Bi-allelic variants in human WDR63 cause male infertility via abnormal inner dynein arms assembly
Abstract Inner dynein arm (IDA), composed of a series of protein complex, is necessary to cilia and flagella bend formation and beating. Previous studies indicated that defects of IDA protein complex result in multiple morphological abnormalities of the sperm flagellum (MMAF) and male infertility. H...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2021-11-01
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| Series: | Cell Discovery |
| Online Access: | https://doi.org/10.1038/s41421-021-00327-5 |
| _version_ | 1818823188334772224 |
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| author | Shuai Lu Yayun Gu Yifei Wu Shenmin Yang Chenmeijie Li Lanlan Meng Wenwen Yuan Tao Jiang Xin Zhang Yang Li Cheng Wang Mingxi Liu Lan Ye Xuejiang Guo Hongbing Shen Xiaoyu Yang Yueqiu Tan Zhibin Hu |
| author_facet | Shuai Lu Yayun Gu Yifei Wu Shenmin Yang Chenmeijie Li Lanlan Meng Wenwen Yuan Tao Jiang Xin Zhang Yang Li Cheng Wang Mingxi Liu Lan Ye Xuejiang Guo Hongbing Shen Xiaoyu Yang Yueqiu Tan Zhibin Hu |
| author_sort | Shuai Lu |
| collection | DOAJ |
| description | Abstract Inner dynein arm (IDA), composed of a series of protein complex, is necessary to cilia and flagella bend formation and beating. Previous studies indicated that defects of IDA protein complex result in multiple morphological abnormalities of the sperm flagellum (MMAF) and male infertility. However, the genetic causes and molecular mechanisms in the IDAs need further exploration. Here we identified two loss-of-function variants of WDR63 in both MMAF and non-obstructive azoospermia (NOA) affected cohorts. WDR63 encodes an IDA-associated protein that is dominantly expressed in testis. We next generated Wdr63-knockout (Wdr63-KO) mice through the CRISPR-Cas9 technology. Remarkably, Wdr63-KO induced decreased sperm number, abnormal flagellar morphology and male infertility. In addition, transmission electron microscopy assay showed severely disorganized “9 + 2” axoneme and absent inner dynein arms in the spermatozoa from Wdr63-KO male mice. Mechanistically, we found that WDR63 interacted with WDR78 mainly via WD40-repeat domain and is necessary for IDA assembly. Furthermore, WDR63-associated male infertility in human and mice could be overcome by intracytoplasmic sperm injection (ICSI) treatment. In conclusion, the present study demonstrates that bi-allelic variants of WDR63 cause male infertility via abnormal inner dynein arms assembly and flagella formation and can be used as a genetic diagnostic indicator for infertility males. |
| first_indexed | 2024-12-18T23:36:00Z |
| format | Article |
| id | doaj.art-b367dda3089c450db57f37b585da4e7e |
| institution | Directory Open Access Journal |
| issn | 2056-5968 |
| language | English |
| last_indexed | 2024-12-18T23:36:00Z |
| publishDate | 2021-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Discovery |
| spelling | doaj.art-b367dda3089c450db57f37b585da4e7e2022-12-21T20:47:32ZengNature Publishing GroupCell Discovery2056-59682021-11-017111510.1038/s41421-021-00327-5Bi-allelic variants in human WDR63 cause male infertility via abnormal inner dynein arms assemblyShuai Lu0Yayun Gu1Yifei Wu2Shenmin Yang3Chenmeijie Li4Lanlan Meng5Wenwen Yuan6Tao Jiang7Xin Zhang8Yang Li9Cheng Wang10Mingxi Liu11Lan Ye12Xuejiang Guo13Hongbing Shen14Xiaoyu Yang15Yueqiu Tan16Zhibin Hu17Department of Epidemiology, School of Public Health, Southeast UniversityState Key Laboratory of Reproductive Medicine, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine, The Affiliated Suzhou Hospital of Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine, Nanjing Medical UniversityInstitute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South UniversityState Key Laboratory of Reproductive Medicine, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine, Nanjing Medical UniversityInstitute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South UniversityDepartment of Epidemiology, School of Public Health, Southeast UniversityAbstract Inner dynein arm (IDA), composed of a series of protein complex, is necessary to cilia and flagella bend formation and beating. Previous studies indicated that defects of IDA protein complex result in multiple morphological abnormalities of the sperm flagellum (MMAF) and male infertility. However, the genetic causes and molecular mechanisms in the IDAs need further exploration. Here we identified two loss-of-function variants of WDR63 in both MMAF and non-obstructive azoospermia (NOA) affected cohorts. WDR63 encodes an IDA-associated protein that is dominantly expressed in testis. We next generated Wdr63-knockout (Wdr63-KO) mice through the CRISPR-Cas9 technology. Remarkably, Wdr63-KO induced decreased sperm number, abnormal flagellar morphology and male infertility. In addition, transmission electron microscopy assay showed severely disorganized “9 + 2” axoneme and absent inner dynein arms in the spermatozoa from Wdr63-KO male mice. Mechanistically, we found that WDR63 interacted with WDR78 mainly via WD40-repeat domain and is necessary for IDA assembly. Furthermore, WDR63-associated male infertility in human and mice could be overcome by intracytoplasmic sperm injection (ICSI) treatment. In conclusion, the present study demonstrates that bi-allelic variants of WDR63 cause male infertility via abnormal inner dynein arms assembly and flagella formation and can be used as a genetic diagnostic indicator for infertility males.https://doi.org/10.1038/s41421-021-00327-5 |
| spellingShingle | Shuai Lu Yayun Gu Yifei Wu Shenmin Yang Chenmeijie Li Lanlan Meng Wenwen Yuan Tao Jiang Xin Zhang Yang Li Cheng Wang Mingxi Liu Lan Ye Xuejiang Guo Hongbing Shen Xiaoyu Yang Yueqiu Tan Zhibin Hu Bi-allelic variants in human WDR63 cause male infertility via abnormal inner dynein arms assembly Cell Discovery |
| title | Bi-allelic variants in human WDR63 cause male infertility via abnormal inner dynein arms assembly |
| title_full | Bi-allelic variants in human WDR63 cause male infertility via abnormal inner dynein arms assembly |
| title_fullStr | Bi-allelic variants in human WDR63 cause male infertility via abnormal inner dynein arms assembly |
| title_full_unstemmed | Bi-allelic variants in human WDR63 cause male infertility via abnormal inner dynein arms assembly |
| title_short | Bi-allelic variants in human WDR63 cause male infertility via abnormal inner dynein arms assembly |
| title_sort | bi allelic variants in human wdr63 cause male infertility via abnormal inner dynein arms assembly |
| url | https://doi.org/10.1038/s41421-021-00327-5 |
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