Erschienen in:
30.04.2019 | Original Article
A pathogenic CtBP1 missense mutation causes altered cofactor binding and transcriptional activity
verfasst von:
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 Jr, Sumit Verma, Darrel Waggoner, Marwan Shinawi, Carsten G. Bönnemann, Wendy K. Chung, G. Chinnadurai
Erschienen in:
Neurogenetics
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Ausgabe 3/2019
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Abstract
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.