BMP15 mutations associated with primary ovarian insufficiency cause a defective production of bioactive protein.
BMP15 mutations associated with primary ovarian insufficiency cause a defective production of bioactive protein.
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DOI：
10.1002/humu.20961
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发表时间：
2009-05
期刊：
影响因子：
3.9
通讯作者：
Persani, Luca
中科院分区：
文献类型：
--
作者：
Rossetti, Raffaella;Di Pasquale, Elisa;Marozzi, Anna;Bione, Silvia;Toniolo, Daniela;Grammatico, Paola;Nelson, Lawrence M.;Beck-Peccoz, Paolo;Persani, Luca
关键词：
BMP 15是由卵母细胞选择性合成的前蛋白原，被认为是卵泡组织者，其足够的功能对女性生育力至关重要。错义突变在原发性卵巢功能不全（POI）中有报道，但其生物学影响尚未探讨。在这里，筛选300名原发性或继发性闭经的无关特发性明显POI妇女，在其中29人中鉴定出6种杂合BMP 15变异。所有改变都是非保守的，包括一个3个核苷酸的插入（p.L262_L263insL）和5个错义取代。除了位于信号序列的p.S5R外，其他变体（p.R68W，p.R138H，p.L148P，p.A180T）均位于前区，这是生物活性二聚体加工和分泌所必需的。突变p.R68W、p.L148P和新的p.R138H导致成熟蛋白质产生的显著减少。他们的生物学效应，在人类颗粒细胞系中的一种新的辅酶A酶-报告基因测定法进行评估，显着降低。缺陷突变体与等量野生型BMP 15 cDNA的共转染实验，从而再现了患者中所见的杂合状态，没有产生野生型活性的完全恢复。对于变体p.L262_L263insL、p.A180T或p.S5R，未检测到有害作用或检测到轻微有害作用。总之，与明显POI的早期发作相关的杂合BMP 15突变导致生物活性二聚体的分泌缺陷。这些发现支持了卵泡液中分泌的足够量的BMP 15对女性生育力至关重要的概念。我们建议在POI风险预测分析中考虑筛选BMP 15突变。
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.
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影响因子：
6.1
作者：
Bodega, B;Bione, S;Marozzi, A
通讯作者：
Marozzi, A
影响因子：
3.6
作者：
Juengel, JL;Hudson, NL;McNatty, KP
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McNatty, KP
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4.8
作者：
Bodin, Loys;Di Pasquale, Elisa;Mulsant, Philippe
通讯作者：
Mulsant, Philippe
影响因子：
3.7
作者：
Beck-Peccoz P;Persani L
通讯作者：
Persani L
影响因子：
9.8
作者：
Di Pasquale, E;Beck-Peccoz, P;Persani, L
通讯作者：
Persani, L