Molecular genetics and pathophysiology of 17β-hydroxysteroid dehydrogenase 3 deficiency

• Published in: The journal of clinical endocrinology and metabolism Vol. 81; no. 1; pp. 130 - 136
• Main Authors: ANDERSSON, S, GEISSLER, W. M, WITCHEL, S. F, CUTLER, G. B, GRIFFIN, J. E, WILSON, J. D, RUSSELL, D. W, WU, L, DAVIS, D. L, GRUMBACH, M. M, NEW, M. I, SCHWARZ, H. P, BLETHEN, S. L, MENDONCA, B. B, BLOISE, W
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 1996
• Subjects: 17-Hydroxysteroid Dehydrogenases - deficiency; 17-Hydroxysteroid Dehydrogenases - genetics; Adolescent; Adult; Base Sequence; Biological and medical sciences; Child; Child, Preschool; Female; Gynecology. Andrology. Obstetrics; Humans; Isoenzymes - deficiency; Isoenzymes - genetics; Male; Male and female genital diseases. Gonadal dysgenesis. Hermaphroditism. Sex hormones resistance; Medical sciences; Molecular Sequence Data; Mutation; Testosterone - blood; Endocrinopathy; Human; Testosterone; Androgen; Deficiency; Virilism; Female; Testicular hormone; Sex steroid hormone; Sexual differentiation
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.81.1.130

Autosomal recessive mutations in the 17 beta-hydroxysteroid dehydrogenase 3 gene impair the formation of testosterone in the fetal testis and give rise to genetic males with female external genitalia. Such individuals are usually raised as females, but virilize at the time of expected puberty as the result of increases in serum testosterone. Here we describe mutations in 12 additional subjects/families with this disorder. The 14 mutations characterized to date include 10 missense mutations, 3 splice junction abnormalities, and 1 small deletion that results in a frame shift. Three of these mutations have occurred in more than 1 family. Complementary DNAs incorporating 9 of the 10 missense mutations have been constructed and expressed in reporter cells; 8 of the 9 missense mutations cause almost complete loss of enzymatic activity. In 2 subjects with loss of function, missense mutations testosterone levels in testicular venous blood were very low. Considered together, these findings strongly suggest that the common mechanism for testosterone formation in postpubertal subjects with this disorder is the conversion of circulating androstenedione to testosterone by one or more of the unaffected 17 beta-hydroxysteroid dehydrogenase isoenzymes.