Defect in the nuclear pore membrane glycoprotein 210-like gene is associated with extreme uncondensed sperm nuclear chromatin and male infertility: a case report
Defect in the nuclear pore membrane glycoprotein 210-like gene is associated with extreme uncondensed sperm nuclear chromatin and male infertility: a case report
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DOI：
10.1093/humrep/deaa329
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发表时间：
2021-03-01
影响因子：
6.1
通讯作者：
Ray, Pierre F.
中科院分区：
文献类型：
--
作者：
Arafah, Karim;Lopez, Fabrice;Ray, Pierre F.
经过两次减数分裂后，单倍体圆形精子细胞发生巨大变化，成为成熟精子。其中一个主要的转变包括压缩细胞核，赋予精子显着的流体动力学特性，并保护其DNA免受其在生殖过程中遇到的氧化应激。在这里，我们研究了一个不育的受试者，精子数量少，活动力差，精子核DNA高度未浓缩，头部异常大。对受试者的DNA进行全外显子组测序，以确定导致这种严重精子异常的遗传缺陷。外显子组序列数据的生物信息学分析揭示了纯合的功能丧失变体ENST 00000368559.7：c.718- 1G>A，改变了预期阻止核孔蛋白210样（NUP 210 L）蛋白合成的共有剪接位点。精子蛋白提取物的高分辨率质谱分析没有显示患者精子中的任何NUP 210 L肽序列，与对照供体中观察到的相反，从而证实患者精子中不存在NUP 210 L。有趣的是，纯合Nup 210 L敲除小鼠由于精子计数减少、圆头精子比例高、其他头部和鞭毛缺陷以及运动性差而显示不育。NUP 210 L几乎只在睾丸中表达，序列模拟表明它编码核孔膜糖蛋白。该蛋白质可能是至关重要的，以调节细胞核的运输过程中和/或精子发生之前，它的缺乏可能会阻碍充分的核压实，通过防止组蛋白变体/过渡蛋白/鱼精蛋白进入细胞核和/或通过防止核心组蛋白的充分取代。这项工作描述了一种男性生育所必需的新基因，可能提高男性不育症基因诊断的效率。NUP 210 L的功能仍有待解决，其未来的研究将有助于了解精子压实所需的复杂机制。
After the two meiotic divisions, haploid round spermatids undergo dramatic changes to become mature spermatozoa. One of the main transformations consists of compacting the cell nucleus to confer the sperm its remarkable hydrodynamic property and to protect its DNA from the oxidative stress it will encounter during its reproductive journey. Here, we studied an infertile subject with low sperm count, poor motility and highly abnormal spermatozoa with strikingly large heads due to highly uncondensed nuclear sperm DNA. Whole-exome sequencing was performed on the subject's DNA to identify the genetic defect responsible for this severe sperm anomaly. Bioinformatics analysis of exome sequence data uncovered a homozygous loss of function variant, ENST00000368559.7:c.718- 1G>A, altering a consensus splice site expected to prevent the synthesis of the nucleoporin 210 like (NUP210L) protein. High-resolution mass spectrometry of sperm protein extracts did not reveal any NUP210L peptide sequence in the patient's sperm, contrary to what was observed in control donors, thus confirming the absence of NUP210L in the patient's sperm. Interestingly, homozygous Nup210L knock-out mice have been shown to be infertile due to a reduced sperm count, a high proportion of round-headed sperm, other head and flagella defects and a poor motility. NUP210L is almost exclusively expressed in the testis and sequence analogy suggests that it encodes a nuclear pore membrane glycoprotein. The protein might be crucial to regulate nuclear trafficking during and/or before spermiogenesis, its absence potentially impeding adequate nuclear compaction by preventing the entry of histone variants/transition proteins/protamines into the nucleus and/or by preventing the adequate replacement of core histones. This work describes a new gene necessary for male fertility, potentially improving the efficiency of the genetic diagnosis of male infertility. The function of NUP210L still remains to be resolved and its future investigation will help to understand the complex mechanisms necessary for sperm compaction.