Characterization of two novel SETX mutations in AOA2 patients reveals aspects of the pathophysiological role of senataxin

Giovanni Airoldi, Andrea Guidarelli, Orazio Cantoni, Chris Panzeri, Chiara Vantaggiato, Sara Bonato, Maria Grazia D'Angelo, Sestina Falcone, Clara De Palma, Alessandra Tonelli, Claudia Crimella, Sara Bondioni, Nereo Bresolin, Emilio Clementi, Maria Teresa Bassi

Research output: Contribution to journalArticlepeer-review


Ataxia with oculomotor apraxia (AOA) type 2 (AOA2 MIM 606002) is a recessive subtype of AOA characterized by cerebellar atrophy, oculomotor apraxia, early loss of reflexes, and peripheral neuropathy. Various mutations either in homozygous or compound heterozygous condition were so far identified in the associated gene SETX (MIM 608465). SETX encodes a large protein called senataxin with a DNA-RNA helicase domain and a putative N-terminus protein interaction domain. Here, we report the identification of two novel homozygous mutations in SETX gene, c.340-342delCTT (p.L114Del) and c.1669C>T (p.R557X), in two AOA2 families. The characterization of the mutant lymphoblastoid cell lines for sensitivity to oxidative DNA-damaging agents indicates that the p.L114Del deletion confers an increased sensitivity to H2O 2, camptothecin, and mitomycin C, previously found to induce death in lymphoblasts harbouring other SETX mutations; the cells carrying the nonsense mutation display instead values within the normal range. Further analysis of a neuronal cell model SKNBE, transfected with the mutant senataxin proteins, reveals increased sensitivity also to staurosporine and excitotoxicity associated with the p.L114Del mutant only. We also demonstrate that the sensitizing effect of p.L114Del on apoptosis can be reversed by senataxin silencing. The ability of a single amino acid deletion to sensitize cells to death by different agents, compared to the lack of effect of a whole protein deletion, seems to exclude a protective role played by the native protein while suggesting that a specific mutation confers to the protein the ability to enhance the toxic effect of various cell damaging agents.

Original languageEnglish
Pages (from-to)91-100
Number of pages10
Issue number1
Publication statusPublished - Feb 2010


  • Excitotoxicity
  • Mutation
  • Oxidative DNA damaging
  • Senataxin
  • Sensitivity

ASJC Scopus subject areas

  • Genetics(clinical)
  • Cellular and Molecular Neuroscience
  • Genetics


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