Ji, L., Yan, J., Losurdo, N.A., Wang, H., Liu, L., Li, K., Liu, Z., Guo, Z., Xu, J., Bibo, A., Ren, D., Yang, K., Luo, Y., Yang, F., Wang, G., Xiang, Z., Wang, Y., Zhan, H., Pan, H., Hu, J., Zhong, J., Abou Jamra, R., Zacher, P., Musante, L., Faletra, F., Costa, P., Zanus, C., Couque, N., Ruaud, L., Cueto-González, A.M., San Nicolas Fernández, H., Tizzano, E., Martinez Gil, N., Liu, X., Liao, W., Abi Farraj, L., Huang, A.Y., Zhang, L., Murali, A., Schmuel, E., Han, C.S., King, K., Gu, W., Wang, P., Li, K., Link, N., He, G., Bian, S., Mao, X. (2025). Mutations in the spliceosomal gene SNW1 cause neurodevelopment disorders with microcephaly.  J. Clin. Invest. 135(18): e186119.

FBrf0263390

Research paper

The spliceosome is a critical cellular machinery responsible for pre-mRNA splicing that is essential for the proper expression of genes. Mutations in its core components are increasingly linked to neurodevelopmental disorders, such as primary microcephaly. Here, we investigated the role of SNW domain-containing protein 1 (SNW1), a spliceosomal protein, in splicing integrity and neurodevelopment. We identified 9 heterozygous mutations in the SNW1 gene in patients presenting with primary microcephaly. These mutations impaired SNW1's interactions with core spliceosomal proteins, leading to defective RNA splicing and reduced protein functionality. Using Drosophila melanogaster and human embryonic stem cell-derived cerebral organoids models, we demonstrated that SNW1 depletion resulted in significant reductions in neural stem cell proliferation and increased apoptosis. RNA-Seq revealed disrupted alternative splicing, especially skipping exons, and altered expression of neurodevelopment-associated genes (CENPE, MEF2C, and NRXN2). Our findings provide crucial insights into the molecular mechanisms by which SNW1 dysfunction contributes to neurodevelopmental disorders and underscore the importance of proper spliceosome function in brain development.

PMC12435841 (PMC) (EuropePMC)