Homozygous deleterious variants in the C-terminal of TDRD5 impair spermiogenesis, causing severe oligoasthenoteratozoospermia in humans
Rui Guo
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, Anhui, China
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
Search for more papers by this authorBiao Ding
Department of Obstetrics and Gynecology, Reproductive Medicine Center, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
Search for more papers by this authorKaiqin Hu
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, Anhui, China
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
Search for more papers by this authorKai Wang
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, Anhui, China
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
Search for more papers by this authorDongdong Tang
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
Search for more papers by this authorXuegu Wang
Department of Obstetrics and Gynecology, Reproductive Medicine Center, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
Search for more papers by this authorJunpei Sun
Department of Obstetrics and Gynecology, Reproductive Medicine Center, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
Search for more papers by this authorKuoKuo Li
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, Anhui, China
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
Search for more papers by this authorHuiru Cheng
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, Anhui, China
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
Search for more papers by this authorChuan Xu
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
Search for more papers by this authorMiao Sun
Institute for Fetology, The First Affiliated Hospital of Soochow University, Suzhou, China
Search for more papers by this authorLikui Lu
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
Search for more papers by this authorMingxi Liu
State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China
Search for more papers by this authorCorresponding Author
Yunxia Cao
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, Anhui, China
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
Correspondence
Xiaojin He, Reproductive Medicine Center, School of Medicine, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China.
Email: [email protected]
Xiaoyu Yang, State Key Laboratory of Reproductive Medicine, The Center for Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Email: [email protected]
Yunxia Cao, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Xiaoyu Yang
State Key Laboratory of Reproductive Medicine, The Center for Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Correspondence
Xiaojin He, Reproductive Medicine Center, School of Medicine, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China.
Email: [email protected]
Xiaoyu Yang, State Key Laboratory of Reproductive Medicine, The Center for Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Email: [email protected]
Yunxia Cao, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Xiaojin He
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, Anhui, China
Department of Obstetrics and Gynecology, Reproductive Medicine Center, School of Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
Correspondence
Xiaojin He, Reproductive Medicine Center, School of Medicine, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China.
Email: [email protected]
Xiaoyu Yang, State Key Laboratory of Reproductive Medicine, The Center for Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Email: [email protected]
Yunxia Cao, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
Email: [email protected]
Search for more papers by this authorRui Guo
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, Anhui, China
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
Search for more papers by this authorBiao Ding
Department of Obstetrics and Gynecology, Reproductive Medicine Center, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
Search for more papers by this authorKaiqin Hu
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, Anhui, China
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
Search for more papers by this authorKai Wang
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, Anhui, China
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
Search for more papers by this authorDongdong Tang
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
Search for more papers by this authorXuegu Wang
Department of Obstetrics and Gynecology, Reproductive Medicine Center, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
Search for more papers by this authorJunpei Sun
Department of Obstetrics and Gynecology, Reproductive Medicine Center, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
Search for more papers by this authorKuoKuo Li
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, Anhui, China
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
Search for more papers by this authorHuiru Cheng
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, Anhui, China
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
Search for more papers by this authorChuan Xu
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
Search for more papers by this authorMiao Sun
Institute for Fetology, The First Affiliated Hospital of Soochow University, Suzhou, China
Search for more papers by this authorLikui Lu
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
Search for more papers by this authorMingxi Liu
State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China
Search for more papers by this authorCorresponding Author
Yunxia Cao
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, Anhui, China
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
Correspondence
Xiaojin He, Reproductive Medicine Center, School of Medicine, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China.
Email: [email protected]
Xiaoyu Yang, State Key Laboratory of Reproductive Medicine, The Center for Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Email: [email protected]
Yunxia Cao, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Xiaoyu Yang
State Key Laboratory of Reproductive Medicine, The Center for Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Correspondence
Xiaojin He, Reproductive Medicine Center, School of Medicine, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China.
Email: [email protected]
Xiaoyu Yang, State Key Laboratory of Reproductive Medicine, The Center for Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Email: [email protected]
Yunxia Cao, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Xiaojin He
NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, Anhui, China
Department of Obstetrics and Gynecology, Reproductive Medicine Center, School of Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
Correspondence
Xiaojin He, Reproductive Medicine Center, School of Medicine, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China.
Email: [email protected]
Xiaoyu Yang, State Key Laboratory of Reproductive Medicine, The Center for Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Email: [email protected]
Yunxia Cao, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
Email: [email protected]
Search for more papers by this authorRui Guo, Biao Ding, Kaiqin Hu and Kai Wang contributed equally to this paper.
Abstract
Background
PiRNA pathway factors, including evolutionarily conserved Tudor domain-containing proteins, play crucial roles in suppressing transposons and regulating post-meiotic gene expression. TDRD5 is essential for retrotransposon silencing and pachytene piRNA biogenesis; however, a causal link between TDRD5 variants and human infertility has not yet been established.
Objective
To identify the likely pathogenic variants of TDRD5 in infertile men, characterised by azoospermia or severe oligozoospermia.
Material and methods
Potential candidate variants were identified and confirmed using whole-exome and Sanger sequencing. Haematoxylin and eosin staining, immunofluorescence, and ultrastructural analyses were performed to investigate the structural and functional abnormalities of spermatozoa. The pathogenicity of the identified TDRD5 variants was verified using in vitro experiments. Functional effects of the C-terminal nonsense variant were assessed via histology, immunofluorescence staining, and small-RNA sequencing. Intracytoplasmic sperm injection (ICSI) was also performed to evaluate the efficacy of the clinical treatment.
Results
We identified a homozygous missense variant (c.3043G > A, p.A1015T) and a homozygous nonsense variant (c.2293G > T, p.E765*) of TDRD5 in two unrelated infertile men. Both patients exhibited severe oligoasthenoteratozoospermia, characterised by the presence of spermatozoa with multiple heads and/or flagella, as well as acrosomal hypoplasia. In vitro experiments revealed that the p.A1015T variant caused a diffuse distribution of TDRD5 granules, whereas the p.E765* variant led to the production of a C-terminal truncated protein with nuclear localisation, instead of the typical cytoplasmic localisation observed for the wild-type protein. Functional investigations also revealed that truncation of the C-terminal region of TDRD5 could potentially lead to a decline in the expression levels of intermitochondrial cement and chromatoid body components, such as MIWI (PIWIL1) and UPF1, and a slight decrease in the abundance of pachytene piRNA, ultimately resulting in compromised spermiogenesis. ICSI may be an effective treatment for these deficiencies.
Discussion and conclusion
This study implicates TDRD5 as a novel candidate gene in the pathogenesis of human male infertility, emphasising the contribution of piRNA pathway genes to male infertility. In addition, our data suggest that ICSI could be a promising treatment for infertile men harbouring TDRD5 variants.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
Open Research
DATA AVAILABILITY STATEMENT
The data underlying this paper will be shared on reasonable request to the corresponding authors.
Supporting Information
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| andr13676-sup-0001-FigureS1.tif4.9 MB | Supporting Information |
| andr13676-sup-0002-FigureS2.tif12.4 MB | Supporting Information |
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| andr13676-sup-0004-FigureS4.tif710.8 KB | Supporting Information |
| andr13676-sup-0005-FigureS5.tif7.4 MB | Supporting Information |
| andr13676-sup-0006-FigureS6.tif6.4 MB | Supporting Information |
| andr13676-sup-0007-FigureS7.tif2.7 MB | Supporting Information |
| andr13676-sup-0008-TableS1.xlsx11.9 KB | Supporting Information |
| andr13676-sup-0009-TableS2.docx14.9 KB | Supporting Information |
| andr13676-sup-0010-TableS3.docx15.2 KB | Supporting Information |
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