Endocrine Abstracts

BMP15 is a TGFβ-like oocyte-derived growth factor involved in ovarian folliculogenesis as a critical regulator of many granulosa cell processes. BMP15 is synthesized as a pro-protein which dimerizes and then is processed in the bioactive mature domain and a large prodomain. The proregion has an important role in the BMP15 processing by driving the dimerization and secretion of the active mature dimers. Since several mutations in the BMP15 gene have been found with different ovarian phenotipic effects, its role seems to differ between mono- and poly-ovulatory species. In fact, heterozygous natural mutations in mono-ovulating sheep cause increased ovulation rates, while poly-ovulating bmp15^−/− null mice are subfertile. In humans, almost all the identified BMP15 mutations are located in the proregion, in heterozygosity and associated with Primary Ovarian Insufficiency (POI). To investigate the BMP15 role in controlling ovarian function in mammals, a phylogenetic analysis of sereval TGFβ/BMP family members was performed. BMP15 shows a very early divergence and a more rapid evolution than other members of the family. Using branch-site models from PAML packages, we detected signals of positive selection for the following residues: F146, L189, I229, Y235, R244. Among them, the Y235C mutation was previously identified in association with primary amenorrhea and ovarian dysgenesis. By luciferase reporter assay, the biological activity of the wild-type (wt) BMP15 was compared to those of mutant variants, obtained by replacing the positively selected aminoacid by alanine or cysteine. The L189A, Y235A and Y235C mutants showed a significant increase of BMP signalling compared to wt. In conclusion, present analysis evidences that Y235 residue is important for BMP15 biological activity, indirectly confirming its role in the onset of POI. Moreover, the BMP15 gene seems to have specialized in regulating proper ovarian function during evolution so that, if altered, poly-ovulation or POI could occur.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported, however funding details unavailable.