| Autor: |
Wang, Pengcheng, Shi, Wenxiang, Liu, Sijie, Shi, Yunjing, Jiang, Xuechao, Li, Fen, Chen, Sun, Sun, Kun, Xu, Rang |
| Zdroj: |
Journal of Genetics and Genomics; September 2024, Vol. 51 Issue: 9 p934-946, 13p |
| Abstrakt: |
Laterality is a crucial physiological process intricately linked to the cilium-centrosome complex during embryo development. Defects in the process can result in severe organ mispositioning. Coiled-coil domain containing 141 (CCDC141) has been previously known as a centrosome-related gene, but its role in left-right (LR) asymmetry has not been characterized. In this study, we utilize the zebrafish model and human exome analysis to elucidate the function of ccdc141in laterality defects. The knockdown of ccdc141in zebrafish disrupts early LR signaling pathways, cilia function, and Kupffer's vesicle formation. Unlike ccdc141-knockdown embryos exhibiting aberrant LR patterns, ccdc141-null mutants show no apparent abnormality, suggesting a genetic compensation response effect. In parallel, we observe a marked reduction in α-tubulin acetylation levels in the ccdc141crispants. The treatment with histone deacetylase (HDAC) inhibitors, particularly the HDAC6 inhibitor, rescues the ccdc141crispant phenotypes. Furthermore, exome analysis of 70 patients with laterality defects reveals an increased burden of CCDC141mutations, with in-vivo studies verifying the pathogenicity of the patient mutation CCDC141-R123G. Our findings highlight the critical role of ccdc141in ciliogenesis and demonstrate that CCDC141mutations lead to abnormal LR patterns, identifying it as a candidate gene for laterality defects. |
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