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

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

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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.

Original languageEnglish
Pages (from-to)129-143
Number of pages15
Issue number3
StatePublished - Aug 7 2019


  • C-terminal binding protein
  • Chromatin modifying complex
  • CtBP1
  • Neurodevelopmental disease
  • p.R342W mutation


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