Dataset Information

Deficiency of the Tmem232 Gene Causes Male Infertility with Morphological Abnormalities of the Sperm Flagellum in Mice.

ABSTRACT: The axoneme and accessory structures of flagella are critical for sperm motility and male fertilization. Sperm production needs precise and highly ordered gene expression to initiate and sustain the many cellular processes that result in mature spermatozoa. Here, we identified a testis enriched gene transmembrane protein 232 (Tmem232), which is essential for the structural integrity of the spermatozoa flagella axoneme. Tmem232 knockout mice were generated for in vivo analyses of its functions in spermatogenesis. Phenotypic analysis showed that deletion of Tmem232 in mice causes male-specific infertility. Transmission electron microscopy together with scanning electron microscopy were applied to analyze the spermatozoa flagella and it was observed that the lack of TMEM232 caused failure of the cytoplasm removal and the absence of the 7th outer microtubule doublet with its corresponding outer dense fiber (ODF). Co-IP assays further identified that TMEM232 interacts with ODF family protein ODF1, which is essential to maintain sperm motility. In conclusion, our findings indicate that TMEM232 is a critical protein for male fertility and sperm motility by regulating sperm cytoplasm removal and maintaining axoneme integrity.

SUBMITTER: He X

PROVIDER: S-EPMC10296807 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Deficiency of the Tmem232 Gene Causes Male Infertility with Morphological Abnormalities of the Sperm Flagellum in Mice.

He Xiuqing X Mu Wenyu W Wang Ziqi Z Xu Ke K Yin Yingying Y Lu Gang G Chan Wai-Yee WY Liu Hongbin H Lv Yue Y Liu Shangming S

Cells 20230613 12

The axoneme and accessory structures of flagella are critical for sperm motility and male fertilization. Sperm production needs precise and highly ordered gene expression to initiate and sustain the many cellular processes that result in mature spermatozoa. Here, we identified a testis enriched gene transmembrane protein 232 (Tmem232), which is essential for the structural integrity of the spermatozoa flagella axoneme. Tmem232 knockout mice were generated for in vivo analyses of it ...[more]

PMID: 37371084

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Project description:BackgroundAsthenozoospermia is the primary cause of male infertility; however, its genetic aetiology remains poorly understood. Adenylate kinase 9 (AK9) is highly expressed in the testes of humans and mice and encodes a type of adenosine kinase that is functionally involved in cellular nucleotide homeostasis and energy metabolism. We aimed to assess whether AK9 is involved in asthenozoospermia.MethodsOne-hundred-and-sixty-five Chinese men with idiopathic asthenozoospermia were recruited. Whole-exome sequencing (WES) and Sanger sequencing were performed for genetic analyses. Papanicolaou staining, Haematoxylin and eosin staining, scanning electron microscopy, and transmission electron microscopy were used to observe the sperm morphology and structure. Ak9-knockout mice were generated using CRISPR-Cas9. Sperm adenosine was detected by liquid chromatography-mass spectrometry. Targeted sperm metabolomics was performed. Intracytoplasmic sperm injection (ICSI) was used to treat patients.FindingsWe identified five patients harbouring bi-allelic AK9 mutations. Spermatozoa from men harbouring bi-allelic AK9 mutations have a decreased ability to sustain nucleotide homeostasis. Moreover, bi-allelic AK9 mutations inhibit glycolysis in sperm. Ak9-knockout male mice also presented similar phenotypes of asthenozoospermia. Interestingly, ICSI was effective in bi-allelic AK9 mutant patients in achieving good pregnancy outcomes.InterpretationDefects in AK9 induce asthenozoospermia with defects in nucleotide homeostasis and energy metabolism. This sterile phenotype could be rescued by ICSI.FundingThe National Natural Science Foundation of China (82071697), Medical Innovation Project of Fujian Province (2020-CXB-051), open project of the NHC Key Laboratory of Male Reproduction and Genetics in Guangzhou (KF202004), Medical Research Foundation of Guangdong Province (A2021269), Guangdong Provincial Reproductive Science Institute Innovation Team grants (C-03), and Outstanding Young Talents Program of Capital Medical University (B2205).

Dataset Information

Deficiency of the Tmem232 Gene Causes Male Infertility with Morphological Abnormalities of the Sperm Flagellum in Mice.

Publications

Deficiency of the <i>Tmem232</i> Gene Causes Male Infertility with Morphological Abnormalities of the Sperm Flagellum in Mice.

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