Mutations in NR5A1 Associated with Ovarian Insufficiency

作者：Lourenco Diana; Brauner Raja; Lin Lin; De Perdigo Arantzazu; Weryha Georges; Muresan Mihaela; Boudjenah Radia; Guerra Junior Gil; Maciel Guerra Andrea T; Achermann John C; McElreavey Ken; Bashamboo Anu^*

来源：New England Journal of Medicine, 2009, 360(12): 1200-1210.

DOI：10.1056/NEJMoa0806228

Background
The genetic causes of nonsyndromic ovarian insufficiency are largely unknown. A nuclear receptor, NR5A1 (also called steroidogenic factor 1), is a key transcriptional regulator of genes involved in the hypothalamic-pituitary-steroidogenic axis. Mutation of NR5A1 causes 46, XY disorders of sex development, with or without adrenal failure, but growing experimental evidence from studies in mice suggests a key role for this factor in ovarian development and function as well.
Methods
To test the hypothesis that mutations in NR5A1 cause disorders of ovarian development and function, we sequenced NR5A1 in four families with histories of both 46, XY disorders of sex development and 46, XX primary ovarian insufficiency and in 25 subjects with sporadic ovarian insufficiency. None of the affected subjects had clinical signs of adrenal insufficiency.
Results
Members of each of the four families and 2 of the 25 subjects with isolated ovarian insufficiency carried mutations in the NR5A1 gene. In-frame deletions and frame-shift and missense mutations were detected. Functional studies indicated that these mutations substantially impaired NR5A1 transactivational activity. Mutations were associated with a range of ovarian anomalies, including 46, XX gonadal dysgenesis and 46, XX primary ovarian insufficiency. We did not observe these mutations in more than 700 control alleles.
Conclusions
NR5A1 mutations are associated with 46, XX primary ovarian insufficiency and 46, XY disorders of sex development.

• 出版日期2009-3-19