Novel bi-allelic variants in DNAH2 cause severe asthenoteratozoospermia with multiple morphological abnormalities of the flagella |
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| Authors: | Yang Gao Shixiong Tian Yanwei Sha Xiaomin Zha Huiru Cheng Anyong Wang Chunyu Liu Mingrong Lv Xiaoqing Ni Qiang Li Huan Wu Qing Tan Dongdong Tang Bing Song Ding Ding Jiangshan Cong Yuping Xu Ping Zhou Xiaojin He |
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| Affiliation: | 1. Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China;2. NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei 230032, China;3. Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People''s Republic of China, Hefei 230032, China;4. Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai 200011, China;5. Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China;6. State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China;7. School of Public Health & Women and Children''s Hospital, Xiamen University, Xiamen Fujian 361005, China;8. State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Centerfor Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen 361102, China;9. Department of clinical laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China;10. Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei 230032, China;11. Anhui Province Key Laboratory of Reproductive Health and Genetics, Hefei 230032, China;12. Anhui Provincial Human Sperm Bank, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China |
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| Abstract: | Research questionMultiple morphological abnormalities of the flagella (MMAF) is characterized by excessive immotile spermatozoa with severe flagellar abnormalities in the ejaculate. Previous studies have reported a heterogeneous genetic profile associated with MMAF. What other genetic variants might explain the cause of MMAF?DesignWhole-exome sequencing was conducted in a cohort of 90 Chinese patients with MMAF. The pathogenicity of identified mutations was assessed through electron microscopy and immunofluorescent examinations.ResultsThree unrelated men with bi-allelic DNAH2 variants were identified. Sanger sequencing verified that the six novel variants originated from every parent. All these variants were located at the conserved domains of DNAH2 and predicted to be deleterious by bioinformatic tools. Haematoxylin and eosin staining and scanning electron microscopy revealed that spermatozoa harbouring DNAH2 variants displayed severely aberrant morphology mainly with absent and short flagella (≥78%). Moreover, transmission electron microscopy revealed the obvious absence of a central pair of microtubules and inner dynein arms in the spermatozoa with mutated DNAH2. Immunofluorescence data further validated these findings, showing reduced DNAH2 protein expression in the spermatozoa with DNAH2 variants, compared with normal spermatozoa. Intracytoplasmic sperm injection using spermatozoa from the three men with mutated DNAH2 resulted in blastocyst formation in all cases. Embryo transfer was carried out in two couples, both resulting in clinical pregnancy.ConclusionsThese experimental and clinical data suggest that bi-allelic DNAH2 variants might induce MMAF-associated asthenoteratozoospermia, which can be overcome through intracytoplasmic sperm injection. These findings contribute to the knowledge of the genetic landscape of asthenoteratozoospermia and clinical counselling of male infertility. |
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