Reproductive BioMedicine Online ( IF 3.7 ) Pub Date : 2021-08-08 , DOI: 10.1016/j.rbmo.2021.07.021 Ihsan Khan 1 , Sobia Dil 1 , Huan Zhang 1 , Beibei Zhang 1 , Teka Khan 2 , Aurang Zeb 1 , Jianteng Zhou 1 , Shoaib Nawaz 3 , Muhammad Zubair 1 , Khalid Khan 1 , Hui Ma 1 , Qinghua Shi 1
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Research question
Male infertility is a global issue worldwide and multiple morphological abnormalities of the sperm flagella (MMAF) is one of the most severe forms of the qualitative sperm defects with a heterogeneous genetic cause that has not been completely understood. Can whole-exome sequencing (WES) reveal novel genetic causes contributing to MMAF in a consanguineous Pakistani family, comprising three infertile brothers?
Design
WES and bioinformatic analysis were conducted to screen potential pathogenic variants. The identified variant was validated by Sanger sequencing in all available family members Transmission electron microscopy analyses was carried out to examine the flagella ultrastructure of spermatozoa from patient.
Results
WES and Sanger sequencing identified a novel homozygous stop-gain mutation (ENST00000392644.4, c.182C>G, p.S61X) in ARMC2, which is expected to lead to loss of protein functions. Transmission electron microscopy analyses revealed that the flagellar ultrastructure of the patient's spermatozoa was disorganized along with a complete absence of central pair complex (CPC), suggesting that ARMC2 is involved in the assembly, stability of the axonemal complex, or both, particularly the CPC.
Conclusion
We report that a familial stop-gain mutation in ARMC2 is associated with male infertility in humans caused by MMAF accompanied with loss of CPCs and axonemal disorganization. We provide genetic evidence that ARMC2 is essential for human spermatogenesis and its mutation may be pathogenic for MMAF. These findings will improve the knowledge about the genetic basis of MMAF and provide information for genetic counselling of this disease.
中文翻译：
ARMC2 中的一种新的停止增益突变与精子鞭毛的多种形态异常有关
研究问题
男性不育是世界范围内的全球性问题，精子鞭毛（MMAF）的多种形态异常是精子质量缺陷的最严重形式之一，其遗传原因异质性尚未完全清楚。全外显子组测序 (WES) 能否揭示一个近亲巴基斯坦家庭（包括三个不育兄弟）中导致 MMAF 的新遗传原因？
设计
进行WES和生物信息学分析以筛选潜在的致病变异。在所有可用的家庭成员中，通过 Sanger 测序验证了鉴定的变体 进行透射电子显微镜分析以检查患者精子的鞭毛超微结构。
结果
WES 和 Sanger 测序在 ARMC2 中鉴定出一种新的纯合终止增益突变 (ENST00000392644.4, c.182C>G, p.S61X)，预计会导致蛋白质功能丧失。透射电子显微镜分析显示，患者精子的鞭毛超微结构杂乱无章，完全没有中央对复合体 (CPC)，这表明ARMC2参与了轴索复合体的组装和/或稳定性，尤其是 CPC。
结论
我们报告称， ARMC2的家族性停止增益突变与由 MMAF 引起的人类男性不育症相关，并伴有 CPCs 的丧失和轴索紊乱。我们提供的遗传证据表明，ARMC2对人类精子发生至关重要，其突变可能对 MMAF 具有致病性。这些发现将提高对 MMAF 遗传基础的认识，并为这种疾病的遗传咨询提供信息。
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