ABSTRACT
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.
Subject(s)
17-Hydroxysteroid Dehydrogenases/deficiency , Isoenzymes/deficiency , 17-Hydroxysteroid Dehydrogenases/genetics , Adolescent , Adult , Base Sequence , Child , Child, Preschool , Female , Humans , Isoenzymes/genetics , Male , Molecular Sequence Data , Mutation , Testosterone/bloodABSTRACT
We measured dehydroepiandrosterone sulfate (DHEA-S) levels in children before and after high dose prednisone therapy. In older children (postadrenarchal), there was a 70% decrease in DHEA-S levels after 1 week. However, even after a month of therapy, DHEA-S was detectable in serum. In contrast, in younger (preadrenarchal) children, the low initial DHEA-S levels were not decreased by prednisone therapy. These findings suggest that there are two distinct regulatory pathways leading to DHEA-S, one of which is independent of ACTH.