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Bone morphogenetic protein‐15 (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 (SA) led to the identification of six heterozygous BMP15 variations in 29 of them. All alterations are nonconservative and include one insertion of three nucleotides (p.L262_L263insL) and five missense substitutions. Except for the p.S5R located in the signal sequence, the other variants (p.R68W, p.R138H, p.L148P, and 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 …