• PMID: 31942643
• Gene Name: SPEF2
• Condition: Multiple morphological abnormalities of the sperm flagella (MMAF) without primary ciliary dyskinesia (PCD)
• Association: Associated
• Mutation: c.2507+5delG, c.C4096T: p.R1366X, c.2649dupA: p.N887Efs*2, c.3400delA: p.I1134fs
• Population size: 682
• Population details: 682 (45 unrelated Chinese families, 637 controls, including 219 with oligoasthenospermia, 195 with non-obstructive azoospermia, and 223 fertile controls)
• Sex: Male
• Infertility type: Male infertility
• Associated genes: NGS
• Other associated phenotypes: PCD-like symptoms, including recurrent airway infections, bronchitis, and rhinosinusitis

Novel mutations in SPEF2 causing different defects between flagella and cilia bridge: the phenotypic link between MMAF and PCD

Tu C, Nie H, Meng L, Wang W, Li H, Yuan S, Cheng D, He W, Liu G, Du J, Gong F, Lu G, Lin G, Zhang Q, Tan YQ.

Severe asthenozoospermia is a common cause of male infertility. Recent studies have revealed that SPEF2 mutations lead to multiple morphological abnormalities of the sperm flagella (MMAF) without primary ciliary dyskinesia (PCD) symptoms in males, but PCD phenotype was also found in one female individual. Therefore, whether there is a phenotypic continuum ranging from infertile patients with PCD to MMAF patients with no or low noise PCD manifestations remains elusive. Here, we performed whole-exome sequencing in 47 patients with severe asthenozoospermia from 45 unrelated Chinese families. We identified four novel biallelic mutations in SPEF2 (8.9%, 4/45) in six affected individuals (12.8%, 6/47), while no deleterious biallelic variants in SPEF2 were detected in 637 controls, including 219 with oligoasthenospermia, 195 with non-obstructive azoospermia, and 223 fertile controls. Notably, all six patients exhibited PCD-like symptoms, including recurrent airway infections, bronchitis, and rhinosinusitis. Ultrastructural analysis revealed normal 9 + 2 axonemes of respiratory cilia but consistently abnormal 9 + 0 axoneme or disordered accessory structures of sperm flagella, indicating different roles of SPEF2 in sperm flagella and respiratory cilia. Subsequently, a Spef2 knockout mouse model was used to validate the PCD-like phenotype and male infertility, where the subfertility of female Spef2(-/-) mice was found unexpectedly. Overall, our data bridge the link between MMAF and PCD based on the association of SPEF2 mutations with both infertility and PCD in males and provide basis for further exploring the molecular mechanism of SPEF2 during spermiogenesis and ciliogenesis. FAU - Tu, Chaofeng AU - Tu C AD - Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410078, China. AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, 410078, China. AD - National Engineering and Research Center of Human Stem Cell, Changsha, China. AD - Key Lab of MOE for Development Biology and Protein Chemistry, The Center for Heart Development, College of Life Sciences, Hunan Normal University, Changsha, China. FAU - Nie, Hongchuan AU - Nie H AD - Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410078, China. AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, 410078, China. AD - National Engineering and Research Center of Human Stem Cell, Changsha, China. FAU - Meng, Lanlan AU - Meng L AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, 410078, China. FAU - Wang, Weili AU - Wang W AD - Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410078, China. FAU - Li, Haiyu AU - Li H AD - Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410078, China. FAU - Yuan, Shimin AU - Yuan S AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, 410078, China. FAU - Cheng, Dehua AU - Cheng D AD - Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410078, China. AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, 410078, China. AD - National Engineering and Research Center of Human Stem Cell, Changsha, China. FAU - He, Wenbin AU - He W AD - Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410078, China. AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, 410078, China. AD - National Engineering and Research Center of Human Stem Cell, Changsha, China. FAU - Liu, Gang AU - Liu G AD - Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410078, China. AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, 410078, China. AD - National Engineering and Research Center of Human Stem Cell, Changsha, China. FAU - Du, Juan AU - Du J AD - Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410078, China. AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, 410078, China. AD - National Engineering and Research Center of Human Stem Cell, Changsha, China. FAU - Gong, Fei AU - Gong F AD - Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410078, China. AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, 410078, China. AD - National Engineering and Research Center of Human Stem Cell, Changsha, China. FAU - Lu, Guangxiu AU - Lu G AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, 410078, China. AD - National Engineering and Research Center of Human Stem Cell, Changsha, China. AD - Key Lab of MOE for Development Biology and Protein Chemistry, The Center for Heart Development, College of Life Sciences, Hunan Normal University, Changsha, China. FAU - Lin, Ge AU - Lin G AD - Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410078, China. AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, 410078, China. AD - National Engineering and Research Center of Human Stem Cell, Changsha, China. AD - Key Lab of MOE for Development Biology and Protein Chemistry, The Center for Heart Development, College of Life Sciences, Hunan Normal University, Changsha, China. FAU - Zhang, Qianjun AU - Zhang Q AD - Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410078, China. 1104365800@qq.com. AD - Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, 410078, China. 1104365800@qq.com. AD - National Engineering and Research Center of Human Stem Cell, Changsha, China. 1104365800@qq.com.