BRCA 2 is essential for ovarian development - novel genes and pathways in gonadal differentiation

Aberrations in the complicated molecular cascade leading to testis or ovarian development can cause gonadal dysgenesis, and infertility. It is now evident that ovarian development (OD) is an active process involving signaling pathways of somatic and germ cells. As XX Gonadal Dysgenesis is clinically rare less is known of the gene network underlying female development. The high rate of consanguinity in Palestinians, enabled the identification of a unique genetic resource (30 families) with familial XX-Disorders of Sexual Development (XX-DSD). We elucidated 5 novel genetic aetiologies for XXDSD including the PSMC-3IP, MCM8, BRCA2, SF-1 and the Nup107 genes. The drosophila animal model served for functional studies. Strikingly, the transgenic NUP107 Drosophila females mimicked the human phenotype, 40-60% of the female mutant flies had non- or under-developed ovaries and all were almost completely sterile with disintegrating egg chambers and increased apoptosis. The larval gonads were fully present, but the mutated ones contained excess primordial germ cells (PGCs) and less intermingled cells (ICs). Transcriptome analysis of larval and adult ovaries identified several genes whose expression is significantly affected by the mutation. For BRCA2 - Two sisters with XX-ovarian dysgenesis carried compound heterozygous truncating BRCA2 mutations, leading to reduced BRCA2 levels and an impaired DNA-damage response with failure of RAD51 to be recruited to double-strand DNA breaks. Drosophila mutants null for a BRCA2 ortholog were sterile, with gonadal dysgenesis in both sexes. These results reveal a novel role for BRCA2 and highlight the importance to ovarian development of genes critical to recombination during meiosis.