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BMP15 mutations associated with primary ovarian insufficiency cause a defective production of bioactive protein
Author(s) -
Rossetti Raffaella,
Di Pasquale Elisa,
Marozzi Anna,
Bione Silvia,
Toniolo Daniela,
Grammatico Paola,
Nelson Lawrence M.,
BeckPeccoz Paolo,
Persani Luca
Publication year - 2009
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20961
Subject(s) - biology , missense mutation , bone morphogenetic protein 15 , mutation , mutant , endocrinology , wild type , medicine , growth differentiation factor 9 , ovarian follicle , premature ovarian insufficiency , follicular phase , andrology , microbiology and biotechnology , gene , genetics , bone morphogenetic protein , folliculogenesis , bone morphogenetic protein 7 , embryogenesis
Abstract 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 reductions of mature protein production. Their biological effects, evaluated by a novel luciferase‐reporter assay in a human granulosa cell (GC) line, were significantly reduced. Cotransfection 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. Hum Mutat 0, 1–7, 2009. © 2009 Wiley‐Liss, Inc.