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dc.contributor.authorTheunissen, F
dc.contributor.authorAnderton, RS
dc.contributor.authorMastaglia, FL
dc.contributor.authorFlynn, LL
dc.contributor.authorWinter, SJ
dc.contributor.authorJames, I
dc.contributor.authorBedlack, R
dc.contributor.authorHodgetts, S
dc.contributor.authorFletcher, S
dc.contributor.authorWilton, SD
dc.contributor.authorLaing, NG
dc.contributor.authorMacShane, M
dc.contributor.authorNeedham, M
dc.contributor.authorMackay-Sim, A
dc.contributor.authoret al.
dc.date.accessioned2021-04-23T00:15:11Z
dc.date.available2021-04-23T00:15:11Z
dc.date.issued2021
dc.identifier.issn1663-4365
dc.identifier.doi10.3389/fnagi.2021.658226
dc.identifier.urihttp://hdl.handle.net/10072/403924
dc.description.abstractObjective: 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.
dc.description.peerreviewedYes
dc.publisherFrontiers Media SA
dc.relation.ispartofpagefrom658226
dc.relation.ispartofjournalFrontiers in Aging Neuroscience
dc.relation.ispartofvolume13
dc.subject.fieldofresearchBiochemistry and cell biology
dc.subject.fieldofresearchNeurosciences
dc.subject.fieldofresearchCognitive and computational psychology
dc.subject.fieldofresearchcode3101
dc.subject.fieldofresearchcode3209
dc.subject.fieldofresearchcode5204
dc.titleNovel STMN2 Variant Linked to Amyotrophic Lateral Sclerosis Risk and Clinical Phenotype
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationTheunissen, 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; Mackay-Sim, A; et al., Novel STMN2 Variant Linked to Amyotrophic Lateral Sclerosis Risk and Clinical Phenotype, Frontiers in Aging Neuroscience, 2021, 13, pp. 658226
dcterms.licensehttps://creativecommons.org/licenses/by/4.0/
dc.date.updated2021-04-23T00:02:33Z
dc.description.versionVersion of Record (VoR)
gro.rights.copyright© 2021 Theunissen, Anderton, Mastaglia, Flynn, Winter, James, Bedlack, Hodgetts, Fletcher, Wilton, Laing, MacShane, Needham, Saunders, Mackay-Sim, Melamed, Ravits, Cleveland and Akkari. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
gro.hasfulltextFull Text
gro.griffith.authorMackay-Sim, Alan


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