Plateforme BioPark d'Archamps, Archamps, France.
INSERM U1090, Marseille, France.
Hum Reprod. 2021 Feb 18;36(3):693-701. doi: 10.1093/humrep/deaa329.
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.
在两次减数分裂后，单倍体圆形精子经历剧烈变化成为成熟精子。主要变化之一是使细胞核浓缩，赋予精子显著的流体动力学特性，并保护其 DNA 免受在生殖过程中遇到的氧化应激。在这里，我们研究了一名患有低精子数、运动能力差和精子头部异常大的不育患者，这是由于核精子 DNA 高度未浓缩导致的。对该患者的 DNA 进行全外显子组测序，以鉴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一个纯合失活变异，ENST00000368559.7:c.718-1G>A，改变了一个预期阻止核孔蛋白 210 样（NUP210L）蛋白合成的保守剪接位点。对精子蛋白提取物的高分辨率质谱分析未在患者精子中发现任何 NUP210L 肽序列，而在对照供体中观察到，因此证实患者精子中不存在 NUP210L。有趣的是，Nup210l 纯合敲除小鼠由于精子数量减少、大头精子比例高、其他头部和鞭毛缺陷以及运动能力差而不育。NUP210L 几乎仅在睾丸中表达，序列类比表明它编码核孔膜糖蛋白。该蛋白可能对调节精子发生过程中和/或之前的核转运至关重要，其缺失可能通过阻止组蛋白变体/转换蛋白/鱼精蛋白进入核内和/或阻止核心组蛋白的适当替换，从而阻碍核的充分浓缩。这项工作描述了一个新的男性生育所必需的基因，可能会提高男性不育遗传诊断的效率。NUP210L 的功能仍有待解决，对其未来的研究将有助于理解精子浓缩所必需的复杂机制。
