2. Academic Validation
  3. A pathogenic CtBP1 missense mutation causes altered cofactor binding and transcriptional activity

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

  • Neurogenetics. 2019 Aug;20(3):129-143. doi: 10.1007/s10048-019-00578-1.
David B Beck 1,  T Subramanian 2,  S Vijayalingam 2,  Uthayashankar R Ezekiel 3,  Sandra Donkervoort 4,  Michele L Yang 5,  Holly A Dubbs 6,  Xilma R Ortiz-Gonzalez 7,  Shenela Lakhani 8,  Devorah Segal 9,  Margaret Au 10,  John M Graham Jr 10,  Sumit Verma 11,  Darrel Waggoner 12,  Marwan Shinawi 13,  Carsten G Bönnemann 4,  Wendy K Chung 14,  G Chinnadurai 15
Affiliations

Affiliations

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

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