Open AccessA pathogenic CtBP1 missense mutation causes altered cofactor binding and transcriptional activity
Author(s) -
David B. Beck,
T. Subramanian,
S. Vijayalingam,
Uthayashankar R. Ezekiel,
Sandra Donkervoort,
Michele Yang,
Holly Dubbs,
Xilma R. Ortiz-González,
Shenela Lakhani,
Devorah Segal,
Margaret Au,
John M. Graham,
Sumit Verma,
Darrel Waggoner,
Marwan Shinawi,
Carsten G. Bönnemann,
Wendy K. Chung,
G. Chinnadurai
Publication year - 2019
Publication title -
neurogenetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.934
H-Index - 61
eISSN - 1364-6753
pISSN - 1364-6745
DOI - 10.1007/s10048-019-00578-1
Subject(s) - biology , missense mutation , genetics , phenotype , mutation , hypotonia , transcriptome , mutant , gene , microbiology and biotechnology , cancer research , gene expression
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.