title: Ataxia with oculomotor apraxia type 2 fibroblasts exhibit increased susceptibility to oxidative DNA damage.
abstract: Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive cerebellar ataxia associated with mutations in SETX, which encodes the senataxin protein, a DNA/RNA helicase. We describe the clinical phenotype and molecular characterization of a Colombian AOA2 patient who is compound heterozygous for a c.994 C>T (p.R332W) missense mutation in exon 7 and a c.6848_6851delCAGA (p.T2283KfsX32) frameshift deletion in SETX exon 21. Immunocytochemistry of patient-derived fibroblasts revealed a normal cellular distribution of the senataxin protein, suggesting that these mutations do not lead to loss or mis-localization of the protein, but rather that aberrant function of senataxin underlies the disease pathogenesis. Furthermore, we used the alkaline comet assay to demonstrate that patient-derived fibroblast cells exhibit an increased susceptibility to oxidative DNA damage. This assay provides a novel and additional means to establish pathogenicity of SETX mutations.
authors.affiliation: Cell Biology Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 35, Room 2C-911, 9000 Rockville Pike, Bethesda, MD 20892-3738, USA. Electronic address: ricardo.roda@nih.gov.
authors.forename: Ricardo H
authors.initials: RH
authors.lastname: Roda
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Carlo
authors.initials: C
authors.lastname: Rinaldi
authors.affiliation: Cell Biology Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 35, Room 2C-911, 9000 Rockville Pike, Bethesda, MD 20892-3738, USA; Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.
authors.forename: Rajat
authors.initials: R
authors.lastname: Singh
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Alice B
authors.initials: AB
authors.lastname: Schindler
authors.affiliation: Cell Biology Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 35, Room 2C-911, 9000 Rockville Pike, Bethesda, MD 20892-3738, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Blackstone
mesh_terms: D001072:Apraxias / Q000151:congenital; D001921:Brain / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D002524:Cerebellar Ataxia / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D055952:Cogan Syndrome / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D003105:Colombia; D004249:DNA Damage / Q000502:physiology*; D004265:DNA Helicases; D005260:Female; D005347:Fibroblasts / Q000502:physiology*; D005542:Forearm / Q000503:physiopathology; D016368:Frameshift Mutation; D006801:Humans; D008875:Middle Aged; D064251:Multifunctional Enzymes; D020125:Mutation, Missense; D018384:Oxidative Stress / Q000502:physiology*; D010375:Pedigree; D010641:Phenotype; D020365:RNA Helicases / Q000235:genetics / Q000378:metabolism
chemical_list: D064251:Multifunctional Enzymes; C484368:SETX protein, human; D004265:DNA Helicases; D020365:RNA Helicases
keywords: AOA2; Autosomal recessive cerebellar ataxia; DNA repair; Helicase; Senataxin