biostudies-literatureZhang QNational Natural Science Foundation of ChinaShanghai Municipal Science and Technology5033-5054https://www.ebi.ac.uk/biostudies/studies/S-EPMC12779330biostudies-literatureUnknown66(12)<h4>Objective</h4>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.<h4>Methods</h4>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 (Brsk1^Δ4-7), with subsequent behavioral, electrophysiological, proteomic, and phosphoproteomic assessments.<h4>Results</h4>Six novel BRSK1 variants were identified in seven probaEpilepsiaHaploinsufficiency of brain-specific kinase BRSK1 causes epilepsy and neurodevelopmental disorders.PMC127793302023SHZDZX0282302103He FLi PYang BLiu TZhang QLiu XLi YXia MPeng BShu YYamanaka HDu KJiang YHWang YLu QLuo TfalseHaploinsufficiency of brain-specific kinase BRSK1 causes epilepsy and neurodevelopmental disorders.<h4>Objective</h4>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.<h4>Methods</h4>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 (Brsk1^Δ4-7), with subsequent behavioral, electrophysiological, proteomic, and phosphoproteomic assessments.<h4>Results</h4>Six novel BRSK1 variants were identified in seven proba2025-01-01T00:00:00Z2025 Dec2026-06-06T12:51:32.319Z2026-05-30T03:11:13.679ZS-EPMC127793304103539410.1111/epi.18621