• PMID: 31048344
• Gene Name: SPEF2
• Condition: Multiple morphological abnormalities of the sperm flagella (MMAF)
• Association: Associated
• Mutation: c.910C>T (p.Arg304*) and c.3400delA (p.Ile1134Serfs*13), c.3240delT (p.Phe1080Leufs*2)
• Population size: 50
• Population details: 50 Han Chinese probands with MMAF
• Sex: Male
• Infertility type: Male infertility
• Associated genes: NGS

Homozygous mutations in SPEF2 induce multiple morphological abnormalities of the sperm flagella and male infertility

Liu C, Lv M, He X, Zhu Y, Amiri-Yekta A, Li W, Wu H, Kherraf ZE, Liu W, Zhang J, Tan Q, Tang S, Zhu YJ, Zhong Y, Li C, Tian S, Zhang Z, Jin L, Ray P, Zhang F, Cao Y.

BACKGROUND: Male infertility due to multiple morphological abnormalities of the sperm flagella (MMAF) is a genetically heterogeneous disorder. Previous studies revealed several MMAF-associated genes, which account for approximately 60% of human MMAF cases. The pathogenic mechanisms of MMAF remain to be illuminated. METHODS AND RESULTS: We conducted genetic analyses using whole-exome sequencing in 50 Han Chinese probands with MMAF. Two homozygous stop-gain variants (c.910C>T (p.Arg304*) and c.3400delA (p.Ile1134Serfs*13)) of the SPEF2 (sperm flagellar 2) gene were identified in two unrelated consanguineous families. Consistently, an Iranian subject from another cohort also carried a homozygous SPEF2 stop-gain variant (c.3240delT (p.Phe1080Leufs*2)). All these variants affected the long SPEF2 transcripts that are expressed in the testis and encode the IFT20 (intraflagellar transport 20) binding domain, important for sperm tail development. Notably, previous animal studies reported spontaneous mutations of SPEF2 causing sperm tail defects in bulls and pigs. Our further functional studies using immunofluorescence assays showed the absence or a remarkably reduced staining of SPEF2 and of the MMAF-associated CFAP69 protein in the spermatozoa from SPEF2-affected subjects. CONCLUSIONS: We identified SPEF2 as a novel gene for human MMAF across the populations. Functional analyses suggested that the deficiency of SPEF2 in the mutated subjects could alter the localisation of other axonemal proteins. CI - © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ. FAU - Liu, Chunyu AU - Liu C AD - 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, China. AD - Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China. AD - State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China. AD - Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. FAU - Lv, Mingrong AU - Lv M AD - Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. AD - Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, China. AD - Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei, China. FAU - He, Xiaojin AU - He X AUID- ORCID: 0000-0001-5919-8478 AD - Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. AD - Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, China. AD - Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei, China. FAU - Zhu, Yong AU - Zhu Y AD - 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, China. FAU - Amiri-Yekta, Amir AU - Amiri-Yekta A AD - Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France. AD - Centre Hospitalier Universitaire de Grenoble, UM GI-DPI, Grenoble, France. AD - Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Academic Center for Education, Culture, and Research, Tehran, Iran. FAU - Li, Weiyu AU - Li W AD - 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, China. AD - Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China. AD - State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China. FAU - Wu, Huan AU - Wu H AD - Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. AD - Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, China. AD - Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei, China. FAU - Kherraf, Zine-Eddine AU - Kherraf ZE AD - Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France. AD - Centre Hospitalier Universitaire de Grenoble, UM GI-DPI, Grenoble, France. FAU - Liu, Wangjie AU - Liu W AD - 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, China. AD - Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China. AD - State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China. FAU - Zhang, Jingjing AU - Zhang J AD - Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. AD - Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, China. AD - Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei, China. FAU - Tan, Qing AU - Tan Q AD - Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. AD - Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, China. AD - Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei, China. FAU - Tang, Shuyan AU - Tang S AD - 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, China. AD - Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China. AD - State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China. FAU - Zhu, Yong-Jun AU - Zhu YJ AD - Department of Thoracic Surgery, Huashan Hospital, Fudan University, Shanghai, China. FAU - Zhong, Yading AU - Zhong Y AD - Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. FAU - Li, Caihua AU - Li C AD - Genesky Biotechnologies Inc, Shanghai, China. FAU - Tian, Shixiong AU - Tian S AD - 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, China. FAU - Zhang, Zhiguo AU - Zhang Z AD - Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. AD - Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, China. AD - Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei, China. FAU - Jin, Li AU - Jin L AD - 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, China. FAU - Ray, Pierre AU - Ray P AD - Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France. AD - Centre Hospitalier Universitaire de Grenoble, UM GI-DPI, Grenoble, France. FAU - Zhang, Feng AU - Zhang F AUID- ORCID: 0000-0003-4556-8276 AD - 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, China zhangfeng@fudan.edu.cn caoyunxia6@126.com. AD - Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China. AD - State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China. AD - Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.