Steroidogenic factor-1 (SF-1) regulates multiple genes involved in the adrenal and gonadal development and in the biosynthesis of a variety of
hormones, including adrenal and gonadal
steroids,
anti-Mullerian hormone (AMH), and
gonadotropins. We identified a novel SF-1 mutation in a 27-yr-old Japanese patient with a 46,XY karyotype. Sequence analysis was performed for all the seven exons of SF-1, revealing a heterozygous single base pair deletion at exon 2 (18delC) that is predicted to cause a frameshift at the sixth
codon and resultant termination at the 74th
codon. Functional studies showed that the mutation produced no demonstrable
protein and had no transcription activity or dominant negative effect. Clinical features included small dysgenetic testes with vasa deferentia and epididymides, absent uterus, blind-ending vagina, clitoromegaly, and psychosexual disturbance. Endocrine studies showed normal adrenal function (
cortisol response to
ACTH stimulation, 13.4-->25.3 microg/dl) and primary
hypogonadism (
testosterone response to hCG stimulation, 0.57-->0.76 ng/ml;
gonadotropin responses to
GnRH stimulation: LH, 10-->59 mIU/ml; FSH, 36-->69 mIU/ml), and urinary
steroid hormone profile analysis indicated grossly normal steroidogenic
enzyme activities. The results suggest that SF-1 haploinsufficiency can selectively impair testicular development and permit the biosynthesis of AMH and
testosterone in dysgenetic testes and the production of
gonadotropins in pituitary gonadotropes.