Patiño Liliana C, Walton Kelly L, Mueller Thomas D, Johnson Katharine E, Stocker William, Richani Dulama, Agapiou David, Gilchrist Robert B, Laissue Paul, Harrison Craig A
Centro de Investigación en Genética y Genómica, Grupo de Investigación en Genética en Investigación de la Universidad del Rosario, Escuela de Medicina y Ciencias de la Salud, Universidad del Rosario, 110010 Bogotá, Colombia.
Department of Physiology, Monash University, Clayton, Victoria 3800, Australia.
J Clin Endocrinol Metab. 2017 Mar 1;102(3):1009-1019. doi: 10.1210/jc.2016-3503.
Bone morphogenetic protein (BMP)15 is an oocyte-specific growth factor, which, together with growth differentiation factor (GDF) 9, regulates folliculogenesis and ovulation rate. Multiple mutations in BMP15 have been identified in women with primary ovarian insufficiency (POI), supporting a pathogenic role; however, the underlying biological mechanism of many of these mutants remains unresolved.
To determine how mutations associated with ovarian dysfunction alter the biological activity of human BMP15.
The effects of 10 mutations in BMP15 on protein production, activation of granulosa cells, and synergy with GDF9 were assessed.
Sequencing of 35 patients with POI identified both an unrecognized BMP15 variant (c.986G>A, R329H) and a variant (c.581T>C, F194S) previously associated with the condition. Assessing expression and activity of these and 8 other BMP15 mutants identified: (1) multiple variants, including L148P, F194S, and Y235C, with reduced mature protein production; (2) three variants (R138H, A180T, and R329H) with ∼fourfold lower activity than wild-type BMP15; and (3) 3 variants (R68W, F194S, and N196K) with a significantly reduced ability to synergize with GDF9.
Mutations in BMP15 associated with POI reduce mature protein production, activity, or synergy with GDF9. The latter effect is perhaps most interesting given that interactions with GDF9 most likely underlie the physiology of BMP15 in the human ovary.
骨形态发生蛋白（BMP）15是一种卵母细胞特异性生长因子，它与生长分化因子（GDF）9共同调节卵泡发生和排卵率。在原发性卵巢功能不全（POI）女性中已鉴定出BMP15的多个突变，这支持了其致病作用；然而，许多这些突变体的潜在生物学机制仍未明确。
确定与卵巢功能障碍相关的突变如何改变人BMP15的生物学活性。
评估BMP15中10个突变对蛋白质产生、颗粒细胞激活以及与GDF9协同作用的影响。
对35例POI患者进行测序，发现了一种未被识别的BMP15变体（c.986G>A，R329H）和一种先前与该疾病相关的变体（c.581T>C，F194S）。评估这些变体以及其他8个BMP15突变体的表达和活性发现：（1）多个变体，包括L148P、F194S和Y235C，成熟蛋白产生减少；（2）三个变体（R138H、A180T和R329H）的活性比野生型BMP15低约四倍；（3）三个变体（R68W、F194S和N196K）与GDF9协同作用的能力显著降低。
与POI相关的BMP15突变会降低成熟蛋白产生、活性或与GDF9的协同作用。鉴于与GDF9的相互作用很可能是BMP15在人类卵巢中生理功能的基础，后一种效应可能最令人感兴趣。
