Genetics-associated asthenoteratozoospermia is often seen in patients with multiple morphological abnormalities of the sperm flagella (MMAF). Although 24 causative genes have been identified, these explain only approximately half of patients with MMAF. Since sperm flagella and motile cilia (especially respiratory cilia) have similar axonemal structures, many patients with MMAF also exhibit respiratory symptoms, such as recurrent airway infection, chronic sinusitis, and bronchiectasis, which are frequently associated with primary ciliary dyskinesia (PCD), another recessive disorder. Here, exome sequencing was conducted to evaluate the genetic cause in 53 patients with MMAF and classic PCD/PCD-like symptoms. Two homozygous missense variants and a compound-heterozygous variant in the BRWD1 gene were identified in three unrelated individuals. BRWD1 staining was detected in the whole flagella and respiratory cilia of normal controls but was absent in BRWD1-mutated individuals. Transmission electron microscopy and immunostaining demonstrated that BRWD1 deficiency in human affected respiratory cilia and sperm flagella differently, as the absence of outer and inner dynein arms in sperm flagellum and respiratory cilia, while with a decreased number and outer doublet microtubule defects of respiratory cilia. To our knowledge, this is the first report of a BRWD1-variant-related disease in humans, manifesting as an autosomal recessive form of MMAF and PCD/PCD-like symptoms. Our data provide a basis for further exploring the molecular mechanism of BRWD1 gene during spermatogenesis and ciliogenesis.

遗传相关的动脉粥样硬化性精子症经常见于多发性精子鞭毛（MMAF）形态异常的患者。尽管已鉴定出24个致病基因，但这些仅解释了大约一半的MMAF患者。由于精子鞭毛和运动性纤毛（尤其是呼吸道纤毛）具有相似的轴突结构，因此许多MMAF患者还表现出呼吸道症状，例如反复发作的气道感染，慢性鼻窦炎和支气管扩张，这通常与原发性睫状运动障碍（PCD）有关。隐性疾病。在这里，进行了外显子组测序以评估53名患有MMAF和典型PCD / PCD样症状的患者的遗传原因。BRWD1中的两个纯合错义变体和一个复合杂合变体在三个无关的个体中鉴定出该基因。在正常对照的整个鞭毛和呼吸道纤毛中检测到BRWD1染色，但在BRWD1突变的个体中未发现。透射电子显微镜和免疫染色表明，人类感染呼吸道纤毛和精子鞭毛的BRWD1缺乏症有所不同，因为精子鞭毛和呼吸道纤毛中没有外部和内部的动力蛋白，而呼吸道纤毛的数量和外部双线微管缺陷减少。据我们所知，这是人类BRWD1变异相关疾病的首次报道，表现为MMAF和PCD / PCD样症状的常染色体隐性形式。我们的数据为进一步探索甲壳素的分子机理提供了基础。BRWD1基因在精子发生和纤毛发生过程中。