Novel STMN2 Variant Linked to Amyotrophic Lateral Sclerosis Risk and Clinical Phenotype

Frances Theunissen*, Ryan S. Anderton, Frank L. Mastaglia, Loren L. Flynn, Samantha J. Winter, Ian James, Richard Bedlack, Stuart Hodgetts, Sue Fletcher, Steve D. Wilton, Nigel G. Laing, Mandi MacShane, Merrilee Needham, Ann Saunders, Alan Mackay-Sim, Ze’ev Melamed, John Ravits, Don W. Cleveland, P. Anthony Akkari*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


Objective: There is a critical need to establish genetic markers that explain the complex phenotypes and pathogenicity of ALS. This study identified a polymorphism in the Stathmin-2 gene and investigated its association with sporadic ALS (sALS) disease risk, age-of onset and survival duration. Methods: The candidate CA repeat was systematically analyzed using PCR, Sanger sequencing and high throughput capillary separation for genotyping. Stathmin-2 expression was investigated using RT-PCR in patient olfactory neurosphere-derived (ONS) cells and RNA sequencing in laser-captured spinal motor neurons. Results: In a case-control analysis of a combined North American sALS cohort (n = 321) and population control group (n = 332), long/long CA genotypes were significantly associated with disease risk (p = 0.042), and most strongly when one allele was a 24 CA repeat (p = 0.0023). In addition, longer CA allele length was associated with earlier age-of-onset (p = 0.039), and shorter survival duration in bulbar-onset cases (p = 0.006). In an Australian longitudinal sALS cohort (n = 67), ALS functional rating scale scores were significantly lower in carriers of the long/long genotype (p = 0.034). Stathmin-2 mRNA expression was reduced in sporadic patient ONS cells. Additionally, sALS patients and controls exhibited variable expression of Stathmin-2 mRNA according to CA genotype in laser-captured spinal motor neurons. Conclusions: We report a novel non-coding CA repeat in Stathmin-2 which is associated with sALS disease risk and has disease modifying effects. The potential value of this variant as a disease marker and tool for cohort enrichment in clinical trials warrants further investigation.

Original languageAmerican English
Article number658226
JournalFrontiers in Aging Neuroscience
StatePublished - 26 Mar 2021
Externally publishedYes

Bibliographical note

Publisher Copyright:
© Copyright © 2021 Theunissen, Anderton, Mastaglia, Flynn, Winter, James, Bedlack, Hodgetts, Fletcher, Wilton, Laing, MacShane, Needham, Saunders, Mackay-Sim, Melamed, Ravits, Cleveland and Akkari.


  • amyotrophic lateral sclerosis
  • genetic association studies
  • genetic marker
  • genetic variant
  • motor neuron disease
  • stathmin-2
  • structural variation


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