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Neurogenetics. 2019 Aug;20(3):129-143. doi: 10.1007/s10048-019-00578-1. Epub 2019 Apr 30.

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

Author information

1
National Human Genome Research Institute, National Institutes of Health, 10 Center Drive, Room B3-4129, Bethesda, MD, 20892, USA.
2
Institute for Molecular Virology, Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, E. A. Doisy Research Center, 6th Floor, St. Louis, MO, 63104, USA.
3
Clinical Health Sciences, Saint Louis University, 3437 Caroline Street, Allied Health Building, Suite 3025, Saint Louis, MO, 63104, USA.
4
National Institute of Neurological Disorders and Stroke Neurogenetics Branch, National Institutes of Health, 10 Center Drive Room 2B39, MSC 1477, Bethesda, MD, 20892, USA.
5
University of Colorado Denver, 13123 E. 16th Ave; Box B155, Aurora, CO, 80238, USA.
6
Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
7
Department of Neurology, Pereleman School of Medicine, University of Pennsylvania; Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
8
Center for Neurogenetics, Brain and Mind Research Institute, Weill Cornell Medicine, 413 E 69th Street, New York, NY, 10021, USA.
9
Department of Pediatrics, Division of Child Neurology, Weill Cornell Medicine, 525 E. 68th St, Box 91, New York, NY, 10065, USA.
10
Medical Genetics, Department of Pediatrics, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90068, USA.
11
Division of Pediatric Neurology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, 30322, USA.
12
Department of Human Genetics, University of Chicago, Chicago, IL, 60637, USA.
13
Department of Pediatrics, Division of Genetics and Genomic Medicine,, Washington University School of Medicine, St. Louis, MO, 63110, USA.
14
Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, NY, USA. wkc15@cumc.columbia.edu.
15
Institute for Molecular Virology, Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, E. A. Doisy Research Center, 6th Floor, St. Louis, MO, 63104, USA. g.chinnadurai@health.slu.edu.

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.

KEYWORDS:

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

PMID:
31041561
DOI:
10.1007/s10048-019-00578-1

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