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

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

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=13

YEAR=2021

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2021.658226

DOI=10.3389/fnagi.2021.658226

ISSN=1663-4365

ABSTRACT=<sec><title>Objective</title><p>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.</p></sec><sec><title>Methods</title><p>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.</p></sec><sec><title>Results</title><p>In a case-control analysis of a combined North American sALS cohort (<italic>n</italic> = 321) and population control group (<italic>n</italic> = 332), long/long CA genotypes were significantly associated with disease risk (<italic>p</italic> = 0.042), and most strongly when one allele was a 24 CA repeat (<italic>p</italic> = 0.0023). In addition, longer CA allele length was associated with earlier age-of-onset (<italic>p</italic> = 0.039), and shorter survival duration in bulbar-onset cases (<italic>p</italic> = 0.006). In an Australian longitudinal sALS cohort (<italic>n</italic> = 67), ALS functional rating scale scores were significantly lower in carriers of the long/long genotype (<italic>p</italic> = 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.</p></sec><sec><title>Conclusions</title><p>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.</p></sec>