Abstract：
Human infertility affects 10-15% of couples. Asthenozoospermia accounts for 18% of men with infertility and is a common male infertility phenotype. The nexin-dynein regulatory complex (N-DRC) is a large protein complex in the sperm flagellum that connects adjacent doublets of microtubules. Defects in the N-DRC can disrupt cilia/flagellum movement, resulting in primary ciliary dyskinesia and male infertility. Using whole-exome sequencing, we identified a pathological homozygous variant of the dynein regulatory complex subunit 3 (DRC3) gene, which expresses leucine-rich repeat-containing protein 48, a component of the N-DRC, in a patient with asthenozoospermia. The variant ENST00000313838.12: c.644dup (p. Glu216GlyfsTer36) causes premature translational arrest of DRC3, resulting in a dysfunctional DRC3 protein. The patient\'s semen count, color, and pH were normal according to the reference values of the World Health Organization guidelines; however, sperm motility and progressive motility were reduced. DRC3 protein was not detected in the patient\'s sperm and the ultrastructure of the patient\'s sperm flagella was destroyed. More importantly, the DRC3 variant reduced its interaction with other components of the N-DRC, including dynein regulatory complex subunits 1, 2, 4, 5, 7, and 8. Our data not only revealed the essential biological functions of DRC3 in sperm flagellum movement and structure but also provided a new basis for the clinical genetic diagnosis of male infertility.
摘要：
人类不孕症影响10-15%的夫妇。无精症占不育男性的18％，是一种常见的男性不育表型。nexin-dynein调节复合物（N-DRC）是精子鞭毛中的大型蛋白质复合物，连接相邻的微管双峰。N-DRC的缺陷会破坏纤毛/鞭毛的运动，导致原发性纤毛运动障碍和男性不育。使用全外显子组测序，我们确定了动力蛋白调节复合物亚基3（DRC3）基因的病理纯合变体，它表达富含亮氨酸的含重复蛋白48，N-DRC的一个组成部分，有弱精子症的病人.变体ENST00000313838.12：c.644dup（p。Glu216GlyfsTer36）导致DRC3的过早翻译停滞，导致功能失调的DRC3蛋白。病人的精液计数,颜色,根据世界卫生组织指南的参考值，pH值正常；然而，精子运动性和进行性运动性降低。在患者的精子中未检测到DRC3蛋白，并且患者精子鞭毛的超微结构被破坏。更重要的是,DRC3变体减少了其与N-DRC的其他成分的相互作用，包括动力蛋白调节复合物亚基1、2、4、5、7和8。我们的数据不仅揭示了DRC3在精子鞭毛运动和结构中的基本生物学功能，而且为男性不育的临床遗传诊断提供了新的依据。
