Novel bi-allelic DNAH3 variants cause oligoasthenoteratozoospermia
BackgroundOligoasthenoteratozoospermia (OAT) is a widespread cause of male infertility. One of the usual clinical manifestations of OAT is multiple morphological abnormalities of the sperm flagella (MMAF), which are frequently associated with mutations and defects in the dynein family. However, the...
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Frontiers Media S.A.
2024-10-01
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| Series: | Frontiers in Endocrinology |
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| author | Shu Li Zexin Zhang Linna Xie Linna Xie Yanqiu Zhao Hongtai Chen Shijia Zhang Yixiang Cai Bingjie Ren Wensheng Liu Songxi Tang Yanwei Sha Yanwei Sha Yanwei Sha |
| author_facet | Shu Li Zexin Zhang Linna Xie Linna Xie Yanqiu Zhao Hongtai Chen Shijia Zhang Yixiang Cai Bingjie Ren Wensheng Liu Songxi Tang Yanwei Sha Yanwei Sha Yanwei Sha |
| author_sort | Shu Li |
| collection | DOAJ |
| description | BackgroundOligoasthenoteratozoospermia (OAT) is a widespread cause of male infertility. One of the usual clinical manifestations of OAT is multiple morphological abnormalities of the sperm flagella (MMAF), which are frequently associated with mutations and defects in the dynein family. However, the relationship between the newly identified Dynein Axonemal Heavy Chain 3 (DNAH3) mutation and oligonasthenospermia in humans has not yet been established.MethodsWhole exome sequencing, pathogenicity analysis, and species conservation analysis of mutation sites were conducted on two patients from different unrelated families with DNAH3 mutations. We identified representative mutation sites and predicted the protein structure following these mutations. The sperm characteristics of the two patients with DNAH3 mutations were verified using Papanicolaou staining, scanning electron microscopy, and transmission electron microscopy. Additionally, mRNA and protein levels were assessed through RT-qPCR and Western blotting.ResultsThe biallelic mutations in the first progenitor included a heterozygous deletion and insertion, c.6535_6536 delinsAC (to infect mutation (p.Asp2179Thr), and stop codon premutation, c.3249G > A (p.Trp1083Ter). In Family II, the patient (P2) harbored a DNAH3 heterozygous missense mutation, c. 10439G> A(p.Arg3480Gln), along with a stop codon premutation, (c.10260G > A; p.Trp3420Ter). Patients with premature termination of transcription or translation due to DNAH3 mutations exhibit OAT phenotypes, including fibrous sheath dysplasia and multiple tail malformations. We identified the representative sites after mutation, predicted the protein structure, and assessed changes in the protein levels of DNAH3 and related genes following mutations. Notably,a significant reduction in DNAH3 protein expression was validated in these patients. We may explore in the future how DNAH3 affects sperm motility and quality through regulatory mechanisms involving protein structural changes.ConclusionNovel biallelic mutations in DNAH3, especially those resulting in a premature stop codon, may alter protein expression, structure, and active site, leading to spermatogenic failure and potentially inducing OAT. The discovery of new mutations in DNAH3 may be the key to the diagnosis and treatment of OAT. |
| format | Article |
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| institution | Kabale University |
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| language | English |
| publishDate | 2024-10-01 |
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| series | Frontiers in Endocrinology |
| spelling | doaj-art-8980aa46c8ec47d6ab74ec7a52712aa52024-11-11T08:39:26ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922024-10-011510.3389/fendo.2024.14625091462509Novel bi-allelic DNAH3 variants cause oligoasthenoteratozoospermiaShu Li0Zexin Zhang1Linna Xie2Linna Xie3Yanqiu Zhao4Hongtai Chen5Shijia Zhang6Yixiang Cai7Bingjie Ren8Wensheng Liu9Songxi Tang10Yanwei Sha11Yanwei Sha12Yanwei Sha13Department of Andrology, Women and Children’s Hospital, School of Medicine, Xiamen University, Xiamen, Fujian, ChinaPeking Union Medical College, Chinese Academy of Medical Sciences, Beijing, ChinaDepartment of Andrology, Women and Children’s Hospital, School of Medicine, Xiamen University, Xiamen, Fujian, ChinaState Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, Fujian, ChinaDepartment of Andrology, Women and Children’s Hospital, School of Medicine, Xiamen University, Xiamen, Fujian, ChinaDepartment of Andrology, Women and Children’s Hospital, School of Medicine, Xiamen University, Xiamen, Fujian, ChinaDepartment of Andrology, Women and Children’s Hospital, School of Medicine, Xiamen University, Xiamen, Fujian, ChinaDepartment of Andrology, Women and Children’s Hospital, School of Medicine, Xiamen University, Xiamen, Fujian, ChinaDepartment of Andrology, Women and Children’s Hospital, School of Medicine, Xiamen University, Xiamen, Fujian, ChinaNational Health Commission (NHC) Key Laboratory of Male Reproduction and Genetics, Guangdong Provincial Reproductive Science Institute (Guangdong Provincial Fertility Hospital), Guangzhou, Guangdong, ChinaDepartment of Andrology and Sexual Medicine, First Affiliated Hospital of Fujian Medical University, Fuzhou, ChinaDepartment of Andrology, Women and Children’s Hospital, School of Medicine, Xiamen University, Xiamen, Fujian, ChinaState Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, Fujian, ChinaFujian Provincial Key Laboratory of Reproductive Health Research, School of Medicine, Xiamen University, Xiamen, Fujian, ChinaBackgroundOligoasthenoteratozoospermia (OAT) is a widespread cause of male infertility. One of the usual clinical manifestations of OAT is multiple morphological abnormalities of the sperm flagella (MMAF), which are frequently associated with mutations and defects in the dynein family. However, the relationship between the newly identified Dynein Axonemal Heavy Chain 3 (DNAH3) mutation and oligonasthenospermia in humans has not yet been established.MethodsWhole exome sequencing, pathogenicity analysis, and species conservation analysis of mutation sites were conducted on two patients from different unrelated families with DNAH3 mutations. We identified representative mutation sites and predicted the protein structure following these mutations. The sperm characteristics of the two patients with DNAH3 mutations were verified using Papanicolaou staining, scanning electron microscopy, and transmission electron microscopy. Additionally, mRNA and protein levels were assessed through RT-qPCR and Western blotting.ResultsThe biallelic mutations in the first progenitor included a heterozygous deletion and insertion, c.6535_6536 delinsAC (to infect mutation (p.Asp2179Thr), and stop codon premutation, c.3249G > A (p.Trp1083Ter). In Family II, the patient (P2) harbored a DNAH3 heterozygous missense mutation, c. 10439G> A(p.Arg3480Gln), along with a stop codon premutation, (c.10260G > A; p.Trp3420Ter). Patients with premature termination of transcription or translation due to DNAH3 mutations exhibit OAT phenotypes, including fibrous sheath dysplasia and multiple tail malformations. We identified the representative sites after mutation, predicted the protein structure, and assessed changes in the protein levels of DNAH3 and related genes following mutations. Notably,a significant reduction in DNAH3 protein expression was validated in these patients. We may explore in the future how DNAH3 affects sperm motility and quality through regulatory mechanisms involving protein structural changes.ConclusionNovel biallelic mutations in DNAH3, especially those resulting in a premature stop codon, may alter protein expression, structure, and active site, leading to spermatogenic failure and potentially inducing OAT. The discovery of new mutations in DNAH3 may be the key to the diagnosis and treatment of OAT.https://www.frontiersin.org/articles/10.3389/fendo.2024.1462509/fulloligoasthenoteratozoospermiadyneinintracytoplasmic sperm injectionmale infertilityDNAH3 |
| spellingShingle | Shu Li Zexin Zhang Linna Xie Linna Xie Yanqiu Zhao Hongtai Chen Shijia Zhang Yixiang Cai Bingjie Ren Wensheng Liu Songxi Tang Yanwei Sha Yanwei Sha Yanwei Sha Novel bi-allelic DNAH3 variants cause oligoasthenoteratozoospermia Frontiers in Endocrinology oligoasthenoteratozoospermia dynein intracytoplasmic sperm injection male infertility DNAH3 |
| title | Novel bi-allelic DNAH3 variants cause oligoasthenoteratozoospermia |
| title_full | Novel bi-allelic DNAH3 variants cause oligoasthenoteratozoospermia |
| title_fullStr | Novel bi-allelic DNAH3 variants cause oligoasthenoteratozoospermia |
| title_full_unstemmed | Novel bi-allelic DNAH3 variants cause oligoasthenoteratozoospermia |
| title_short | Novel bi-allelic DNAH3 variants cause oligoasthenoteratozoospermia |
| title_sort | novel bi allelic dnah3 variants cause oligoasthenoteratozoospermia |
| topic | oligoasthenoteratozoospermia dynein intracytoplasmic sperm injection male infertility DNAH3 |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2024.1462509/full |
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