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

Frontiers in Neuroscience

Fenglian Xu¹  Kyle Pemberton¹  Brittany Hoelscher¹  Aravinda Ganapathy²  Uthayashanker R. Ezekiel²  KayKay San²  G. Chinnadurai³  Amelia K. Pinto³  Elizabeth Geerling³  James D. Brien³  T. Subramanian³  S. Vijayalingam³  Christina A. Gurnett⁴  Wendy K. Chung⁵  Eric Tycksen⁶  David B. Beck⁷ 

[1] Department of Biology and Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis University, St. Louis, MO, United States;Department of Clinical Health Sciences, Doisy College of Health Science, Saint Louis University School of Medicine, Saint Louis, MO, United States;Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Edward A. Doisy Research Center, St. Louis, MO, United States;Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States;Department of Pediatrics and Medicine, Columbia University Medical Center, New York, NY, United States;McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, United States;National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States;

关键词: transcriptional repression;    CtBP;    de novo mutation;    interferon response;    intellectual and developmental disabilities;    transcriptome analysis;   

DOI  :  10.3389/fnins.2020.562292

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown