biostudies-literatureDugger SANational Institute of Neurological Disorders and StrokeRobins Family FoundationNCATS NIH HHST32 National Research Service AwardNINDS NIH HHSNIGMS NIH HHSe1010952https://www.ebi.ac.uk/biostudies/studies/S-EPMC10569524biostudies-literatureUnknown19(10)Heterozygous de novo loss-of-function mutations in the gene expression regulator HNRNPU cause an early-onset developmental and epileptic encephalopathy. To gain insight into pathological mechanisms and lay the potential groundwork for developing targeted therapies, we characterized the neurophysiologic and cell-type-specific transcriptomic consequences of a mouse model of HNRNPU haploinsufficiency. Heterozygous mutants demonstrated global developmental delay, impaired ultrasonic vocalizations, cognitive dysfunction and increased seizure susceptibility, thus modeling aspects of the human disease. Single-cell RNA-sequencing of hippocampal and neocortical cells revealed widespread, yet modest, dysregulation of gene expression across mutant neuronal subtypes. We observed an increased burden ofPLoS geneticsNeurodevelopmental deficits and cell-type-specific transcriptomic perturbations in a mouse model of HNRNPU haploinsufficiency.PMC10569524R37 NS031348T32 GM007367GM007367Private family foundationTL1 TR001875TL1TR001875Peng YDhindsa RSRafikian EEGoldstein DBYang MLetts VARessler AKPetri STeoh JDugger SABoland MJColombo SFrankel WNSampaio GAYe JfalseNeurodevelopmental deficits and cell-type-specific transcriptomic perturbations in a mouse model of HNRNPU haploinsufficiency.Heterozygous de novo loss-of-function mutations in the gene expression regulator HNRNPU cause an early-onset developmental and epileptic encephalopathy. To gain insight into pathological mechanisms and lay the potential groundwork for developing targeted therapies, we characterized the neurophysiologic and cell-type-specific transcriptomic consequences of a mouse model of HNRNPU haploinsufficiency. Heterozygous mutants demonstrated global developmental delay, impaired ultrasonic vocalizations, cognitive dysfunction and increased seizure susceptibility, thus modeling aspects of the human disease. Single-cell RNA-sequencing of hippocampal and neocortical cells revealed widespread, yet modest, dysregulation of gene expression across mutant neuronal subtypes. We observed an increased burden of2023-01-01T00:00:00Z2023 Oct2026-07-14T22:03:18.413Z2025-04-05T12:06:03.212ZS-EPMC105695243778266910.1371/journal.pgen.1010952