Alternative splicing-triggered mRNA decay informs splice-switching targets for neurodevelopmental disorders

Kaining Hu; Runwei Yang; Jiaming Qiu; Xinran Feng; Kayleigh J. LaPre; Jessica Tanouye; Yalan Yang; Xiaochang Zhang

doi:10.1172/JCI197271

¹Department of Human Genetics, The Neuroscience Institute, University of Chicago, Chicago, United States of America

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¹Department of Human Genetics, The Neuroscience Institute, University of Chicago, Chicago, United States of America

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¹Department of Human Genetics, The Neuroscience Institute, University of Chicago, Chicago, United States of America

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¹Department of Human Genetics, The Neuroscience Institute, University of Chicago, Chicago, United States of America

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¹Department of Human Genetics, The Neuroscience Institute, University of Chicago, Chicago, United States of America

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¹Department of Human Genetics, The Neuroscience Institute, University of Chicago, Chicago, United States of America

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¹Department of Human Genetics, The Neuroscience Institute, University of Chicago, Chicago, United States of America

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¹Department of Human Genetics, The Neuroscience Institute, University of Chicago, Chicago, United States of America

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J Clin Invest. https://doi.org/10.1172/JCI197271.
Copyright © 2026, Hu et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published February 12, 2026 - Version history

Alternative splicing-triggered nonsense-mediated mRNA decay (AS-NMD) critically regulates gene expression, but the extent to which neuronal genes are regulated by AS-NMD remains understudied. Here, we identified more than 3,000 developmentally regulated AS-NMD exons in mouse and human brains, and validated them in cultured neurons. AS-NMD suppresses synaptic genes during brain development and differentially regulates more than 200 causal genes for neurodevelopmental disorders (NDDs). We detected an AS-NMD exon in GRIA2 and identified splice-switching antisense oligonucleotides that suppressed GRIA2 NMD and increased its functional isoforms. In summary, this study uncovers genes repressed by AS-NMD in the brain and nominates amenable splice-switching targets for treating dominant NDDs such as autism spectrum disorders and developmental epileptic encephalopathy.

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Alternative splicing-triggered mRNA decay informs splice-switching targets for neurodevelopmental disorders

Kaining Hu,¹ Runwei Yang,¹ Jiaming Qiu,¹ Xinran Feng,¹ Kayleigh J. LaPre,¹ Jessica Tanouye,¹ Yalan Yang,¹ and Xiaochang Zhang¹

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Alternative splicing-triggered mRNA decay informs splice-switching targets for neurodevelopmental disorders

Kaining Hu,1 Runwei Yang,1 Jiaming Qiu,1 Xinran Feng,1 Kayleigh J. LaPre,1 Jessica Tanouye,1 Yalan Yang,1 and Xiaochang Zhang1

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Kaining Hu,¹ Runwei Yang,¹ Jiaming Qiu,¹ Xinran Feng,¹ Kayleigh J. LaPre,¹ Jessica Tanouye,¹ Yalan Yang,¹ and Xiaochang Zhang¹