Human iPSC-Derived Neuronal Cells From CTBP1-Mutated Patients Reveal Altered Expression of Neurodevelopmental Gene Networks

S. Vijayalingam, Uthayashanker R. Ezekiel, Fenglian Xu, T. Subramanian, Elizabeth Geerling, Brittany Hoelscher, Kay Kay San, Aravinda Ganapathy, Kyle Pemberton, Eric Tycksen, Amelia K. Pinto, James D. Brien, David B. Beck, Wendy K. Chung, Christina A. Gurnett, G. Chinnadurai

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

A recurrent de novo mutation in the transcriptional corepressor CTBP1 is associated with neurodevelopmental disabilities in children (Beck et al., 2016, 2019; Sommerville et al., 2017). All reported patients harbor a single recurrent de novo heterozygous missense mutation (p.R342W) within the cofactor recruitment domain of CtBP1. To investigate the transcriptional activity of the pathogenic CTBP1 mutant allele in physiologically relevant human cell models, we generated induced pluripotent stem cells (iPSC) from the dermal fibroblasts derived from patients and normal donors. The transcriptional profiles of the iPSC-derived “early” neurons were determined by RNA-sequencing. Comparison of the RNA-seq data of the neurons from patients and normal donors revealed down regulation of gene networks involved in neurodevelopment, synaptic adhesion and anti-viral (interferon) response. Consistent with the altered gene expression patterns, the patient-derived neurons exhibited morphological and electrophysiological abnormalities, and susceptibility to viral infection. Taken together, our studies using iPSC-derived neuron models provide novel insights into the pathological activities of the CTBP1 p.R342W allele.

Original languageEnglish
Article number562292
JournalFrontiers in Neuroscience
Volume14
DOIs
StatePublished - Oct 27 2020

Bibliographical note

Publisher Copyright:
© Copyright © 2020 Vijayalingam, Ezekiel, Xu, Subramanian, Geerling, Hoelscher, San, Ganapathy, Pemberton, Tycksen, Pinto, Brien, Beck, Chung, Gurnett and Chinnadurai.

Funding

We thank the families of patients with CTBP1 mutations for their generous contributions. We thank Cure, C. and Anne Rutkowski with their help in patient recruitment. Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under Award Number U54 HD087011 to the Intellectual and Developmental Disorders Research Center at Washington University and the Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) and a Presidential Research support from Saint Louis University. The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH. WC is supported from grants from SFARI and the JPB Foundation. KS and AG were supported by a grant from the DeNardo Education and Research Foundation. FX was supported by a National Science Foundation (NSF) research grant (Award Number 1916563).

FundersFunder number
DeNardo Education and Research Foundation
National Science Foundation Arctic Social Science Program1916563
National Institutes of Health (NIH)U54 HD087011
National Center for Advancing Translational Sciences (NCATS)
JPB Foundation
The George Washington University
Indiana Clinical and Translational Sciences InstituteUL1TR002345
Eunice Kennedy Shriver National Institute of Child Health and Human Development
Saint Louis University
Simons Foundation Autism Research Initiative

    Keywords

    • CtBP
    • de novo mutation
    • intellectual and developmental disabilities
    • interferon response
    • transcriptional repression
    • transcriptome analysis

    ASJC Scopus subject areas

    • General Neuroscience

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