Journal Article

A pathogenic CtBP1 missense mutation causes altered cofactor binding and transcriptional activity

Chinnadurai, G, Subramanian, T, Lakhani, Shenela, Ortiz-Gonzalez, Xilma R, Chung, Wendy K, Donkervoort, Sandra, Shinawi, Marwan, Verma, Sumit, Beck, David B, Graham, John M, Dubbs, Holly A, Vijayalingam, S, Au, Margaret, Waggoner, Darrel, Segal, Devorah, Yang, Michele L, Ezekiel, Uthayashankar R, Bönnemann, Carsten G

2019

Overview

We previously reported a pathogenic de novo p.R342W mutation in the transcriptional corepressor CTBP1 in four independent patients with neurodevelopmental disabilities [1]. Here, we report the clinical phenotypes of seven additional individuals with the same recurrent de novo CTBP1 mutation. Within this cohort, we identified consistent CtBP1-related phenotypes of intellectual disability, ataxia, hypotonia, and tooth enamel defects present in most patients. The R342W mutation in CtBP1 is located within a region implicated in a high affinity-binding cleft for CtBP-interacting proteins. Unbiased proteomic analysis demonstrated reduced interaction of several chromatin-modifying factors with the CtBP1 W342 mutant. Genome-wide transcriptome analysis in human glioblastoma cell lines expressing -CtBP1 R342 (wt) or W342 mutation revealed changes in the expression profiles of genes controlling multiple cellular processes. Patient-derived dermal fibroblasts were found to be more sensitive to apoptosis during acute glucose deprivation compared to controls. Glucose deprivation strongly activated the BH3-only pro-apoptotic gene NOXA, suggesting a link between enhanced cell death and NOXA expression in patient fibroblasts. Our results suggest that context-dependent relief of transcriptional repression of the CtBP1 mutant W342 allele may contribute to deregulation of apoptosis in target tissues of patients leading to neurodevelopmental phenotypes.

• Publisher: Springer Nature B.V
• Subject: Apoptosis / Ataxia / Cell death / Cell lines / Chromatin / Dental enamel / Fibroblasts / Gene expression / Gene silencing / Genomes / Glioblastoma / Missense mutation / Mutation / Neurodevelopmental disorders / Patients / Phenotypes / Proteomics / Skin / Teeth