Approximately 7% of men worldwide suffer from infertility, with sperm abnormalities being the most common defect. Though genetic causes are thought to underlie a substantial fraction of idiopathic cases, the actual molecular bases are usually undetermined. Because the consequences of most genetic variants in populations are unknown, this complicates genetic diagnosis even after genome sequencing of patients. Some patients with ciliopathies, including primary ciliary dyskinesia and Bardet–Biedl syndrome, also suffer from infertility because cilia and sperm flagella share several characteristics. Here, we identified two deleterious alleles of RABL2A, a gene essential for normal function of cilia and flagella. Our in silico predictions and in vitro assays suggest that both alleles destabilize the protein. We constructed and analyzed mice homozygous for these two single-nucleotide polymorphisms, Rabl2^L119F (rs80006029) and Rabl2^V158F (rs200121688), and found that they exhibit ciliopathy-associated disorders including male infertility, early growth retardation, excessive weight gain in adulthood, heterotaxia, pre-axial polydactyly, neural tube defects and hydrocephalus. Our study provides a paradigm for triaging candidate infertility variants in the population for in vivo functional validation, using computational, in vitro and in vivo approaches.

中文翻译：

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RABL2A 变异导致男性不育和纤毛病


全球大约 7% 的男性患有不育症，其中精子异常是最常见的缺陷。尽管遗传原因被认为是大部分特发性病例的基础，但实际的分子基础通常尚未确定。由于大多数遗传变异在人群中的后果尚不清楚，因此即使在对患者进行基因组测序后，这也会使遗传诊断变得复杂。一些纤毛病患者，包括原发性纤毛运动障碍和 Bardet-Biedl 综合征，也患有不孕症，因为纤毛和精子鞭毛有几个共同特征。在这里，我们鉴定了RABL2A的两个有害等位基因，这是纤毛和鞭毛正常功能所必需的基因。我们的计算机预测和体外测定表明，这两个等位基因都会使蛋白质不稳定。我们构建并分析了这两种单核苷酸多态性Rabl2 ^L119F (rs80006029) 和Rabl2 ^V158F (rs200121688) 的纯合小鼠，发现它们表现出纤毛病相关疾病，包括男性不育、早期生长迟缓、成年期体重过度增加、异位性等。 、轴前多指畸形、神经管缺陷和脑积水。我们的研究为利用计算、体外和体内方法对人群中候选不育变异进行分类以进行体内功能验证提供了范例。