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: Ricardo H Roda, Carlo Rinaldi, Rajat Singh, Alice B Schindler, Craig Blackstone
• Journal: Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia (J Clin Neurosci) Vol. 21 Issue 9 Pg. 1627-31 (Sep 2014) ISSN: 1532-2653 [Electronic] Scotland
• PMID: 24814856 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Intramural)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Multifunctional Enzymes
• SETX protein, human
• DNA Helicases
• RNA Helicases

Topics

• Apraxias (congenital)
• Brain (pathology)
• Cell Nucleus (metabolism)
• Cells, Cultured
• Cerebellar Ataxia (genetics, pathology, physiopathology)
• Cogan Syndrome (genetics, pathology, physiopathology)
• Colombia
• DNA Damage (physiology)
• DNA Helicases
• Female
• Fibroblasts (physiology)
• Forearm (physiopathology)
• Frameshift Mutation
• Humans
• Middle Aged
• Multifunctional Enzymes
• Mutation, Missense
• Oxidative Stress (physiology)
• Pedigree
• Phenotype
• RNA Helicases (genetics, metabolism)