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.
Highlights
The C-terminal Binding Protein (CtBP) family consists of two highly related paralogs, CtBP1 and CtBP2 in vertebrates (Chinnadurai, 2007)
Since the CTBP1 p.R342W mutation is associated with neurodevelopmental disabilities, we designed experiments to compare the transcriptional profiles of patient and healthy control derived neuronal cell models
We generated induced pluripotent stem cells (iPSC) from the dermal fibroblasts of two patients with the CTBP1 p.R342W heterozygous mutation and two age-matched normal donors using Sendai virus delivery of the Yamanaka factors (Klf-4, Sox-2, Oct3/4, and c-Myc) (Ban et al, 2011; Nayler et al, 2017)
Summary
The C-terminal Binding Protein (CtBP) family consists of two highly related paralogs, CtBP1 and CtBP2 (and their splice forms) in vertebrates (Chinnadurai, 2007). CtBPs mediate transcriptional repression by CTBP1 Mutation in Neuronal Developmental Defects targeting various chromatin-modifying enzymes to the promoter regions and by interacting with DNA-bound repressors. CtBPs bind with the chromatin modifying factors and various repressors through a high-affinity protein-binding interface known as PXDLS-binding cleft. An auxiliary protein-binding interface termed RRT-binding groove in CtBPs is involved in interaction with certain Zinc-finger-containing transcription factors. CtBPs activate transcription under certain specific contexts (Fang et al, 2006; Paliwal et al, 2012; Bajpe et al, 2013; Itoh et al, 2013; Ray et al, 2014). Since CtBPs are NAD(H)binding proteins (Kumar et al, 2002; Nardini et al, 2003), the intracellular levels of NAD(H) dinucleotides differentially regulate their transcriptional activity through oligomerization (Zhang et al, 2002)
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