BMP15 mutations associated with primary ovarian insufficiency cause a defective production of bioactive protein

Abstract

BMP15 is selectively synthesized by oocytes as a pre-proprotein and is considered an ovarian follicle organizer whose adequate function is critical for female fertility. Missense mutations were reported in Primary Ovarian Insufficiency (POI) but their biological impact remained unexplored. Here, screening of 300 unrelated idiopathic overt POI women with primary or secondary amenorrhea led to the identification of 6 heterozygous BMP15 variations in 29 of them. All alterations are non-conservative and include one insertion of 3 nucleotides (p.L262_L263insL) and 5 missense substitutions. Except for the p.S5R located in the signal sequence, the other variants (p.R68W, p.R138H, p.L148P, p.A180T) localize in the proregion, which is essential for the processing and secretion of bioactive dimers. The mutations p.R68W, p.L148P and the novel p.R138H lead to marked reductions of mature protein production. Their biological effects, evaluated by a novel luciferase-reporter assay in a human granulosa cell line, were significantly reduced. Co-transfection experiments of defective mutants with equal amounts of wild-type BMP15 cDNA, thus reproducing the heterozygous state seen in patients, did not generate a complete recovery of wild-type activity. No or minor deleterious effects were detected for the variants p.L262_L263insL, p.A180T or p.S5R. In conclusion, heterozygous BMP15 mutations associated with the early onset of overt POI lead to defective secretion of bioactive dimers. These findings support the concept that an adequate amount of BMP15 secreted in the follicular fluid is critical for female fertility. We propose to consider the screening of BMP15 mutations among the analyses for the prediction of POI risk.

Computational Molecular Analysis of the Sequences of BMP15 Gene of Ruminants and Non-Ruminants

“…This is due to the fact that nsSNPs have been reported to be linked to economically important traits and disease development [17]. Some nsSNP are beneficial because the altered proteins result in increased sensitivity of granulosa cells to follicle stimulating hormone (FSH), which leads to accelerated follicular development and precocious ovulation of small follicles [27] while the reverse is the case for harmful or deleterious amino acid mutations [28]. According to Tariq et al [29], the prediction of SNPs status is promising in modern genetics analysis and breeding programmes as they have been used to identify those animals with higher breeding value.…”

Expression of GDF-9, BMP-15 and their receptors in mammalian ovary follicles

“…BMP-15 defects were associated with the pathogenesis of human hypergonadotropic ovarian failure (HOF)(Di Pasquale et al 2004). Moreover, some reports indicated that a point mutation in BMP-15 and a deficiency of GDF-9 were involved in premature ovarian failure (POF) (Montgomery et al 2004;Laissue et al 2006;Rossetti et al 2009). Therefore, mutation of GDF-9 and BMP-15 or abnormal expression of the proteins could be possible reasons for woman ovarian disease.…”

Genetics pathogenesis in the ovarian insufficiency

“…Instead, in the control-group this polymorphic variant has a frequency of 5%, demonstrating that this variant is mainly present in cases of ovarian failure and of primary amenorrhea rather than in patients-control. This has led us to think that the c.308 A > G and 788 TCT 789 polymorphisms may be correlated with POF [21][22][23][24][25].…”