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 (PCD) and Bardet-Biedl syndrome (BBS), 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 SNPs (single nucleotide polymorphisms), Rabl2L119F (rs80006029) and Rabl2V158F (rs200121688), and found they exhibit ciliopathy-associated disorders including male infertility, early growth retardation, excessive weight gain in adulthood, heterotaxia, pre-axial polydactyly, neural tube defects (NTD) 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.
Human molecular genetics. 2020 Oct 19 [Epub ahead of print]
Xinbao Ding, Robert Fragoza, Priti Singh, Shu Zhang, Haiyuan Yu, John C Schimenti
Cornell University, College of Veterinary Medicine, Department of Biomedical Sciences, Ithaca, NY 14853., Cornell University, Department of Biological Statistics and Computational Biology, Ithaca, NY 14853, USA.