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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Theunissen, F; Anderton, RS; Mastaglia, FL; Flynn, LL; Winter, SJ; James, I; Bedlack, R; Hodgetts, S; Fletcher, S; Wilton, SD; Laing, NG; MacShane, M; Needham, M; Saunders, A; Mackay-Sim, A; Melamed, Z; Ravits, J; Cleveland, DW; Akkari, PA

Published Date

  • 2021

Published In

Volume / Issue

  • 13 /

Start / End Page

  • 658226 -

PubMed ID

  • 33841129

Pubmed Central ID

  • PMC8033025

International Standard Serial Number (ISSN)

  • 1663-4365

Digital Object Identifier (DOI)

  • 10.3389/fnagi.2021.658226


  • eng

Conference Location

  • Switzerland