Background: Though the genes and signalling pathways involved in sexual development have only been partially elucidated, it is known that their disruption can result in disorders of sexual development (DSD). XX ovarian dysgenesis (XX-OD) is a rare, genetically heterogeneous disorder characterized by underdeveloped and dysfunctional ovaries. We previously identified a novel missense mutation in Nucleoporin107 (Nup107, c.1339G>A, p.D447N), an essential component of the nuclear pore complex, as the cause of XX-OD in a consanguineous family.
Methods: The Nup107 mutation (D364N) was modelled in Drosophila, a powerful genetic tool sharing gene orthologues and fundamental pathways with humans, specifically in gonadogenesis. The structural integrity and presence of both adult mutant ovaries and the earlier-stage larval gonad were assessed using dissection. Differential gene expression between mutant and wild-type larval gonads was measured using genome-wide RNA-Seq followed by qRT-PCR. Immunohistochemistry was used to characterize cellular and signalling effects of the Nup107 mutation on both adult and larval stage ovaries.
Results: The Nup107 mutant flies directly mirrored the human phenotype of ovarian dysgenesis, where 40% of female transgenic flies possessed under- or non-developed ovaries. In contrast, the larval gonads were fully present, signifying that the underlying defects causing the condition occur following the larval gonad formation. The RNA-Seq studies revealed candidate genes with differential gonadal expression resulting from the Nup107 mutation, most of which possess human orthologs, including genes such as the serine protease scarface and ECM protein collagen type IVa1. Several of the candidates were found to be related to the Dpp/BMP signalling pathway. Antibody staining revealed both excess primordial germ cells (PGCs) in the larval gonad and high numbers of germline stem cells (GSCs) in the adult ovary phenotypes resembling that of Dpp/BMP overactivation and suggesting problematic germ cell differentiation.
Conclusion: The transcriptomic and cellular analyses strongly suggest that ovarian failure resulting from Nup107 mutation is mediated through the BMP pathway. This concept has implications for clinical evaluation as the human BMP signalling pathway and specifically BMP15 and BMP receptor BmprIB have been implicated in subfertility, and have been shown to be essential for female reproductive function. Testing of this pathway may be indicated in clinical cases of XX-DSD and premature ovarian failure.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology