2. Academic Validation
  3. Haploinsufficiency of brain-specific kinase BRSK1 causes epilepsy and neurodevelopmental disorders

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

  • Epilepsia. 2025 Dec;66(12):5033-5054. doi: 10.1111/epi.18621.
Qi Zhang 1,  Hiroshi Yamanaka 1,  Ping Li 1,  Yingfeng Li 1,  Tian Luo 1,  Miao Xia 1,  Ting Liu 1,  Xueyan Liu 2,  Qing Lu 3,  Bin Yang 4,  Fan He 4,  Kaixian Du 5,  Yousheng Shu 6,  Bo Peng 7,  Yong-Hui Jiang 8,  Yi Wang 1
Affiliations

Affiliations

  • 1 Department of Neurology, Children's Hospital of Fudan University, Shanghai, China.
  • 2 Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China.
  • 3 Epilepsy Center, The Second Affiliated Hospital of Dalian Medical University, Dalian, China.
  • 4 Department of Neurology, Anhui Hospital, Children's Hospital of Fudan University, Hefei, Anhui, China.
  • 5 Department of Pediatric Neurology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 6 Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China.
  • 7 Institute 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.
  • 8 Department of Genetics, Neuroscience, and Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA.
PMID: 41035394 DOI: 10.1111/epi.18621
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 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 human epilepsy syndrome. To our knowledge, this is the first study to implicate the brain-specific serine/threonine kinase BRSK1 in epilepsy and neurodevelopmental disorders.

Keywords

BRSK1; epilepsy; loss of function; neurodevelopmental disorders.

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