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

• Authors: David B. Beck, NHGRI; T. Subramanian, St Louis University; S. Vijayalingam, St Louis University; Uthayashankar R. Ezekiel, St Louis University; Sandra Donkervoort, NINDS; Michele L. Yang, University of Colorado Denver; Holly A. Dubbs, Childrens Hospital of Philadelphia; Xilma R. Ortiz-Gonzalez, Childrens Hospital of Philadelphia; Shenela Lakhani, Weill Cornell Medicine; Devorah Segal, Weill Cornell Medicine; Margaret Au, Cedars Sinai Medical Center; John M. Graham, Cedars Sinai Medical Center; Sumit Verma, Emory University; Darrel Waggoner, University of Chicago; Marwan Shinawi, Washington University; Carsten G. Bonnemann, NINDS; Wendy K. Chung, Columbia University; G. Chinnadurai, St Louis University
• Journal Title: Neurogenetics
• Volume: Volume 20, Number 3
• Publisher: Springer | 2019-08-01, Pages 129-143
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1007/s10048-019-00578-1
• Subjects: Biology, Genetics; Biology, Virology; Biology, Molecular; Biology, Neuroscience
• Keywords: Science & Technology; Life Sciences & Biomedicine; Genetics & Heredity; Clinical Neurology; Neurosciences & Neurology; C-terminal binding protein; CtBP1; Chromatin modifying complex; Neurodevelopmental disease; R342W mutation; Co-repressor; Negative modulation; Gene expression; Corepressor; Protein; Coactivator; Region

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.