Ataxia with oculomotor apraxia type 2 fibroblasts exhibit increased susceptibility to oxidative DNA damage

Area of Science:

• Genetics
• Molecular Biology
• Neuroscience

Background:

• Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive neurodegenerative disorder.
• AOA2 is caused by mutations in the SETX gene, which encodes the senataxin protein, a DNA/RNA helicase.
• Understanding the molecular basis of AOA2 is crucial for developing therapeutic strategies.

Observation:

• A Colombian patient with AOA2 was found to be compound heterozygous for two novel mutations in the SETX gene.
• Immunocytochemistry revealed normal cellular distribution of the senataxin protein in patient-derived fibroblasts.
• This suggests that the mutations lead to aberrant protein function rather than protein loss or mislocalization.

Findings:

• The identified SETX mutations (c.994 C>T and c.6848_6851delCAGA) result in a missense and a frameshift deletion, respectively.
• Patient-derived fibroblasts exhibited increased susceptibility to oxidative DNA damage, as evidenced by the alkaline comet assay.
• This indicates a functional defect in senataxin's DNA repair capabilities.

Implications:

• The study elucidates the molecular pathogenesis of AOA2, highlighting aberrant senataxin function.
• The alkaline comet assay is proposed as a valuable tool for assessing the pathogenicity of novel SETX mutations.
• These findings contribute to a better understanding of AOA2 and may guide future diagnostic and therapeutic approaches.