Purpose

The etiology of premature ovarian insufficiency (POI) is heterogeneous, and genetic factors account for 20–25% of the patients. The primordial follicle pool is determined by the meiosis process, which is initiated by programmed DNA double strand breaks (DSB) and homologous recombination. The objective of the study is to explore the role of DSB formation genes in POI pathogenesis.

Methods

Variants in DSB formation genes were analyzed from a database of exome sequencing in 1,030 patients with POI. The pathogenic effects of the potentially causative variants were verified by further functional studies.

Results

Three pathogenic heterozygous variants in PRDM9 and two in ANKRD31 were identified in seven patients. Functional studies showed the variants in PRDM9 impaired its methyltransferase activity, and the ANKRD31 variations disturbed its interaction with another DSB formation factor REC114 by haploinsufficiency effect, indicating the pathogenic effects of the two genes on ovarian function were dosage dependent.

Conclusion

Our study identified pathogenic variants of PRDM9 and ANKRD31 in POI patients, shedding new light on the contribution of meiotic DSB formation genes in ovarian development, further expanding the genetic architecture of POI.

中文翻译：

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减数分裂双链断裂 (DSB) 形成基因 PRDM9 和 ANKRD31 在卵巢早衰中的致病变异

目的

卵巢早衰 (POI) 的病因是异质的，遗传因素占患者的 20-25%。原始卵泡池由减数分裂过程决定，减数分裂过程由程序性 DNA 双链断裂 (DSB) 和同源重组启动。本研究的目的是探讨 DSB 形成基因在 POI 发病机制中的作用。

方法

从 1,030 名 POI 患者的外显子组测序数据库中分析了 DSB 形成基因的变异。通过进一步的功能研究验证了潜在致病变异的致病作用。

结果

在 7 名患者中鉴定出PRDM9中的三个致病性杂合变异和ANKRD31中的两个致病性杂合变异。功能研究表明，PRDM9的变异损害了其甲基转移酶活性，而ANKRD31变异通过单倍体不足效应干扰了其与另一种 DSB 形成因子 REC114 的相互作用，表明这两个基因对卵巢功能的致病作用是剂量依赖性的。

结论

我们的研究确定了 POI 患者中PRDM9和ANKRD31的致病变异，揭示了减数分裂 DSB 形成基因在卵巢发育中的作用，进一步扩展了 POI 的遗传结构。