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

• Type of Material: Article
• 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
• Language: English
• Date: 2019-08-01
• Publisher: Springer
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 Springer Nature Switzerland AG. Part of Springer Nature..
• Final Published Version (URL): http://dx.doi.org/10.1007/s10048-019-00578-1
• Title of Journal or Parent Work: Neurogenetics
• Volume: 20
• Issue: 3
• Start Page: 129
• End Page: 143
• Grant/Funding Information: M.Y. is supported by the following industry sponsored research: Reveragen, Italfarmaco.; This work was supported by an ICTS pilot grant from Washington University in St. Louis and Presidential Research support from Saint Louis University.; This work was supported in part by grants from the JPB Foundation and the Simons Foundation.; Work in C.G. Bönnemann’s laboratory is supported by intramural funds from the NIH National Institute of Neurological Disorders and Stroke.
• Keywords: Protein; Co-repressor; Region; Science & Technology; Coactivator; C-terminal binding protein; Life Sciences & Biomedicine; Neurodevelopmental disease; Neurosciences & Neurology; CtBP1; Clinical Neurology; Gene expression; Corepressor; R342W mutation; Chromatin modifying complex; Negative modulation; Genetics & Heredity
• Research Categories: Biology, Neuroscience; Biology, Molecular; Biology, Genetics; Biology, Virology

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.