone, and dihydrotestosterone. We did not observe a clear steroidogenic pattern suggestive of 3ß-HSD deficiency in any patient. DNA was extracted from peripheral lymphocytes; and exons 1, 2, 3, and 4 were amplified by PCR and analyzed by denaturing gradient gel electrophoresis. An abnormal electrophoretic migration pattern of exon 4 was observed in five patients. Two patients had missense heterozygous mutations (S213T and S284R). In another three patients, we observed heterozygous nucleotide variants in exon 4 that did not produce a change in amino acids (A238, T259, T320). In vitro enzymatic activity was diminished by 40% and 32% in the S213T and S284R heterozygous mutations, respectively. One control exhibited a heterozygous mutation in exon 3 (V78I), which did not alter in vitro enzyme activity. In addition, we observed possible polymorphisms in intron 1 in four patients and one control. We conclude that subtle molecular abnormalities in the HSD3B2 gene may be observed in some patients with apparent idiopathic hypospadias but that this finding is uncommon.

This work was supported by FONDECYT 1990628 (to F.C.).

E.C. and C.O. contributed equally to this study and should be considered first authors.

Abbreviations: CV, Coefficient of variation; DGGE, denaturing gradient gel electrophoresis; DHEA, dehydroepiandrosterone; HCG, human chorionic gonadotropin; HSD, hydroxysteroid dehydrogenase; 17OH Preg, 17-OH-pregnenolone; 17OH Prog, 17-OH-progesterone; TBS, Tris-buffered saline.

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