| 1. |
- Brotherton, Terrell, et al.
(författare)
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A novel ALS SOD1 C6S mutation with implications for aggregation related toxicity and genetic counseling
- 2011
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Ingår i: Amyotrophic Lateral Sclerosis and other Motor Neuron Disorders. - : Informa UK Limited. - 1466-0822 .- 1743-4483. ; 12:3, s. 215-219
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Tidskriftsartikel (refereegranskat)abstract
- In this report we describe an ALS family with a novel missense SOD1 mutation with substitution of serine for cysteine at the sixth amino acid (C6S). This mutation has interesting implications for the role of disulfides in causing disease. After identification of the ALS proband, we examined 17 members of an extended family and performed DNA mutation analysis on 21 family members. The level and activity of SOD1 in C6S carriers and wild-type family members was analyzed in erythrocytes. We found that the C6S mutation results in disease with an autosomal dominant mode of inheritance and markedly reduced penetrance. The S6 mutated protein demonstrates high stability relative to the C6 wild-type protein. The specific dismutation activity of S6 SOD1 is normal. In conclusion, C6S is a novel FALS associated mutation with reduced disease penetrance, long survival time and a phenotype very different from the other SOD1 mutations reported in codon C6. This mutation may provide insight into the role of SOD1 structural changes in disease.
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| 2. |
- Keskin, Isil, et al.
(författare)
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Comprehensive analysis to explain reduced or increased SOD1 enzymatic activity in ALS patients and their relatives
- 2017
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Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : TAYLOR & FRANCIS LTD. - 2167-8421 .- 2167-9223. ; 18:5-6, s. 457-463
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Tidskriftsartikel (refereegranskat)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 C9orf72(HRE). 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.
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| 3. |
- Keskin, Isil, 1987-, et al.
(författare)
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Comprehensive analysis to explain reduced or increased SOD1 enzymatic activity in erythrocytes in ALS patients and their relatives
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Our objective was to in blood samples from 3723 individuals including ALS patients without a coding SOD1 mutation and 372 control individuals characterize stabilities of mutant SOD1s, 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. Erythrocyte SOD1 enzymatic activities normalized to hemoglobin content were determined. Coding SOD1 sequences were analyzed by Sanger sequencing, copy number variations by fragment length analysis and by TaqMan Assay. Hemoglobin disorders were searched for. Of the 46 SOD1 mutations found, ¾ caused severe destabilization of the mutant protein but in ¼ SOD1 was essentially physically stable. Mutations producing structural changes all caused halved SOD activities. There were no differences in SOD1 activities between controls and patients without any detected SOD1 mutations or patients with C9ORF72HRE or TBK1 mutations. In the low and high SOD1 activity groups no deviations were found in exon copy numbers and intron gross structures. Also, no uncommon variants in exon-flanking sequences were detected. Thalassemias and iron deficiency anemia were associated with increased SOD1 activity/hemoglobin ratios. In conclusion, adjunct erythrocyte SOD activity analysis is of value to signal the presence of exon and splice-site-intron mutations that influence the SOD1 structure.
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