Isil Keskin1, Anna Birve1, Mariusz Berdynski1,2, Karin Hjertkvist3, Reza Rofougaran1, Torbjörn K Nilsson3, Jonathan D Glass4, Stefan L Marklund3, Peter M Andersen1. 1. a Department of Pharmacology and Clinical Neurosciences , Umeå University , Umeå , Sweden. 2. b Department of Neurodegenerative Disorders , Mossakowski Medical Research Centre, Polish Academy of Sciences , Warsaw , Poland. 3. c Department of Medical Biosciences, Clinical Chemistry , Umeå University , Umeå , Sweden , and. 4. d Department of Neurology , Emory University School of Medicine , Atlanta , GA , USA.
Abstract
OBJECTIVE: To characterise stabilities in erythrocytes of mutant SOD1 proteins, compare SOD1 enzymatic activities between patients with different genetic causes of ALS and search for underlying causes of deviant SOD1 activities in individuals lacking SOD1 mutations. METHODS: Blood samples from 4072 individuals, ALS patients with or without a SOD1 mutation, family members and controls were studied. Erythrocyte SOD1 enzymatic activities normalised to haemoglobin content were determined, and effects of haemoglobin disorders on dismutation assessed. Coding SOD1 sequences were analysed by Sanger sequencing, exon copy number variations by fragment length analysis and by TaqMan Assay. RESULTS: Of the 44 SOD1 mutations found, 75% caused severe destabilisation of the mutant protein but in 25% it was physically stable. Mutations producing structural changes caused halved erythrocyte SOD1 activities. There were no differences in SOD1 activities between patients without a SOD1 mutation and control individuals or carriers of TBK1 mutations and C9orf72HRE. In the low and high SOD1 activity groups no deviations were found in exon copy numbers and intron gross structures. Thalassemias and iron deficiency were associated with increased SOD1 activity/haemoglobin ratios. CONCLUSION: Adjunct erythrocyte SOD1 activity analysis reliably signals destabilising SOD1 mutations including intronic mutations that are missed by exon sequencing.
OBJECTIVE: To characterise stabilities in erythrocytes of mutant SOD1 proteins, compare SOD1 enzymatic activities between patients with different genetic causes of ALS and search for underlying causes of deviant SOD1 activities in individuals lacking SOD1 mutations. METHODS: Blood samples from 4072 individuals, ALSpatients with or without a SOD1 mutation, family members and controls were studied. Erythrocyte SOD1 enzymatic activities normalised to haemoglobin content were determined, and effects of haemoglobin disorders on dismutation assessed. Coding SOD1 sequences were analysed by Sanger sequencing, exon copy number variations by fragment length analysis and by TaqMan Assay. RESULTS: Of the 44 SOD1 mutations found, 75% caused severe destabilisation of the mutant protein but in 25% it was physically stable. Mutations producing structural changes caused halved erythrocyte SOD1 activities. There were no differences in SOD1 activities between patients without a SOD1 mutation and control individuals or carriers of TBK1 mutations and C9orf72HRE. In the low and high SOD1 activity groups no deviations were found in exon copy numbers and intron gross structures. Thalassemias and iron deficiency were associated with increased SOD1 activity/haemoglobin ratios. CONCLUSION: Adjunct erythrocyte SOD1 activity analysis reliably signals destabilising SOD1 mutations including intronic mutations that are missed by exon sequencing.
Authors: Julien H Park; Christiane Elpers; Janine Reunert; Michael L McCormick; Julia Mohr; Saskia Biskup; Oliver Schwartz; Stephan Rust; Marianne Grüneberg; Anja Seelhöfer; Ulrike Schara; Eugen Boltshauser; Douglas R Spitz; Thorsten Marquardt Journal: Brain Date: 2019-08-01 Impact factor: 13.501
Authors: Isil Keskin; Elin Forsgren; Manuela Lehmann; Peter M Andersen; Thomas Brännström; Dale J Lange; Matthis Synofzik; Ulrika Nordström; Per Zetterström; Stefan L Marklund; Jonathan D Gilthorpe Journal: Acta Neuropathol Date: 2019-03-12 Impact factor: 17.088
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Authors: René Günther; Arun Pal; Chloe Williams; Vitaly L Zimyanin; Maria Liehr; Cläre von Neubeck; Mechthild Krause; Mrudula G Parab; Susanne Petri; Norman Kalmbach; Stefan L Marklund; Jared Sterneckert; Peter Munch Andersen; Florian Wegner; Jonathan D Gilthorpe; Andreas Hermann Journal: Cells Date: 2022-04-06 Impact factor: 6.600