Although premature ovarian insufficiency (POI), a common cause of female infertility and subfertility, has a well-established hereditary component, the genetic factors currently implicated in POI account for only a limited proportion of cases. Here, using an exome-wide, gene-based case-control analysis in a discovery cohort comprising 1,027 POI cases and 2,733 ethnically matched women controls from China, we found that heterozygous loss-of-function (LoF) variants of MAX dimerization protein (MGA) were significantly enriched in the discovery cohort, accounting for 2.6% of POI cases, while no MGA LoF variants were found in the matched control females. Further exome screening was conducted in 4 additional POI cohorts (2 from China and 2 from the United States) for replication studies, and we identified heterozygous MGA LoF variants in 1.0%, 1.4%, 1.0%, and 1.0% of POI cases, respectively. Overall, a total of 37 distinct heterozygous MGA LoF variants were discovered in 38 POI cases, accounting for approximately 2.0% of the total 1,910 POI cases analyzed in this study. Accordingly, Mga+/− female mice were subfertile, exhibiting shorter reproductive lifespan and decreased follicle number compared with WT, mimicking the observed phenotype in humans. Our findings highlight the essential role of MGA deficiency for impaired female reproductive ability.
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机译：尽管卵巢早衰 （POI） 是女性不孕症和不孕症的常见原因，具有公认的遗传成分，但目前与 POI 有关的遗传因素仅占病例的有限比例。在这里，在由 1,027 例 POI 病例和 2,733 名来自中国的种族匹配的女性对照组成的发现队列中使用外显子组范围、基于基因的病例对照分析，我们发现 MAX 二聚化蛋白 （MGA） 的杂合功能丧失 （LoF） 变体在发现队列中显着富集，占 POI 病例的 2.6%，而在匹配的对照女性中未发现 MGA LoF 变体。在另外 4 个 POI 队列 （2 个来自中国，2 个来自美国） 中进行了进一步的外显子组筛选以进行复制研究，我们分别在 1.0% 、 1.4% 、 1.0% 和 1.0% 的 POI 病例中鉴定了杂合子 MGA LoF 变异。总体而言，在 38 例 POI 病例中共发现了 37 种不同的杂合子 MGA LoF 变异，约占本研究分析的 1,910 例 POI 病例总数的 2.0%。因此，Mga + / - 雌性小鼠的生育能力低，与 WT 相比，生殖寿命较短，卵泡数量减少，模仿了在人类中观察到的表型。我们的研究结果强调了 MGA 缺乏对女性生殖能力受损的重要作用。
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