Epilepsy-associated digenic variants affecting an actin–mitochondria–glutamate pathway promote seizure susceptibility

Shenzhao Lu; Mengqi Ma; Shabab B. Hannan; Mingxi Deng; Hu Chen; Zhijian Yu; Lindsey D. Goodman; Haein Kim; Yun Zhao; Sandeep Kumar Dubey; Wen-Wen Lin; Xueyang Pan; Debdeep Dutta; Vishnu Anand Cuddapah; Jill A. Rosenfeld; Xi Luo; Zhandong Liu; Joshua M. Shulman; Hugo J. Bellen

doi:10.1172/JCI198696

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

²Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, United States of America

³Department of Neurology, Baylor College of Medicine, Houston, United States of America

Find articles by Lu, S. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

²Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, United States of America

³Department of Neurology, Baylor College of Medicine, Houston, United States of America

Find articles by Ma, M. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

²Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, United States of America

³Department of Neurology, Baylor College of Medicine, Houston, United States of America

Find articles by Hannan, S. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

²Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, United States of America

³Department of Neurology, Baylor College of Medicine, Houston, United States of America

Find articles by Deng, M. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

²Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, United States of America

³Department of Neurology, Baylor College of Medicine, Houston, United States of America

Find articles by Chen, H. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

²Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, United States of America

³Department of Neurology, Baylor College of Medicine, Houston, United States of America

Find articles by Yu, Z. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

²Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, United States of America

³Department of Neurology, Baylor College of Medicine, Houston, United States of America

Find articles by Goodman, L. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

²Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, United States of America

³Department of Neurology, Baylor College of Medicine, Houston, United States of America

Find articles by Kim, H. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

²Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, United States of America

³Department of Neurology, Baylor College of Medicine, Houston, United States of America

Find articles by Zhao, Y. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

²Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, United States of America

³Department of Neurology, Baylor College of Medicine, Houston, United States of America

Find articles by Dubey, S. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

²Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, United States of America

³Department of Neurology, Baylor College of Medicine, Houston, United States of America

Find articles by Lin, W. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

²Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, United States of America

³Department of Neurology, Baylor College of Medicine, Houston, United States of America

Find articles by Pan, X. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

²Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, United States of America

³Department of Neurology, Baylor College of Medicine, Houston, United States of America

Find articles by Dutta, D. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

²Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, United States of America

³Department of Neurology, Baylor College of Medicine, Houston, United States of America

Find articles by Cuddapah, V. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

²Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, United States of America

³Department of Neurology, Baylor College of Medicine, Houston, United States of America

Find articles by Rosenfeld, J. in: PubMed | Google Scholar |

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

²Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, United States of America

³Department of Neurology, Baylor College of Medicine, Houston, United States of America

Find articles by Luo, X. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

²Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, United States of America

³Department of Neurology, Baylor College of Medicine, Houston, United States of America

Find articles by Liu, Z. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

²Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, United States of America

³Department of Neurology, Baylor College of Medicine, Houston, United States of America

Find articles by Shulman, J. in: PubMed | Google Scholar

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States of America

²Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, United States of America

³Department of Neurology, Baylor College of Medicine, Houston, United States of America

Find articles by Bellen, H. in: PubMed | Google Scholar

J Clin Invest. https://doi.org/10.1172/JCI198696.
Copyright © 2026, Lu 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 July 16, 2026 - Version history

Epilepsy affects approximately 50 million people worldwide, yet more than half of individuals with a presumed genetic cause still lack a molecular diagnosis despite the identification of over 1,000 monogenic epilepsy genes. This diagnostic gap is unlikely to be resolved by improved variant detection alone, suggesting that variants affecting the same biological pathway may combine to cause disease. By studying epilepsy-associated actin regulatory genes, we identified a conserved “actin-mitochondria-glutamate (AMG) pathway”. We demonstrate that reduced actin polymerization promotes DRP1-mediated mitochondrial fission, increases reactive oxygen species (ROS) levels, and enhances glutamatergic transmission, leading to seizures. The glial innate immune pathway, a recently recognized contributor to epilepsy, is activated when the AMG pathway is affected. Reducing mitochondrial fission with the DRP1 inhibitor Mdivi-1, or suppressing ROS with N-acetyl-L-cysteine amide (NACA), significantly alleviates seizures. Importantly, digenic heterozygous loss‑of‑function variants in AMG‑pathway genes combine to cause seizures, and individuals with epilepsy of unknown etiology show an increased burden of such variants when compared to the controls. Modeling patient‑specific digenic combinations in Drosophila confirms that many combinations promote seizure susceptibility. Together, these findings establish the AMG pathway as a mechanistic framework for identifying digenic etiologies in epilepsy and highlight potential therapeutic targets.

Version 1 (July 16, 2026): In-Press Preview

Epilepsy-associated digenic variants affecting an actin–mitochondria–glutamate pathway promote seizure susceptibility

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Epilepsy-associated digenic variants affecting an actin–mitochondria–glutamate pathway promote seizure susceptibility

Shenzhao Lu,1 Mengqi Ma,1 Shabab B. Hannan,2 Mingxi Deng,1 Hu Chen,2 Zhijian Yu,2 Lindsey D. Goodman,1 Haein Kim,2 Yun Zhao,2 Sandeep Kumar Dubey,3 Wen-Wen Lin,1 Xueyang Pan,1 Debdeep Dutta,1 Vishnu Anand Cuddapah,2 Jill A. Rosenfeld,1 Xi Luo,1 Zhandong Liu,2 Joshua M. Shulman,1 and Hugo J. Bellen1

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