Deficiency in DNAH12 causes male infertility by impairing DNAH1 and DNALI1 recruitment in humans and mice
Asthenoteratozoospermia, a prevalent cause of male infertility, lacks a well-defined etiology. DNAH12 is a special dynein featured by the absence of a microtubule-binding domain, however, its functions in spermatogenesis remain largely unknown. Through comprehensive genetic analyses involving whole-...
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eLife Sciences Publications Ltd
2025-03-01
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| author | Menglei Yang Hafiz Muhammad Jafar Hussain Manan Khan Zubair Muhammad Jianteng Zhou Ao Ma Xiongheng Huang Jingwei Ye Min Chen Aoran Zhi Tao Liu Ranjha Khan Ali Asim Wasim Shah Aurang Zeb Nisar Ahmad Huan Zhang Bo Xu Hui Ma Qinghua Shi Baolu Shi |
| author_facet | Menglei Yang Hafiz Muhammad Jafar Hussain Manan Khan Zubair Muhammad Jianteng Zhou Ao Ma Xiongheng Huang Jingwei Ye Min Chen Aoran Zhi Tao Liu Ranjha Khan Ali Asim Wasim Shah Aurang Zeb Nisar Ahmad Huan Zhang Bo Xu Hui Ma Qinghua Shi Baolu Shi |
| author_sort | Menglei Yang |
| collection | DOAJ |
| description | Asthenoteratozoospermia, a prevalent cause of male infertility, lacks a well-defined etiology. DNAH12 is a special dynein featured by the absence of a microtubule-binding domain, however, its functions in spermatogenesis remain largely unknown. Through comprehensive genetic analyses involving whole-exome sequencing and subsequent Sanger sequencing on infertile patients and fertile controls from six distinct families, we unveiled six biallelic mutations in DNAH12 that co-segregate recessively with male infertility in the studied families. Transmission electron microscopy (TEM) revealed pronounced axonemal abnormalities, including inner dynein arms (IDAs) impairment and central pair (CP) loss in sperm flagella of the patients. Mouse models (Dnah12-/- and Dnah12mut/mut) were generated and recapitulated the reproductive defects in the patients. Noteworthy, DNAH12 deficiency did not show effects on cilium organization and function. Mechanistically, DNAH12 was confirmed to interact with two other IDA components DNALI1 and DNAH1, while disruption of DNAH12 leads to failed recruitment of DNALI1 and DNAH1 to IDAs and compromised sperm development. Furthermore, DNAH12 also interacts with radial spoke head proteins RSPH1, RSPH9, and DNAJB13 to regulate CP stability. Moreover, the infertility of Dnah12-/- mice could be overcome by intracytoplasmic sperm injection (ICSI) treatment. Collectively, DNAH12 plays a crucial role in the proper organization of axoneme in sperm flagella, but not cilia, by recruiting DNAH1 and DNALI1 in both humans and mice. These findings expand our comprehension of dynein component assembly in flagella and cilia and provide a valuable marker for genetic counseling and diagnosis of asthenoteratozoospermia in clinical practice. |
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| language | English |
| publishDate | 2025-03-01 |
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| spelling | doaj-art-f399dce144a24189b5f0c47e7d7d818e2025-08-20T02:54:29ZengeLife Sciences Publications LtdeLife2050-084X2025-03-011310.7554/eLife.100350Deficiency in DNAH12 causes male infertility by impairing DNAH1 and DNALI1 recruitment in humans and miceMenglei Yang0Hafiz Muhammad Jafar Hussain1Manan Khan2Zubair Muhammad3Jianteng Zhou4Ao Ma5Xiongheng Huang6Jingwei Ye7Min Chen8Aoran Zhi9Tao Liu10Ranjha Khan11Ali Asim12Wasim Shah13Aurang Zeb14Nisar Ahmad15Huan Zhang16Bo Xu17Hui Ma18Qinghua Shi19Baolu Shi20https://orcid.org/0000-0002-5791-4300Center for Reproduction and Genetics, Department of Obstetrics and Gynecology, First Affiliated Hospital of USTC, Hefei National Research Center for Physical Sciences at the Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Biomedical Sciences and Health Laboratory of Anhui Province, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaCenter for Reproduction and Genetics, Department of Obstetrics and Gynecology, First Affiliated Hospital of USTC, Hefei National Research Center for Physical Sciences at the Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Biomedical Sciences and Health Laboratory of Anhui Province, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaCenter for Reproduction and Genetics, Department of Obstetrics and Gynecology, First Affiliated Hospital of USTC, Hefei National Research Center for Physical Sciences at the Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Biomedical Sciences and Health Laboratory of Anhui Province, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaCenter for Reproduction and Genetics, Department of Obstetrics and Gynecology, First Affiliated Hospital of USTC, Hefei National Research Center for Physical Sciences at the Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Biomedical Sciences and Health Laboratory of Anhui Province, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaCenter for Reproduction and Genetics, Department of Obstetrics and Gynecology, First Affiliated Hospital of USTC, Hefei National Research Center for Physical Sciences at the Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Biomedical Sciences and Health Laboratory of Anhui Province, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaCenter for Reproduction and Genetics, Department of Obstetrics and Gynecology, First Affiliated Hospital of USTC, Hefei National Research Center for Physical Sciences at the Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Biomedical Sciences and Health Laboratory of Anhui Province, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaCenter for Reproduction and Genetics, Department of Obstetrics and Gynecology, First Affiliated Hospital of USTC, Hefei National Research Center for Physical Sciences at the Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Biomedical Sciences and Health Laboratory of Anhui Province, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaCenter for Reproduction and Genetics, Department of Obstetrics and Gynecology, First Affiliated Hospital of USTC, Hefei National Research Center for Physical Sciences at the Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Biomedical Sciences and Health Laboratory of Anhui Province, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaCenter for Reproduction and Genetics, Department of Obstetrics and Gynecology, First Affiliated Hospital of USTC, Hefei National Research Center for Physical Sciences at the Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Biomedical Sciences and Health Laboratory of Anhui Province, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaCenter for Reproduction and Genetics, Department of Obstetrics and Gynecology, First Affiliated Hospital of USTC, Hefei National Research Center for Physical Sciences at the Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Biomedical Sciences and Health Laboratory of Anhui Province, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaCenter for Reproduction and Genetics, Department of Obstetrics and Gynecology, First Affiliated Hospital of USTC, Hefei National Research Center for Physical Sciences at the Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Biomedical Sciences and Health Laboratory of Anhui Province, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaCenter for Reproduction and Genetics, Department of Obstetrics and Gynecology, First Affiliated Hospital of USTC, Hefei National Research Center for Physical Sciences at the Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Biomedical Sciences and Health Laboratory of Anhui Province, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaCenter for Reproduction and Genetics, Department of Obstetrics and Gynecology, First Affiliated Hospital of USTC, Hefei National Research Center for Physical Sciences at the Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Biomedical Sciences and Health Laboratory of Anhui Province, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaCenter for Reproduction and Genetics, Department of Obstetrics and Gynecology, First Affiliated Hospital of USTC, Hefei National Research Center for Physical Sciences at the Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Biomedical Sciences and Health Laboratory of Anhui Province, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaCenter for Reproduction and Genetics, Department of Obstetrics and Gynecology, First Affiliated Hospital of USTC, Hefei National Research Center for Physical Sciences at the Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Biomedical Sciences and Health Laboratory of Anhui Province, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaCenter for Reproduction and Genetics, Department of Obstetrics and Gynecology, First Affiliated Hospital of USTC, Hefei National Research Center for Physical Sciences at the Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Biomedical Sciences and Health Laboratory of Anhui Province, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaCenter for Reproduction and Genetics, Department of Obstetrics and Gynecology, First Affiliated Hospital of USTC, Hefei National Research Center for Physical Sciences at the Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Biomedical Sciences and Health Laboratory of Anhui Province, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaCenter for Reproduction and Genetics, Department of Obstetrics and Gynecology, First Affiliated Hospital of USTC, Hefei National Research Center for Physical Sciences at the Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Biomedical Sciences and Health Laboratory of Anhui Province, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaCenter for Reproduction and Genetics, Department of Obstetrics and Gynecology, First Affiliated Hospital of USTC, Hefei National Research Center for Physical Sciences at the Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Biomedical Sciences and Health Laboratory of Anhui Province, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaCenter for Reproduction and Genetics, Department of Obstetrics and Gynecology, First Affiliated Hospital of USTC, Hefei National Research Center for Physical Sciences at the Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Biomedical Sciences and Health Laboratory of Anhui Province, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaCenter for Reproduction and Genetics, Department of Obstetrics and Gynecology, First Affiliated Hospital of USTC, Hefei National Research Center for Physical Sciences at the Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Biomedical Sciences and Health Laboratory of Anhui Province, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaAsthenoteratozoospermia, a prevalent cause of male infertility, lacks a well-defined etiology. DNAH12 is a special dynein featured by the absence of a microtubule-binding domain, however, its functions in spermatogenesis remain largely unknown. Through comprehensive genetic analyses involving whole-exome sequencing and subsequent Sanger sequencing on infertile patients and fertile controls from six distinct families, we unveiled six biallelic mutations in DNAH12 that co-segregate recessively with male infertility in the studied families. Transmission electron microscopy (TEM) revealed pronounced axonemal abnormalities, including inner dynein arms (IDAs) impairment and central pair (CP) loss in sperm flagella of the patients. Mouse models (Dnah12-/- and Dnah12mut/mut) were generated and recapitulated the reproductive defects in the patients. Noteworthy, DNAH12 deficiency did not show effects on cilium organization and function. Mechanistically, DNAH12 was confirmed to interact with two other IDA components DNALI1 and DNAH1, while disruption of DNAH12 leads to failed recruitment of DNALI1 and DNAH1 to IDAs and compromised sperm development. Furthermore, DNAH12 also interacts with radial spoke head proteins RSPH1, RSPH9, and DNAJB13 to regulate CP stability. Moreover, the infertility of Dnah12-/- mice could be overcome by intracytoplasmic sperm injection (ICSI) treatment. Collectively, DNAH12 plays a crucial role in the proper organization of axoneme in sperm flagella, but not cilia, by recruiting DNAH1 and DNALI1 in both humans and mice. These findings expand our comprehension of dynein component assembly in flagella and cilia and provide a valuable marker for genetic counseling and diagnosis of asthenoteratozoospermia in clinical practice.https://elifesciences.org/articles/100350male infertilityhuman geneticsdyneinsperm flagellainner dynein armscilia |
| spellingShingle | Menglei Yang Hafiz Muhammad Jafar Hussain Manan Khan Zubair Muhammad Jianteng Zhou Ao Ma Xiongheng Huang Jingwei Ye Min Chen Aoran Zhi Tao Liu Ranjha Khan Ali Asim Wasim Shah Aurang Zeb Nisar Ahmad Huan Zhang Bo Xu Hui Ma Qinghua Shi Baolu Shi Deficiency in DNAH12 causes male infertility by impairing DNAH1 and DNALI1 recruitment in humans and mice eLife male infertility human genetics dynein sperm flagella inner dynein arms cilia |
| title | Deficiency in DNAH12 causes male infertility by impairing DNAH1 and DNALI1 recruitment in humans and mice |
| title_full | Deficiency in DNAH12 causes male infertility by impairing DNAH1 and DNALI1 recruitment in humans and mice |
| title_fullStr | Deficiency in DNAH12 causes male infertility by impairing DNAH1 and DNALI1 recruitment in humans and mice |
| title_full_unstemmed | Deficiency in DNAH12 causes male infertility by impairing DNAH1 and DNALI1 recruitment in humans and mice |
| title_short | Deficiency in DNAH12 causes male infertility by impairing DNAH1 and DNALI1 recruitment in humans and mice |
| title_sort | deficiency in dnah12 causes male infertility by impairing dnah1 and dnali1 recruitment in humans and mice |
| topic | male infertility human genetics dynein sperm flagella inner dynein arms cilia |
| url | https://elifesciences.org/articles/100350 |
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