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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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Analysis of DPP6 and FGGY as candidate genes for amyotrophic lateral sclerosis.

https://arctichealth.org/en/permalink/ahliterature146774
Source
Amyotroph Lateral Scler. 2010 Aug;11(4):389-91
Publication Type
Article
Date
Aug-2010
Author
Hussein Daoud
Paul N Valdmanis
Patrick A Dion
Guy A Rouleau
Author Affiliation
Centre of Excellence in Neuromics, Université de Montréal, Montreal, Quebec, Canada.
Source
Amyotroph Lateral Scler. 2010 Aug;11(4):389-91
Date
Aug-2010
Language
English
Publication Type
Article
Keywords
Amyotrophic Lateral Sclerosis - genetics
Canada
Cohort Studies
DNA Mutational Analysis
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - genetics
European Continental Ancestry Group
Gene Frequency
Genotype
Humans
Nerve Tissue Proteins - genetics
Polymorphism, Single Nucleotide - genetics
Potassium Channels - genetics
Proteins - genetics
Abstract
DPP6 and FGGY genes have been recently associated with an increased susceptibility for sporadic amyotrophic lateral sclerosis. Here, we evaluated the role of these genes in ALS pathogenesis by undertaking a sequence analysis of a cohort of 190 ALS patients from France and Quebec. We did not observe any evidence that mutations in DPP6 and FGGY genes are involved in ALS. Our data indicate that mutations in these genes are unlikely to be a common cause of ALS in the French and French Canadian populations.
PubMed ID
20001489 View in PubMed
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Four familial ALS pedigrees discordant for two SOD1 mutations: are all SOD1 mutations pathogenic?

https://arctichealth.org/en/permalink/ahliterature97016
Source
J Neurol Neurosurg Psychiatry. 2010 May;81(5):572-7
Publication Type
Article
Date
May-2010
Author
Ansgar Felbecker
William Camu
Paul N Valdmanis
Anne-Dorte Sperfeld
Stefan Waibel
Peter Steinbach
Guy A Rouleau
Albert C Ludolph
Peter M Andersen
Author Affiliation
Department of Clinical Neuroscience, Umeå University, Umeå SE-901 85, Sweden.
Source
J Neurol Neurosurg Psychiatry. 2010 May;81(5):572-7
Date
May-2010
Language
English
Geographic Location
Finland
Sweden
Multi-National
Publication Type
Article
Keywords
Adult
Age of Onset
Aged
Alleles
Amyotrophic Lateral Sclerosis - genetics - pathology
DNA - genetics
Disease Progression
Female
Finland
Genes, Dominant - genetics
Genes, Recessive - genetics
Germany
Haplotypes
Heterozygote
Humans
Male
Middle Aged
Mutation - genetics - physiology
Mutation, Missense
Pedigree
Phenotype
Reverse Transcriptase Polymerase Chain Reaction
Superoxide Dismutase - genetics
Sweden
Abstract
BACKGROUND: 153 mutations in the Cu/Zn superoxide dismutase (SOD1) gene have been claimed to be associated with amyotrophic lateral sclerosis (ALS) in familial and sporadic ALS in an autosomal dominant or autosomal recessive pattern with complete or reduced penetrance. The authors now report four ALS pedigrees from Finland, France, Germany and Sweden with either the D90A or E100K SOD1 mutations in some but not all affected members. After re-collecting DNA, the non-segregation of the SOD1 mutations with disease was confirmed by three independent laboratories using different PCR primers: while some of the affected patients carry SOD1 mutations, other affected family members have two wildtype/normal SOD1 genes. In addition, some unaffected members within the same families are carriers of SOD1 gene mutations. To exclude other known genetic causes, the authors ruled out mutations within the genes coding for VAPB, ANG, TDP43, FUS and DCTN1 in affected individuals in the four pedigrees. CONCLUSIONS: The authors find that the D90A and E100K SOD1 gene mutations found in some patients are not the exclusive cause of ALS in these pedigrees. Whether this is also the case for the other 151 SOD1 mutations reported in ALS pedigrees is unknown. The findings have consequences for genetic testing in clinical practice when diagnosing ALS and for genetic counselling in ALS. Some SOD1 mutations may be part of an oligo- or epigentic pattern of inheritance. Such a pattern of inheritance may model other oligo- or polygenetic traits responsible for other forms of ALS.
Notes
RefSource: J Neurol Neurosurg Psychiatry. 2010 May;81(5):473
PubMed ID
20460594 View in PubMed
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