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© 2023 Dugger et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

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 of differentially-expressed genes in mutant excitatory neurons of the subiculum—a 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 HNRNPU-mediated disease mechanisms and provides a framework for using single-cell RNA-sequencing to study transcriptional regulators implicated in disease.

Details

Title
Neurodevelopmental deficits and cell-type-specific transcriptomic perturbations in a mouse model of HNRNPU haploinsufficiency
Author
Dugger, Sarah A  VIAFID ORCID Logo  ; Dhindsa, Ryan S  VIAFID ORCID Logo  ; De Almeida Sampaio, Gabriela  VIAFID ORCID Logo  ; Ressler, Andrew K; Rafikian, Elizabeth E; Petri, Sabrina; Letts, Verity A; Teoh, JiaJie  VIAFID ORCID Logo  ; Ye, Junqiang; Colombo, Sophie; Peng, Yueqing  VIAFID ORCID Logo  ; Yang, Mu; Boland, Michael J; Frankel, Wayne N  VIAFID ORCID Logo  ; Goldstein, David B
First page
e1010952
Section
Research Article
Publication year
2023
Publication date
Oct 2023
Publisher
Public Library of Science
ISSN
15537390
e-ISSN
15537404
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3069178961
Copyright
© 2023 Dugger et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.