Fundamental role of BMP15 in human ovarian folliculogenesis revealed by null and missense mutations associated with primary ovarian insufficiency

Abstract

Bone morphogenetic protein 15 (BMP15) encodes an oocyte factor with a relevant role for folliculogenesis as homodimer or cumulin heterodimer (BMP15-GDF9).Heterozygous BMP15 variants in the precursor or mature peptide had been associated with primary ovarian insufficiency (POI), but the underlying mechanism remains elusive and a double dose of BMP15 was suggested to be required for adequate ovarian reserve. We uncovered two homozygous BMP15 null variants found in two girls with POI and primary amenorrhea. Both heterozygous mothers reported physiological menopause. We then performed western blot, immunofluorescence, and reporter assays to investigate how previously reported missense variants, p.Y235C and p.R329C, located in the precursor or mature domains of BMP15, may affect protein function. The p.R329C variant demonstrates an impaired colocalization with growth/differentiation factor 9 (GDF9) at confocal images and diminished activation of the SMAD pathways at western blot and reporter assays in COV434 follicular cell line. In conclusion, BMP15 null mutations cause POI only in the homozygous state, thus discarding the possibility that isolated BMP15 haploinsufficiency can cause evident ovarian defects. Alternatively, heterozygous BMP15 missense variants may affect ovarian function by interfering with cumulin activity.Our data definitely support the fundamental role of BMP15 in human ovarian folliculogenesis.

Transforming Growth Factor-Beta (TGF-β) Signaling in Cancer-A Betrayal Within

“…All these proteins which act as ligands are synthesized as dimeric pre-proprotiens. The pre-proproteins are processed for cleavage by proteases to generate mature functional growth factors which are then finally secreted as latent forms but remains interacted noncovalently with their respective polypeptides ( Rossetti et al, 2020 ). Although, TGF-β activation requires release of active ligands, however, reports suggest that the precursor form of the protein nodal binds to the receptors directly to activate signaling without being processed ( Schmierer and Hill, 2007 ).…”

Bone morphogenetic protein 15 induces differentiation of mesenchymal stem cells derived from human follicular fluid to oocyte‐like cell

“…Among these factors, bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF‐9) are expressed in each stage of follicular growth and are involved in controlling proliferation and steroidogenesis of GCs (de Castro et al, 2016). BMP15 is another oocyte‐derived factor, which is detected in oocytes of primordial and primary follicles of different species, and takes a significant mitogenic effect on the GCs (de Castro et al, 2016; Rossetti et al, 2020). It has been shown that BMP15 regulates the proliferation of undifferentiated GCs in a follicle‐stimulating hormone‐independent manner, so it has a unique role in regulating folliculogenesis and GC activities (Persani et al, 2014).…”

TGIF1 and SF1 polymorphisms are associated with litter size in Small Tail Han sheep

“…Furthermore, we failed to detect the mutant homozygous genotype TT, and the lethality was the most likely reason for lack of TT genotype (g.37871539C>T) in all sheep breeds. TGIF1 can negatively regulate TGF-β-activated genes such as SMAD2 and SMAD4 (Hu et al, 2011;Hyman et al, 2003;Wotton et al, 1999), and TGF-β/SMAD signalling plays crucial roles in mediating reproduction (Knight & Glister, 2006;Liu, Chang, Yi, Yao, & Leung, 2019;Rossetti et al, 2020;Yin et al, 2020). For example, the disruption of TGF-β/SMAD signalling can cause reproductive problems (Chand et al, 2007), including sterility (Li et al, 2017).…”