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SOD1 mutations associated with amyotrophic lateral sclerosis analysis of variant severity

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dc.abstract.enMutations in superoxide dismutase 1 gene (SOD1) are linked to amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder predominantly affecting upper and lower motor neurons. The clinical phenotype of ALS shows inter- and intrafamilial heterogeneity. The aim of the study was to analyze the relations between individual SOD1 mutations and the clinical presentation using in silico methods to assess the SOD1 mutations severity. We identified SOD1 causative variants in a group of 915 prospectively tested consecutive Polish ALS patients from a neuromuscular clinical center, performed molecular modeling of mutated SOD1 proteins and in silico analysis of mutation impact on clinical phenotype and survival analysis of associations between mutations and hazard of clinical end-points. Fifteen SOD1 mutations were identified in 21.1% familial and 2.3% sporadic ALS cases. Their effects on SOD1 protein structure and functioning inferred from molecular modeling and in silico analyses correlate well with the clinical data. Molecular modeling results support the hypothesis that folding intermediates rather than mature SOD1 protein give rise to the source of cytotoxic conformations in ALS. Significant associations between type of mutation and clinical end-points were found.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorKuźma-Kozakiewicz, Magdalena
dc.contributor.authorSafranow, Krzysztof
dc.contributor.authorFilipek, Sławomir
dc.contributor.authorMiszta, Przemysław
dc.contributor.authorŻekanowski, Cezary
dc.contributor.authorAndersen, Peter M.
dc.contributor.authorMorita, Mitsuya
dc.contributor.authorBerdyński, Mariusz
dc.date.accessioned2024-01-26T07:52:06Z
dc.date.available2024-01-26T07:52:06Z
dc.date.copyright2022-01-07
dc.date.issued2022
dc.description.accesstimeAT_PUBLICATION
dc.description.financePublikacja bezkosztowa
dc.description.number1
dc.description.versionFINAL_PUBLISHED
dc.description.volume12
dc.identifier.doi10.1038/S41598-021-03891-8
dc.identifier.issn2045-2322
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/120156
dc.identifier.weblinkhttps://www.nature.com/articles/s41598-021-03891-8.pdf
dc.languageeng
dc.pbn.affiliationchemical sciences
dc.relation.ispartofScientific Reports
dc.relation.pages103
dc.rightsCC-BY
dc.sciencecloudnosend
dc.subject.enAmyotrophic lateral sclerosis
dc.subject.enGenetic testing
dc.titleSOD1 mutations associated with amyotrophic lateral sclerosis analysis of variant severity
dc.typeJournalArticle
dspace.entity.typePublication