Haploinsufficiency of brain-specific kinase BRSK1 causes epilepsy and neurodevelopmental disorders

Sep 30, 2026

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Objective: BRSK1 encodes a brain-specific serine/threonine kinase (SAD-B kinase) essential for neuronal polarization, neurotransmitter release, mitochondrial dynamics, and maturation. This study investigated whether BRSK1 variants cause epilepsy and neurodevelopmental disorders. Methods: Trio-based exome sequencing was performed in 394 epilepsy probands, followed by expression analyses and functional testing using a Brsk1 exon 4–7 knockout mouse line with behavioral, electrophysiological, proteomic, and phosphoproteomic assays. Results: Six novel variants were identified in seven probands, and knockout mice showed increased seizure susceptibility, neuronal hyperexcitability, and neurobehavioral impairments. Proteomics indicated disrupted axon development and synaptic pathways.

LanguageEnglish

CategoryHealthcare

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Pages22

Reading Time55 min

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Abstract

Objective

Methods

Results

Significance

Introduction

Background on epilepsy genetics

Role of BRSK1 in the brain

DOI: 10.1111/epi.18621 RESEAR CH ARTICLE Haploinsufficiency of brain-specific kinase BRSK1 causes epilepsy and neurodevelopmental disorders Qi Zhang1 | Hiroshi Yamanaka1 | Ping Li1 | Yingfeng Li1 | Tian Luo1 | Miao Xia1 | Ting Liu1 | Xueyan Liu2 | Qing Lu3 | Bin Yang4 | Fan He4 | Kaixian Du5 | Yousheng Shu6 | Bo Peng7 | Yong-hui Jiang8 | Yi Wang1 1Department of Neurology, Children's Hospital of Fudan University, Shanghai, China 2Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China 3Epilepsy Center, The Second Affiliated Hospital of Dalian Medical University, Dalian, China 4Department of Neurology, Anhui Hospital, Children's Hospital of Fudan University, Hefei, Anhui, China 5Department of Pediatric Neurology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China 6Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China 7Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, MOE Innovative Center for New Drug Development of Immune Inflammatory Diseases, Fudan University, Shanghai, China 8Department of Genetics, Neuroscience, and Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA Correspondence Yong-hui Jiang, Department of Genetics, Neuroscience, and Pediatrics, Yale University School of Medicine, New Haven, CT 06510, USA. [Email:](Email: yong-hui.jiang@yale.edu)[ yong-hui.jiang@yale.edu](Email: yong-hui.jiang@yale.edu) (Y.J) Yi Wang, Department of Neurology, Children's Hospital of Fudan University, Shanghai 200433, China. [Email:](Email: yiwang@shmu.edu.cn)[ yiwang@shmu.edu.cn](Email: yiwang@shmu.edu.cn) (Y.W.) Funding information Shanghai Municipal Science and Technology, Grant/Award Number: 2023SHZDZX02; National Natural Science Foundation of China, Grant/ Award Number: 82302103 Abstract Objective: The BRSK1 gene encodes brain-specific serine/threonine kinase 1 (also known as SAD-B kinase), which is almost exclusively expressed in the brain and plays critical roles in neuronal polarization, neurotransmitter release, mitochondrial dynamics, and neuronal maturation. This study aimed to investigate the pathogenicity of BRSK1 variants in epilepsy and neurodevelopmental disorders. Methods: Trio-based exome sequencing was performed in 394 probands with epilepsy. Expression analyses and functional validation were conducted using a newly generated Brsk1 exon 4–7 knockout mouse line (Brsk1Δ4–7), with subsequent behavioral, electrophysiological, proteomic, and phosphoproteomic assessments. Results: Six novel BRSK1 variants were identified in seven probands, including four single nucleotide variants (SNVs) and two indels; five were de novo, one inherited, and one recurrent. Frameshift or nonsense variants led to complete loss of detectable BRSK1 protein, whereas one missense variant reduced protein levels. Both heterozygous and homozygous Brsk1Δ4–7 mice exhibit increased seizure susceptibility, neuronal hyperexcitability, and neurobehavioral impairments—recapitulating key clinical features associated with BRSK1 haploinsufficiency in Qi Zhang, Hiroshi Yamanaka, and Ping Li contributed equally to this work. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2025 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy. humans. Proteomic and phosphoproteomic analyses revealed dysregulation of pathways critical for axonal development and synaptic function. Significance: Our genomic and functional studies strongly support BRSK1 haploinsufficiency as a pathogenic mechanism in a hum

FAQs

What is BRSK1 and why is it important for the study?

BRSK1 is a brain-specific serine/threonine kinase involved in neuronal polarization, neurotransmitter release, mitochondrial dynamics, and neuronal maturation, making it a strong candidate for disorders affecting brain development.

How were BRSK1 variants identified in patients?

Trio-based exome sequencing was performed in 394 probands with epilepsy, identifying six novel BRSK1 variants across seven affected individuals, including de novo and inherited/recurrent variants.

What functional evidence links BRSK1 haploinsufficiency to epilepsy?

A Brsk1 exon 4–7 knockout mouse model was used and showed increased seizure susceptibility, neuronal hyperexcitability, and neurobehavioral impairments, alongside proteomic/phosphoproteomic dysregulation of axonal development and synaptic pathways.

Sep 30, 2026

Uploaded by moss~