{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T04:18:22Z","timestamp":1792642702580,"version":"4.5.0"},"update-to":[{"DOI":"10.1371\/journal.pgen.1010952","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,10,12]],"date-time":"2023-10-12T00:00:00Z","timestamp":1697068800000}}],"reference-count":90,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2023,10,2]],"date-time":"2023-10-02T00:00:00Z","timestamp":1696204800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R37 NS031348"],"award-info":[{"award-number":["R37 NS031348"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"name":"T32 National Research Service Award","award":["TL1TR001875"],"award-info":[{"award-number":["TL1TR001875"]}]},{"name":"T32 National Research Service Award","award":["GM007367"],"award-info":[{"award-number":["GM007367"]}]},{"name":"Robins Family Foundation","award":["Private family foundation"],"award-info":[{"award-number":["Private family foundation"]}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>Heterozygous <jats:italic>de novo<\/jats:italic> loss-of-function mutations in the gene expression regulator <jats:italic>HNRNPU<\/jats:italic> 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 <jats:italic>HNRNPU<\/jats:italic> 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 of differentially-expressed genes in mutant excitatory neurons of the subiculum\u2014a region of the hippocampus implicated in temporal lobe epilepsy. Evaluation of transcriptomic signature reversal as a therapeutic strategy highlights the potential importance of generating cell-type-specific signatures. Overall, this work provides insight into <jats:italic>HNRNPU<\/jats:italic>-mediated disease mechanisms and provides a framework for using single-cell RNA-sequencing to study transcriptional regulators implicated in disease.<\/jats:p>","DOI":"10.1371\/journal.pgen.1010952","type":"journal-article","created":{"date-parts":[[2023,10,2]],"date-time":"2023-10-02T17:28:00Z","timestamp":1696267680000},"page":"e1010952","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":22,"title":["Neurodevelopmental deficits and cell-type-specific transcriptomic perturbations in a mouse model of HNRNPU haploinsufficiency"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8005-6754","authenticated-orcid":true,"given":"Sarah 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vocalisations","volume":"256","author":"E Ey","year":"2013","journal-title":"Behavioural Brain Research"},{"key":"pgen.1010952.ref043","article-title":"Recording Mouse Ultrasonic Vocalizations to Evaluate Social Communication","author":"A-T Ferhat","year":"2016","journal-title":"J Vis Exp"},{"key":"pgen.1010952.ref044","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.1093\/brain\/awaa147","article-title":"Modelling and treating GRIN2A developmental and epileptic encephalopathy in mice","volume":"143","author":"A Amador","year":"2020","journal-title":"Brain"},{"key":"pgen.1010952.ref045","doi-asserted-by":"crossref","first-page":"104632","DOI":"10.1016\/j.nbd.2019.104632","article-title":"Arfgef1 haploinsufficiency in mice alters neuronal endosome composition and decreases membrane surface postsynaptic GABAA receptors","volume":"134","author":"J Teoh","year":"2020","journal-title":"Neurobiol 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