Molecular genetics and pathophysiology of 17 beta-hydroxysteroid dehydrogenase 3 deficiency.

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.