CEP128 mutations impair spermatogenesis in humans and mice

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Testis

SUBMITTER: zhang zhiwei  

LAB HEAD: Shen Ying

PROVIDER: PXD025330 | Pride | 2022-05-20

REPOSITORIES: pride