Dataset Information

Bi-allelic Mutations in TTC29 Cause Male Subfertility with Asthenoteratospermia in Humans and Mice.

ABSTRACT: As a type of severe asthenoteratospermia, multiple morphological abnormalities of the flagella (MMAF) are characterized by the presence of immotile spermatozoa with severe flagellar malformations. MMAF is a genetically heterogeneous disorder, and the known MMAF-associated genes can only account for approximately 60% of human MMAF cases. Here we conducted whole-exome sequencing and identified bi-allelic truncating mutations of the TTC29 (tetratricopeptide repeat domain 29) gene in three (3.8%) unrelated cases from a cohort of 80 MMAF-affected Han Chinese men. TTC29 is preferentially expressed in the testis, and TTC29 protein contains the tetratricopeptide repeat domains that play an important role in cilia- and flagella-associated functions. All of the men harboring TTC29 mutations presented a typical MMAF phenotype and dramatic disorganization in axonemal and/or other peri-axonemal structures. Immunofluorescence assays of spermatozoa from men harboring TTC29 mutations showed deficiency of TTC29 and remarkably reduced staining of intraflagellar-transport-complex-B-associated proteins (TTC30A and IFT52). We also generated a Ttc29-mutated mouse model through the use of CRISPR-Cas9 technology. Remarkably, Ttc29-mutated male mice also presented reduced sperm motility, abnormal flagellar ultrastructure, and male subfertility. Furthermore, intracytoplasmic sperm injections performed for Ttc29-mutated mice and men harboring TTC29 mutations consistently acquired satisfactory outcomes. Collectively, our experimental observations in humans and mice suggest that bi-allelic mutations in TTC29, as an important genetic pathogeny, can induce MMAF-related asthenoteratospermia. Our study also provided effective guidance for clinical diagnosis and assisted reproduction treatments.

SUBMITTER: Liu C

PROVIDER: S-EPMC6904824 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Bi-allelic Mutations in TTC29 Cause Male Subfertility with Asthenoteratospermia in Humans and Mice.

Liu Chunyu C He Xiaojin X Liu Wangjie W Yang Shenmin S Wang Lingbo L Li Weiyu W Wu Huan H Tang Shuyan S Ni Xiaoqing X Wang Jiaxiong J Gao Yang Y Tian Shixiong S Zhang Lin L Cong Jiangshan J Zhang Zhihua Z Tan Qing Q Zhang Jingjing J Li Hong H Zhong Yading Y Lv Mingrong M Li Jinsong J Jin Li L Cao Yunxia Y Zhang Feng F

American journal of human genetics 20191114 6

As a type of severe asthenoteratospermia, multiple morphological abnormalities of the flagella (MMAF) are characterized by the presence of immotile spermatozoa with severe flagellar malformations. MMAF is a genetically heterogeneous disorder, and the known MMAF-associated genes can only account for approximately 60% of human MMAF cases. Here we conducted whole-exome sequencing and identified bi-allelic truncating mutations of the TTC29 (tetratricopeptide repeat domain 29) gene in three (3.8%) un ...[more]

PMID: 31735294

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Project description:Study questionAre there other pathogenic genes for asthenoteratozoospermia (AT)?Summary answerDNAH3 is a novel candidate gene for AT in humans and mice.What is known alreadyAT is a major cause of male infertility. Several genes underlying AT have been reported; however, the genetic aetiology remains unknown in a majority of affected men.Study design size durationA total of 432 patients with AT were recruited in this study. DNAH3 mutations were identified by whole-exome sequencing (WES). Dnah3 knockout mice were generated using the genome editing tool. The morphology and motility of sperm from Dnah3 knockout mice were investigated. The entire study was conducted over 3 years.Participants/materials setting methodsWES was performed on 432 infertile patients with AT. In addition, two lines of Dnah3 knockout mice were generated. Haematoxylin and eosin (H&E) staining, transmission electron microscopy (TEM), immunostaining, and computer-aided sperm analysis (CASA) were performed to investigate the morphology and motility of the spermatozoa. ICSI was used to overcome the infertility of one patient and of the Dnah3 knockout mice.Main results and the role of chanceDNAH3 biallelic variants were identified in three patients from three unrelated families. H&E staining revealed various morphological abnormalities in the flagella of sperm from the patients, and TEM and immunostaining further showed the loss of the central pair of microtubules, a dislocated mitochondrial sheath and fibrous sheath, as well as a partial absence of the inner dynein arms. In addition, the two Dnah3 knockout mouse lines demonstrated AT. One patient and the Dnah3 knockout mice showed good treatment outcomes after ICSI.Large scale dataN/A.Limitations reasons for cautionThis is a preliminary report suggesting that defects in DNAH3 can lead to asthenoteratozoospermia in humans and mice. The pathogenic mechanism needs to be further examined in a future study.Wider implications of the findingsOur findings show that DNAH3 is a novel candidate gene for AT in humans and mice and provide crucial insights into the biological underpinnings of this disorder. The findings may also be beneficial for counselling affected individuals.Study funding/competing interestsThis work was supported by grants from National Natural Science Foundation of China (82201773, 82101961, 82171608, 32322017, 82071697, and 81971447), National Key Research and Development Program of China (2022YFC2702604), Scientific Research Foundation of the Health Committee of Hunan Province (B202301039323, B202301039518), Hunan Provincial Natural Science Foundation (2023JJ30716), the Medical Innovation Project of Fujian Province (2020-CXB-051), the Science and Technology Project of Fujian Province (2023D017), China Postdoctoral Science Foundation (2022M711119), and Guilin technology project for people's benefit (20180106-4-7). The authors declare no competing interests.

Dataset Information

Bi-allelic Mutations in TTC29 Cause Male Subfertility with Asthenoteratospermia in Humans and Mice.

Publications

Bi-allelic Mutations in TTC29 Cause Male Subfertility with Asthenoteratospermia in Humans and Mice.

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