Mutations in the spliceosomal gene SNW1 cause neurodevelopment disorders with microcephaly

Abstract

Embryonic stem cells; Genetic diseases; Neurodevelopment

Cèl·lules mare embrionàries; Malalties genètiques; Neurodesenvolupament

Células madre embrionarias; Enfermedades genéticas; Neurodesarrollo

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.

We extend our sincere appreciation to the authors and laboratories who made this work possible. We are thankful to the patients and their families for their participation in this research project. We thank the Chigene (Beijing), Gene4Denovo, GeneMatcher, and China Epilepsy Gene V.1.0 and their contributors for providing these valuable public datasets. This project is supported by the National Key Research and Development Program (2024YFC2707002, 2020YFA0112500, and 2021YFA1100400), Innovation Program of Shanghai Municipal Education Commission (2023ZKZD16), the National Natural Science Foundation of China (82071262, 32300464, and 32271019), the Natural Science Foundation of Shanghai (20ZR1427200, 20511101900, 21ZR1433000, and 22ZR1462600), the Shanghai Municipal Science and Technology Major Project (20JC1418600), the Shanghai Leading Academic Discipline Project (B205), the China Postdoctoral Science Foundation (2023M732266), the Major Scientific and Technological Projects for Collaborative Prevention and Control of Birth Defects in Hunan Province (2019SK1010 and 2019SK1014), the Natural Science Foundation of Hunan Province (2022JJ40206), the Ruixin project of Hunan Provincial Maternal and Child Health Care Hospital (2023RX01), the Key Technology Breakthrough Program of Ningbo Sci-Tech Innovation YONGJIANG 2035 (2024Z221), the Municipal Public Welfare Project (2022S035), the Jiangxi Provincial Department of Science and Technology (20203BBGL73132), Shanghai Jiao Tong University STAR Grants (YG2023ZD26 and YG2023LC14), and National Science Foundation Graduate Research Fellowship Program (2139322). XM wishes to extend deepest appreciation to Tan Guanhao and Li Zhongju for their unwavering support and invaluable encouragement throughout this research journey.