鉴定 GDF9 中的一个突变是导致年轻女性卵巢储备功能降低的一个新原因。
Identification of a mutation in GDF9 as a novel cause of diminished ovarian reserve in young women.
机构信息
Key Laboratory of Reproductive Genetics, Zhejiang University, Ministry of Education, Hangzhou, China.
出版信息
Hum Reprod. 2013 Sep;28(9):2473-81. doi: 10.1093/humrep/det291. Epub 2013 Jul 12.
STUDY QUESTION
Do any mutations in growth differentiation factor 9 (GDF9) have a role in diminished ovarian reserve (DOR) in young women?
SUMMARY ANSWER
The GDF9 p.R146C mutation may be a source of DOR in some young women.
WHAT IS KNOWN ALREADY
DOR affects 10% of women under 37 years of age and is associated with accelerated expenditure of follicles. GDF9 is an oocyte-secreted factor that plays a critical role in follicular development and female fertility. Several GDF9 variants have been linked to ovarian dysfunction.
STUDY DESIGN, SIZE, DURATION: This case-control study included 139 women with DOR and 152 controls aged under 37 years.
PARTICIPANTS/MATERIALS, SETTING, METHODS: All women were recruited in a Chinese tertiary center and underwent DNA sequencing of GDF9 gene. We then determined the molecular and biological properties of mutant GDF9 proteins using protein expression, structural prediction and functional analyses.
MAIN RESULTS AND THE ROLE OF CHANCE
We identified two mutations in the proregion of GDF9 gene: c.169T > G (p.D57Y) and c.436T > C (p.R146C). The p.R146C mutation was found in three women with DOR but was absent in the control population. This mutation was also associated with significant reductions in GDF9 mature protein secretion in cultured cells. Functional studies with human granulosa cells (GCs) showed that the p.R146C mutation reduced the abilities of GDF9 to stimulate GC proliferation and to activate the Smad2 pathway. Protein structure modeling predicted that p.R146C disrupted an α-helix in GDF9 protein. In contrast with p.R146C, the p.D57Y mutation, found in both the DOR and control groups (6 versus 2), had no obvious deleterious effects.
LIMITATIONS, REASONS FOR CAUTION: Larger studies in varying populations may validate the role of GDF9 mutation in young women with DOR.
WIDER IMPLICATIONS OF THE FINDINGS
These results may provide new insights into the pathophysiological mechanisms of early-onset DOR.
研究问题
生长分化因子 9（GDF9）中的任何突变是否与年轻女性的卵巢储备功能降低（DOR）有关？
总结答案
GDF9 p.R146C 突变可能是一些年轻女性 DOR 的来源。
已知信息
DOR 影响 10%的 37 岁以下女性，与卵泡加速消耗有关。GDF9 是一种卵母细胞分泌的因子，在卵泡发育和女性生育中起着关键作用。已有几种 GDF9 变体与卵巢功能障碍有关。
研究设计、大小和持续时间：这项病例对照研究纳入了 139 名 DOR 患者和 152 名年龄在 37 岁以下的对照组。
参与者/材料、设置、方法：所有女性均在中国一家三级中心招募，并对 GDF9 基因进行 DNA 测序。然后，我们使用蛋白表达、结构预测和功能分析来确定突变 GDF9 蛋白的分子和生物学特性。
主要结果及其偶然性的作用
我们在 GDF9 基因的前导区发现了两个突变：c.169T > G（p.D57Y）和 c.436T > C（p.R146C）。DOR 患者中有 3 名女性发现了 p.R146C 突变，但对照组中没有。该突变还与培养细胞中 GDF9 成熟蛋白分泌的显著减少有关。用人类颗粒细胞（GCs）进行的功能研究表明，p.R146C 突变降低了 GDF9 刺激 GC 增殖和激活 Smad2 途径的能力。蛋白质结构建模预测 p.R146C 破坏了 GDF9 蛋白中的一个α-螺旋。与 p.R146C 不同，在 DOR 和对照组中均发现的 p.D57Y 突变（分别为 6 例和 2 例）没有明显的有害影响。
局限性、谨慎的原因：在不同人群中进行更大规模的研究可能会验证 GDF9 突变在年轻 DOR 女性中的作用。
研究结果的意义
这些结果可能为早期 DOR 的病理生理机制提供新的见解。
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