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Erythrocyte SOD1 enzyme activity in ALS patients is not modulated by a 50 bp deletion in the alleged SOD1 promotor
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience. (ALS)
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background A known cause of ALS are mutations in the SOD1 gene. There is also evidence that SOD1 may be involved in cases lacking mutations in the gene. A 50 bp deletion located 1684 bp upstream of the start codon of SOD1 has been suggested to reduce transcription of SOD1, affect enzymatic activity and to be associated with later disease onset in ALS patients. The findings have been challenged by a study of Italian ALS patients, and here we examined the 50 bp deletion in Swedish ALS patients and controls. 

Methods Blood samples from 543 Swedish ALS patients and 356 Swedish controls were analysed for the 50 bp deletion and for SOD1 enzymic activity. The results were related to the disease phenotype of the patients.

Results The frequency of the 50 bp deletion was the same in the patient and control cohorts, and both were found to be in Hardy-Weinberg equilibrium regarding the deletion. In relation to the different genotypes, no differences were detected in SOD1 enzymic activity, duration of disease, age of onset or site of onset.

Conclusions When interpreting the present results together with previous results from other populations, we find it unlikely that the 50 bp deletion region has any regulatory function for the SOD1 gene, nor any effects on the phenotype of ALS.

Keyword [en]
ALS, SOD1, promotor, deletion, age at onset
National Category
Neurosciences
Research subject
Neurology
Identifiers
URN: urn:nbn:se:umu:diva-67456OAI: oai:DiVA.org:umu-67456DiVA: diva2:612001
Projects
On the aetiology of ALS: A comprehensive genetic study
Available from: 2013-03-21 Created: 2013-03-19 Last updated: 2013-04-09Bibliographically approved
In thesis
1. On the aetiology of ALS: a comprehensive genetic study
Open this publication in new window or tab >>On the aetiology of ALS: a comprehensive genetic study
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Introduction: Amyotrophic lateral sclerosis (ALS) is a deadly, progressive neuromuscular disease that affects individuals all over the world. About 10% of the patients have a familial predisposition (FALS) while the remainder of cases are isolated or sporadic (SALS) and of unknown cause. To date, the principal recognized risk factors for ALS are higher age, male gender, slim figure (BMI<23) and a family history of ALS. In 1993, Rosen et al. observed that some FALS cases were associated with mutations in the gene encoding the CuZn superoxide dismutase enzyme (SOD1). Since then, several mutations in the SOD1 gene have been discovered, and mutations in more than 18 other genes have been associated with causing ALS. The aim of this thesis was to identify new mutations associated with ALS pathogenesis, and by comparing patients from different countries, were we also able to identify population-specific genetic variations. The studies are referred to as I–V.

Methods: With written informed consent and adhering to the tenets of the Declaration of Helsinki, through a national network of ALS clinicians´, venous blood samples were collected from ALS patients and healthy subjects in Europe and the USA. The patients were diagnosed according to the El Escorial criteria, and as having FALS according to the criteria of Byrne et al. (2011). The DNA variations were amplified by various PCR techniques. (I, III and IV) The amplicons of ataxin 2 (ATXN2), profilin 1 (PFN1), and vesicle-associated membrane protein type B (VAPB) were characterised by direct sequencing. (II) After quantitative PCR, a genotype-phenotype correlation was performed to assess whether the survival motor neuron gene (SMN) modulates the phenotype of ALS. (V) The amplicons of the 50 base pair deletion in the SOD1 promotor (50 bp) were separated by electrophoresis on agarose.

Results: (I) We observed a significant association between CAG expansions in the ATXN2 gene and ALS in a European cohort. (II) Abnormal copy number of the SMN1 gene was identified as a risk factor in France, but not in Sweden. Homozygosity of the SMN2 deletion prolonged survival among Swedish ALS patients, compared to French patients. (III) We identified two mutations in the PFN1 gene, the novel p.Thr109Met mutation and the p.Gln117Gly mutation, in two unrelated FALS patients. (IV) In our cohort, we identified five VAPB mutations p.Asp130Glu, p.Ser160del, p.Asp162Glu, p.Met170Ile, and p.Arg184Trp, two of which are novel. (V) The 50 bp deletion upstream of the SOD1 gene was found in equal frequencies in both the patient and control cohorts. The 50 bp deletion did not affect SOD1 enzymatic activity. Furthermore, we found no differences in age of onset or disease duration in relation to the 50 bp deletion genotype.VI

Conclusions: (I) Our findings indicate that ATXN2 plays an important role in the pathogenesis of ALS, and that CAG expansions in ATXN2 are a significant risk factor for the disease. (II) We suggest that abnormal SMN1 gene copynumber cannot be considered a universal genetic susceptibility factor for ALS. We also propose that the effect of abnormal SMN2 gene copy number on ALS phenotype may differ between populations. (III) This work provides evidence that PFN1 mutations can cause ALS as a Mendelian dominant trait. The novel p.Thr109Met mutation also shows that disturbance of actin dynamics can cause motor neuron degeneration. (IV) We find it unlikely that the VAPB mutations cause ALS in our cohorts. (V) We find it unlikely that the 50 bp region contains important regulatory elements for SOD1 expression. This thesis supports the theory that ALS is a multigenetic disease, but there appears to be great genetic variation among apparently identical populations. These studies emphasise the importance of continuous genetic screening, to identify further mutations and genes involved in ALS disease, but it also highlights the importance of cooperation and comparison between countries.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2013. 82 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1563
Keyword
ALS, risk factor, VAPB, SOD1, amyotrophic lateral sclerosis, ATXN2, SMN1, SMN2, PFN1, 50 bp deletion in SOD1 promotor, population-specific genetic variations
National Category
Neurosciences
Research subject
Neurology
Identifiers
urn:nbn:se:umu:diva-67460 (URN)978-91-7459-582-6 (ISBN)
Public defence
2013-04-17, Sal Betula, By 6M, Norrlands Universitessjukhus, Umeå, 10:00 (English)
Opponent
Supervisors
Projects
On the aetiology of ALS: A comprehensive genetic study
Funder
Swedish Research Council
Available from: 2013-03-27 Created: 2013-03-19 Last updated: 2013-04-12Bibliographically approved

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Ingre, CarolineBirve, AnnaMarklund, Stefan LAndersen, Peter M

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