MOLECULAR-GENETICS AND PATHOPHYSIOLOGY OF 17-BETA-HYDROXYSTEROID DEHYDROGENASE-3 DEFICIENCY

Autosomal recessive mutations in the 17 beta-hydroxysteroid dehydrogen ase 3 gene impair the formation of testosterone in the fetal testis an d give rise to genetic males with female external genitalia. Such indi viduals are usually raised as females, but virilize at the time of exp ected puberty as the result of increases in serum testosterone. Here w e describe mutations in 12 additional subjects/families with this diso rder. The 14 mutations characterized to date include 10 missense mutat ions, 3 splice junction abnormalities, and 1 small deletion that resul ts in a frame shift. Three of these mutations have occurred in more th an 1 family. Complementary DNAs incorporating 9 of the 10 missense mut ations 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 testost erone formation in postpubertal subjects with this disorder is the con version of circulating androstenedi one to testosterone by one or more of the unaffected 17 beta-hydroxysteroid dehydrogenase isoenzymes.