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50bp deletion in the promoter for superoxide dismutase 1 (SOD1) reduces SOD1 expression in vitro and may correlate with increased age of onset of sporadic amyotrophic lateral sclerosis.

https://arctichealth.org/en/permalink/ahliterature156293
Source
Amyotroph Lateral Scler. 2008 Aug;9(4):229-37
Publication Type
Article
Date
Aug-2008
Author
Wendy J Broom
Matthew Greenway
Ghazaleh Sadri-Vakili
Carsten Russ
Kristen E Auwarter
Kelly E Glajch
Nicolas Dupre
Robert J Swingler
Shaun Purcell
Caroline Hayward
Peter C Sapp
Diane McKenna-Yasek
Paul N Valdmanis
Jean-Pierre Bouchard
Vincent Meininger
Betsy A Hosler
Jonathan D Glass
Meraida Polack
Guy A Rouleau
Jang-Ho J Cha
Orla Hardiman
Robert H Brown
Author Affiliation
Day Neuromuscular Research Laboratory, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA. wendy.broom@gmail.com
Source
Amyotroph Lateral Scler. 2008 Aug;9(4):229-37
Date
Aug-2008
Language
English
Publication Type
Article
Keywords
Age of Onset
Amyotrophic Lateral Sclerosis - enzymology - epidemiology - genetics
Base Sequence
DNA Mutational Analysis
Female
Gene Expression
Genetic Predisposition to Disease
Genotype
Homozygote
Humans
Ireland - epidemiology
Male
Middle Aged
Phenotype
Polymorphism, Genetic
Promoter Regions, Genetic
Quebec - epidemiology
Risk factors
Scotland - epidemiology
Sequence Deletion
Sp1 Transcription Factor - metabolism
Superoxide Dismutase - genetics - metabolism
United States - epidemiology
Abstract
The objective was to test the hypothesis that a described association between homozygosity for a 50bp deletion in the SOD1 promoter 1684bp upstream of the SOD1 ATG and an increased age of onset in SALS can be replicated in additional SALS and control sample sets from other populations. Our second objective was to examine whether this deletion attenuates expression of the SOD1 gene. Genomic DNA from more than 1200 SALS cases from Ireland, Scotland, Quebec and the USA was genotyped for the 50bp SOD1 promoter deletion. Reporter gene expression analysis, electrophoretic mobility shift assays and chromatin immunoprecipitation studies were utilized to examine the functional effects of the deletion. The genetic association for homozygosity for the promoter deletion with an increased age of symptom onset was confirmed overall in this further study (p=0.032), although it was only statistically significant in the Irish subset, and remained highly significant in the combined set of all cohorts (p=0.001). Functional studies demonstrated that this polymorphism reduces the activity of the SOD1 promoter by approximately 50%. In addition we revealed that the transcription factor SP1 binds within the 50bp deletion region in vitro and in vivo. Our findings suggest the hypothesis that this deletion reduces expression of the SOD1 gene and that levels of the SOD1 protein may modify the phenotype of SALS within selected populations.
PubMed ID
18608091 View in PubMed
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A 50?bp deletion in the SOD1 promoter lowers enzyme expression but is not associated with ALS in Sweden.

https://arctichealth.org/en/permalink/ahliterature286592
Source
Amyotroph Lateral Scler Frontotemporal Degener. 2016 Jul-Aug;17(5-6):452-7
Publication Type
Article
Author
Caroline Ingre
Anna Wuolikainen
Stefan L Marklund
Anna Birve
Rayomand Press
Peter M Andersen
Source
Amyotroph Lateral Scler Frontotemporal Degener. 2016 Jul-Aug;17(5-6):452-7
Language
English
Publication Type
Article
Keywords
Adult
Aged
Amyotrophic Lateral Sclerosis - enzymology - epidemiology - genetics
Analysis of Variance
Cohort Studies
Erythrocytes - enzymology
Female
Genotype
Humans
Male
Middle Aged
Polymorphism, Genetic - genetics
Sequence Deletion - genetics
Superoxide Dismutase-1 - genetics - metabolism
Sweden - epidemiology
Abstract
Mutations in the superoxide dismutase (SOD1) gene have been linked to amyotrophic lateral sclerosis (ALS). A 50 base pair (bp) deletion of SOD1 has been suggested to reduce transcription and to be associated with later disease onset in ALS. This study was aimed to reveal if the 50?bp deletion influenced SOD1 enzymatic activity, occurrence and phenotype of the disease in a Swedish ALS/control cohort. Blood samples from 512 Swedish ALS patients and 354 Swedish controls without coding SOD1 mutations were analysed for the 50?bp deletion allele. The enzymatic activity of SOD1 in erythrocytes was analysed and genotype-phenotype correlations were assessed. Results demonstrated that the genotype frequencies of the 50?bp deletion were all found to be in Hardy-Weinberg equilibrium. No significant differences were found for age of onset, disease duration or site of onset. SOD1 enzymatic activity showed a statistically significant decreasing trend in the control group, in which the allele was associated with a 5% reduction in SOD1 activity. The results suggest that the 50?bp deletion has a moderate reducing effect on SOD1 synthesis. No modulating effects, however, were found on ALS onset, phenotype and survival in the Swedish population.
PubMed ID
27002425 View in PubMed
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Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study.

https://arctichealth.org/en/permalink/ahliterature141194
Source
Lancet Neurol. 2010 Oct;9(10):978-85
Publication Type
Article
Date
Oct-2010
Author
Hannu Laaksovirta
Terhi Peuralinna
Jennifer C Schymick
Sonja W Scholz
Shaoi-Lin Lai
Liisa Myllykangas
Raimo Sulkava
Lilja Jansson
Dena G Hernandez
J Raphael Gibbs
Michael A Nalls
David Heckerman
Pentti J Tienari
Bryan J Traynor
Author Affiliation
Department of Neurology, Helsinki University Central Hospital and Molecular Neurology Programme, Biomedicum, University of Helsinki, Helsinki, Finland.
Source
Lancet Neurol. 2010 Oct;9(10):978-85
Date
Oct-2010
Language
English
Publication Type
Article
Keywords
Adult
Aged
Aged, 80 and over
Amyotrophic Lateral Sclerosis - enzymology - epidemiology - genetics
Chromosomes, Human, Pair 9 - genetics
Cohort Studies
Female
Finland - epidemiology
Genetic Loci - genetics
Genetic Predisposition to Disease - epidemiology - genetics
Genome-Wide Association Study - methods
Humans
Male
Middle Aged
Polymorphism, Single Nucleotide - genetics
Superoxide Dismutase - genetics
Young Adult
Abstract
The genetic cause of amyotrophic lateral sclerosis (ALS) is not well understood. Finland is a well suited location for a genome-wide association study of ALS because the incidence of the disease is one of the highest in the world, and because the genetic homogeneity of the Finnish population enhances the ability to detect risk loci. We aimed to identify genetic risk factors for ALS in the Finnish population.
We did a genome-wide association study of Finnish patients with ALS and control individuals by use of Illumina genome-wide genotyping arrays. DNA was collected from patients who attended an ALS specialty clinic that receives referrals from neurologists throughout Finland. Control samples were from a population-based study of elderly Finnish individuals. Patients known to carry D90A alleles of the SOD1 gene (n=40) were included in the final analysis as positive controls to assess whether our genome-wide association study was able to detect an association signal at this locus.
We obtained samples from 442 patients with ALS and 521 control individuals. After quality control filters were applied, 318?167 single nucleotide polymorphisms (SNPs) from 405 people with ALS and 497 control individuals were available for analysis. We identified two association peaks that exceeded genome-wide significance. One was located on chromosome 21q22 (rs13048019, p=2·58×10(-8)), which corresponds to the autosomal recessive D90A allele of the SOD1 gene. The other was detected in a 232 kb block of linkage disequilibrium (rs3849942, p=9·11×10(-11)) in a region of chromosome 9p that was previously identified in linkage studies of families with ALS. Within this region, we defined a 42-SNP haplotype that was associated with significantly increased risk of ALS (p=7·47×10(-33) when people with familial ALS were compared with controls, odds ratio 21·0, 95% CI 11·2-39·1) and which overlapped with an association locus recently reported for frontotemporal dementia. For the 93 patients with familial ALS, the population attributable risk for the chromosome 9p21 locus was 37·9% (95% CI 27·7-48·1) and that for D90A homozygosity was 25·5% (16·9-34·1).
The chromosome 9p21 locus is a major cause of familial ALS in the Finnish population. Our data suggest the presence of a founder mutation for chromosome 9p21-linked ALS. Furthermore, the overlap with the risk haplotype recently reported for frontotemporal dementia provides further evidence of a shared genetic cause for these two neurodegenerative diseases.
National Institutes of Health and National Institute on Aging, Microsoft Research, ALS Association, Helsinki University Central Hospital, Finnish Academy, Finnish Medical Society Duodecim, and Kuopio University.
Notes
Cites: Bioinformatics. 2005 Jan 15;21(2):263-515297300
Cites: Brain. 2006 Apr;129(Pt 4):868-7616495328
Cites: Neurology. 2006 Mar 28;66(6):839-4416421333
Cites: Arch Neurol. 2007 Feb;64(2):240-517296840
Cites: Neurology. 2007 Feb 20;68(8):600-217310031
Cites: Lancet Neurol. 2007 Apr;6(4):322-817362836
Cites: Neurology. 2007 Mar 27;68(13):1002-717389304
Cites: Am J Hum Genet. 2007 Sep;81(3):559-7517701901
Cites: N Engl J Med. 2007 Aug 23;357(8):775-8817671248
Cites: Lancet Neurol. 2007 Oct;6(10):869-7717827064
Cites: Nat Genet. 2008 Jan;40(1):29-3118084291
Cites: Am J Hum Genet. 2008 Feb;82(2):453-6318252225
Cites: Hum Mol Genet. 2008 Mar 1;17(5):768-7418057069
Cites: BMC Neurol. 2008;8:3218755042
Cites: Hum Mol Genet. 2009 Apr 15;18(8):1524-3219193627
Cites: Neurology. 2009 May 12;72(19):1669-7619433740
Cites: Proc Natl Acad Sci U S A. 2009 Jun 2;106(22):9004-919451621
Cites: Nat Genet. 2010 Mar;42(3):234-920154673
Cites: J Neurol Neurosurg Psychiatry. 2011 Feb;82(2):196-20320562461
Cites: N Engl J Med. 2001 May 31;344(22):1688-70011386269
Cites: Neurology. 2001 Jun 26;56(12):1690-611425935
Cites: Nat Genet. 2001 Aug;28(4):309-1011479587
Cites: Annu Rev Genomics Hum Genet. 2001;2:103-2811701645
Cites: J Neurol Neurosurg Psychiatry. 2003 Jul;74(7):867-7112810769
Cites: Int J Epidemiol. 1978 Jun;7(2):175-82681063
Cites: Acta Neurol Scand. 1983 Jan;67(1):41-76601351
Cites: J Neurol Sci. 1994 Jul;124 Suppl:96-1077807156
Cites: Nat Genet. 1995 May;10(1):61-67647793
Cites: Neuropathol Appl Neurobiol. 1998 Apr;24(2):104-179634206
Cites: Hum Mol Genet. 1999;8(10):1913-2310469845
Comment In: Lancet Neurol. 2010 Oct;9(10):945-720801719
PubMed ID
20801718 View in PubMed
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