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CEP128 Mutations Impair Spermatogenesis in Humans and Mice

ABSTRACT: CEP128 Mutations Impair Spermatogenesis in Humans and Mice

PROVIDER: PRJNA741287 | ENA |

REPOSITORIES: ENA

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CEP128 mutations impair spermatogenesis in humans and mice

Project description:The centrosome is a conserved eukaryotic organelle essential to the reproductive process, and centrosomal proteins are necessary for the components of the centrosome. However, few centrosomal proteins have been genetically linked to fertility, and the related molecular mechanisms remain unknown. Here, we identified a novel homozygous missense mutation of CEP128 (c.665G>A [p.R222Q]) in two infertile males with cryptozoospermia from a consanguineous family. This variant abnormally increased CEP128 protein expression. Remarkably, mouse models harbouring the orthologous variant of CEP128 R222Q were sterile, showing anomalies in the sperm morphology, count and motility. To confirm the important role of CEP128 in male fertility, we also generated Cep128 knock-out (KO) male mice, which were infertile associated with the disrupted sperm quality. Importantly, the defective sperm flagella were obviously observed in the two mouse strains, while the number, morphology and ultrastructure of cilia in other organs were normal, suggesting that CEP128 mutations only affect ciliogenesis in testes. Mechanistically, the imbalance expression of CEP128, whatever increase or decrease, perturbed the normal expression of genes and/or the phosphorylation of TGF-β/BMP signaling members involved in spermatogenesis. Altogether, our findings unprecedentedly unveil a crucial role for CEP128 in male fertility and provide new insights into the functions of centrosomal proteins in human disease.

2022-05-20 | PXD025330 | Pride

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Dysfunction of CEP128 impairs spermatogenesis but not ciliogenesis in humans and mice

Project description:The centrosome is a conserved eukaryotic organelle essential for reproductive process, and centrosomal proteins (CEP) are necessary for composition of the centrosome. However, few CEPs have been genetically linked to fertility, and the related molecular mechanisms remains mysterious. Here, we identified a new CEP, CEP128, which is functional in spermatogenesis, fertilization and embryonic development in both humans and mice. The variants of CEP128/Cep128 could lead to aberrant centrosome structures of the sperm inducing to anomalies in sperm morphology, count as well as motility, and further result in male infertility, but did not grossly affect ciliogenesis. Mechanistically, both loss and up-regulation of CEP128 could cause suppressed expressions of the genes involved in the spermatogenesis and fertilization phase. Altogether, our findings unprecedentedly unveil a crucial role of CEP128 in male fertility and provides new insight into the function of CEPs in human disease.

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