Novel Variant Linked to Amyotrophic Lateral Sclerosis Risk and Clinical Phenotype.

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Amyotrophic Lateral Sclerosis (ALS) presents complex phenotypes and pathogenicity, necessitating the identification of robust genetic markers.
• Establishing genetic markers is crucial for understanding ALS and developing targeted therapies.

Purpose of the Study:

• To identify and investigate a polymorphism in the Stathmin-2 gene for its association with sporadic ALS (sALS) risk, age-of-onset, and survival duration.
• To explore the Stathmin-2 gene's expression levels in relation to sALS and specific genotypes.

Main Methods:

• Systematic analysis of a Stathmin-2 CA repeat polymorphism using PCR, Sanger sequencing, and capillary electrophoresis for genotyping.
• Investigation of Stathmin-2 mRNA expression via RT-PCR in olfactory neurosphere-derived (ONS) cells and RNA sequencing in spinal motor neurons.

Main Results:

• A significant association was found between long/long CA genotypes of Stathmin-2 and sALS risk (p=0.042), particularly with a 24 CA repeat allele (p=0.0023).
• Longer CA allele length correlated with earlier age-of-onset (p=0.039) and shorter survival in bulbar-onset sALS cases (p=0.006).
• Reduced Stathmin-2 mRNA expression was observed in sALS patient ONS cells, with expression varying by genotype in spinal motor neurons.

Conclusions:

• A novel non-coding CA repeat in the Stathmin-2 gene is associated with sALS risk and demonstrates disease-modifying effects.
• This Stathmin-2 variant holds potential as a disease marker and a tool for enriching patient cohorts in clinical trials for ALS.