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Deleterious Missense Mutations and Silent Polymorphism in the Human 17ß-Hydroxysteroid Dehydrogenase 3 Gene (HSD17B3)¹

Cecil H. and Ida Green Center for Reproductive Biology Sciences and the Departments of Obstetrics-Gynecology and Biochemistry (N.M., S.A.), University of Texas Southwestern Medical Center, Dallas, Texas 75235; the Department of Pediatrics (I.A.H.), University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom; and the Department of Medicine (A.D.), Section of Diabetes and Metabolism, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033

Address all correspondence and requests for reprints to: Stefan Andersson, Ph.D., Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235-9051. E-mail: andersson{at}grnctr.swmed.edu

Isozymes of 17ß-hydroxysteroid dehydrogenase (17ßHSD) regulate levels of bioactive androgens and estrogens in a variety of tissues. For example, the 17ßHSD type 3 isozyme catalyzes the conversion of the inactive C₁₉-steroid androstenedione to the biologically active androgen, testosterone, in the testis. Testosterone is essential for the correct development of male internal and external genitalia; hence, deleterious mutations in the HSD17B3 gene give rise to a rare form of male pseudohermaphroditism termed 17ßHSD deficiency. Here, 2 additional missense mutations in the HSD17B3 gene in subjects with 17ßHSD deficiency are described. One mutation (A56T) impairs enzyme function by affecting NADPH cofactor binding. A second mutation (N130S) led to complete loss of enzyme activity. Also, a single base pair polymorphism in exon 11 of the HSD17B3 gene is described. The polymorphic A allele encodes a protein with a serine rather than a glycine at position 289 (GGT AGT). The frequency of the G allele (Gly) was 0.94, and that of the A allele (Ser) was 0.06. No difference in the frequencies of the G and A alleles was detected in 32 apparently normal women and 46 women with polycystic ovary syndrome. Enzymes bearing either glycine or serine at this position have similar substrate specificities and kinetic constants. The current findings boost to 16 the number of mutations in the HSD17B3 gene that impair testosterone synthesis and cause male pseudohermaphroditism, and add 1 apparently silent polymorphism to this tally.

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