Rare mutations in the complement regulatory gene CSMD1 are associated with male and female infertility.,Nature Communications

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Rare mutations in the complement regulatory gene CSMD1 are associated with male and female infertility.
Nature Communications ( IF 14.7 ) Pub Date : 2019-10-11 , DOI: 10.1038/s41467-019-12522-w
Arthur S Lee ₁ , Jannette Rusch ₁ , Ana C Lima ₁ , Abul Usmani ₁ , Ni Huang ₁ , Maarja Lepamets ₂ , Katinka A Vigh-Conrad ₃ , Ronald E Worthington ₄ , Reedik Mägi ₂ , Xiaobo Wu ₅ , Kenneth I Aston ₆ , John P Atkinson ₅ , Douglas T Carrell ₆ , Rex A Hess ₇ , Moira K O'Bryan ₈ , Donald F Conrad _{1,

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Affiliation

Infertility in men and women is a complex genetic trait with shared biological bases between the sexes. Here, we perform a series of rare variant analyses across 73,185 women and men to identify genes that contribute to primary gonadal dysfunction. We report CSMD1, a complement regulatory protein on chromosome 8p23, as a strong candidate locus in both sexes. We show that CSMD1 is enriched at the germ-cell/somatic-cell interface in both male and female gonads. Csmd1-knockout males show increased rates of infertility with significantly increased complement C3 protein deposition in the testes, accompanied by severe histological degeneration. Knockout females show significant reduction in ovarian quality and breeding success, as well as mammary branching impairment. Double knockout of Csmd1 and C3 causes non-additive reduction in breeding success, suggesting that CSMD1 and the complement pathway play an important role in the normal postnatal development of the gonads in both sexes.

中文翻译：

补体调节基因 CSMD1 的罕见突变与男性和女性不育有关。

男性和女性不孕症是一种复杂的遗传特征，两性之间具有共同的生物学基础。在这里，我们对 73,185 名女性和男性进行了一系列罕见变异分析，以确定导致原发性性腺功能障碍的基因。我们报告 CSMD1（染色体 8p23 上的补体调节蛋白）在两性中都是一个强有力的候选基因座。我们发现，CSMD1 在男性和女性性腺的生殖细胞/体细胞界面处富集。 Csmd1 敲除男性的不育率增加，睾丸中补体 C3 蛋白沉积显着增加，并伴有严重的组织学退化。基因敲除的雌性表现出卵巢质量和繁殖成功率显着下降，以及乳腺分支受损。 Csmd1和C3的双敲除会导致育种成功率的非加性降低，这表明CSMD1和补体途径在两性性腺的正常产后发育中发挥着重要作用。

更新日期：2019-10-12

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