| 11. |
- Couthouis, Julien, et al.
(författare)
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A yeast functional screen predicts new candidate ALS disease genes
- 2011
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 108:52, s. 20881-20890
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics to predict prion-like domains in a subset of them. We sequenced one of the segenes, TAF15, in patients with ALS and identified missense variants, which were absent in a large number of healthy controls. These disease-associated variants of TAF15 caused formation of cytoplasmic foci when expressed in primary cultures of spinal cord neurons. Very similar to TDP-43 and FUS, TAF15 aggregated in vitro and conferred neurodegeneration in Drosophila, with the ALS-linked variants having amore severe effect than wild type. Immunohistochemistry of postmortem spinal cord tissue revealed mislocalization of TAF15 in motor neurons of patients with ALS. We propose that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery.
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| 12. |
- Diekstra, Frank P., et al.
(författare)
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C9orf72 and UNC13A Are Shared Risk Loci for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia : A Genome-Wide Meta-Analysis
- 2014
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Ingår i: Annals of Neurology. - : John Wiley & Sons. - 0364-5134 .- 1531-8249. ; 76:1, s. 120-133
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Substantial clinical, pathological, and genetic overlap exists between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 inclusions have been found in both ALS and FTD cases (FTD-TDP). Recently, a repeat expansion in C9orf72 was identified as the causal variant in a proportion of ALS and FTD cases. We sought to identify additional evidence for a common genetic basis for the spectrum of ALS-FTD. Methods: We used published genome-wide association studies data for 4,377 ALS patients and 13,017 controls, and 435 pathology-proven FTD-TDP cases and 1,414 controls for genotype imputation. Data were analyzed in a joint meta-analysis, by replicating topmost associated hits of one disease in the other, and by using a conservative rank products analysis, allocating equal weight to ALS and FTD-TDP sample sizes. Results: Meta-analysis identified 19 genome-wide significant single nucleotide polymorphisms (SNPs) in C9orf72 on chromosome 9p21.2 (lowest p = 2.6 x 10(-12)) and 1 SNP in UNC13A on chromosome 19p13.11 (p = 1.0 x 10(-11)) as shared susceptibility loci for ALS and FTD-TDP. Conditioning on the 9p21.2 genotype increased statistical significance at UNC13A. A third signal, on chromosome 8q24.13 at the SPG8 locus coding for strumpellin (p = 3.91 x 10(-7)) was replicated in an independent cohort of 4,056 ALS patients and 3,958 controls (p = 0.026; combined analysis p = 1.01 x 10(-7)). Interpretation: We identified common genetic variants in C9orf72, but in addition in UNC13A that are shared between ALS and FTD. UNC13A provides a novel link between ALS and FTD-TDP, and identifies changes in neurotransmitter release and synaptic function as a converging mechanism in the pathogenesis of ALS and FTD-TDP.
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| 13. |
- Eschbach, Judith, et al.
(författare)
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PGC-1 is a male-specific disease modifier of human and experimental amyotrophic lateral sclerosis
- 2013
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 22:17, s. 3477-3484
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a devastating, adult-onset neurodegenerative disorder of the upper and lower motor systems. It leads to paresis, muscle wasting and inevitably to death, typically within 35 years. However, disease onset and survival vary considerably ranging in extreme cases from a few months to several decades. The genetic and environmental factors underlying this variability are of great interest as potential therapeutic targets. In ALS, men are affected more often and have an earlier age of onset than women. This gender difference is recapitulated in transgenic rodent models, but no underlying mechanism has been elucidated. Here we report that SNPs in the brain-specific promoter region of the transcriptional co-activator PGC-1, a master regulator of metabolism, modulate age of onset and survival in two large and independent ALS populations and this occurs in a strictly male-specific manner. In complementary animal studies, we show that deficiency of full-length (FL) Pgc-1 leads to a significantly earlier age of onset and a borderline shortened survival in male, but not in female ALS-transgenic mice. In the animal model, FL Pgc-1-loss is associated with reduced mRNA levels of the trophic factor Vegf-A in males, but not in females. In summary, we indentify PGC-1 as a novel and clinically relevant disease modifier of human and experimental ALS and report a sex-dependent effect of PGC-1 in this neurodegenerative disorder.
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| 14. |
- Fogh, Isabella, et al.
(författare)
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A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis
- 2014
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Ingår i: Human Molecular Genetics. - Oxford : Oxford University Press. - 0964-6906 .- 1460-2083. ; 23:8, s. 2220-2231
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Tidskriftsartikel (refereegranskat)abstract
- Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided novel insights into the aetiology of this rapidly progressing fatal neurodegenerative disease. However, genome-wide association studies (GWAS) of the more common (90) sporadic form have been less successful with the exception of the replicated locus at 9p21.2. To identify new loci associated with disease susceptibility, we have established the largest association study in ALS to date and undertaken a GWAS meta-analytical study combining 3959 newly genotyped Italian individuals (1982 cases and 1977 controls) collected by SLAGEN (Italian Consortium for the Genetics of ALS) together with samples from Netherlands, USA, UK, Sweden, Belgium, France, Ireland and Italy collected by ALSGEN (the International Consortium on Amyotrophic Lateral Sclerosis Genetics). We analysed a total of 13 225 individuals, 6100 cases and 7125 controls for almost 7 million single-nucleotide polymorphisms (SNPs). We identified a novel locus with genome-wide significance at 17q11.2 (rs34517613 with P 1.11 10(8); OR 0.82) that was validated when combined with genotype data from a replication cohort (P 8.62 10(9); OR 0.833) of 4656 individuals. Furthermore, we confirmed the previously reported association at 9p21.2 (rs3849943 with P 7.69 10(9); OR 1.16). Finally, we estimated the contribution of common variation to heritability of sporadic ALS as 12 using a linear mixed model accounting for all SNPs. Our results provide an insight into the genetic structure of sporadic ALS, confirming that common variation contributes to risk and that sufficiently powered studies can identify novel susceptibility loci.
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| 15. |
- Shatunov, Aleksey, et al.
(författare)
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Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries : a genome-wide association study
- 2010
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Ingår i: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 9:10, s. 986-994
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Tidskriftsartikel (refereegranskat)abstract
- We have found strong evidence of a genetic association of two single nucleotide polymorphisms on chromosome 9 with sporadic ALS, in line with findings from previous independent GWAS of ALS and linkage studies of ALS-frontotemporal dementia. Our findings together with these earlier findings suggest that genetic variation at this locus on chromosome 9 causes sporadic ALS and familial ALS-frontotemporal dementia. Resequencing studies and then functional analysis should be done to identify the defective gene.
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| 16. |
- Bogaert, Elke, et al.
(författare)
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Polymorphisms in the GluR2 gene are not associated with amyotrophic lateral sclerosis
- 2012
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 33:2, s. 418-420
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Tidskriftsartikel (refereegranskat)abstract
- Excitotoxicity is thought to play a pathogenic role in amyotrophic lateral sclerosis (ALS). Excitotoxic motor neuron death is mediated through the Ca(2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type of glutamate receptors and Ca(2+) permeability is determined by the GluR2 subunit. We investigated whether polymorphisms or mutations in the GluR2 gene (GRIA2) predispose patients to ALS. Upon sequencing 24 patients and 24 controls no nonsynonymous coding variants were observed but 24 polymorphisms were identified, 9 of which were novel. In a screening set of 310 Belgian ALS cases and 794 healthy controls and a replication set of 3157 cases and 5397 controls from 6 additional populations no association with susceptibility, age at onset, or disease duration was observed. We conclude that polymorphisms in the GluR2 gene (GRIA2) are not a major contributory factor in the pathogenesis of ALS.
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| 17. |
- Burgunder, J-M, et al.
(författare)
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EFNS guidelines for the molecular diagnosis of neurogenetic disorders : motoneuron, peripheral nerve and muscle disorders
- 2011
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Ingår i: European Journal of Neurology. - : Wiley-Blackwell. - 1351-5101 .- 1468-1331. ; 18:2, s. 207-E20
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: These EFNS guidelines on the molecular diagnosis of motoneuron disorders, neuropathies and myopathies are designed to summarize the possibilities and limitations of molecular genetic techniques and to provide diagnostic criteria for deciding when a molecular diagnostic work-up is indicated. Search strategy: To collect data about planning, conditions and performance of molecular diagnosis of these disorders, a literature search in various electronic databases was carried out and original papers, meta-analyses, review papers and guideline recommendations reviewed. Results: The best level of evidence for genetic testing recommendation (B) can be found for the disorders with specific presentations, including familial amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, Charcot-Marie-Tooth 1A, myotonic dystrophy and Duchenne muscular dystrophy. For a number of less common disorders, a precise description of the phenotype, including the use of immunologic methods in the case of myopathies, is considered as good clinical practice to guide molecular genetic testing. Conclusion: These guidelines are provisional and the future availability of molecular-genetic epidemiological data about the neurogenetic disorders under discussion in this article will allow improved recommendation with an increased level of evidence.
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| 18. |
- Carew, J. D., et al.
(författare)
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Presymptomatic spinal cord neurometabolic findings in SOD1-positive people at risk for familial ALS
- 2011
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Ingår i: Neurology. - Minneapolis, Minn : Lancet Publications Inc.. - 0028-3878 .- 1526-632X. ; 77:14, s. 1370-1375
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: It has been speculated that amyotrophic lateral sclerosis (ALS) is characterized by a premanifest period during which neurodegeneration precedes the appearance of clinical manifestations. Magnetic resonance spectroscopy (MRS) was used to measure rations of neurometabolites in the cervical spine of asymptomatic individuals with a mutation in the SOD1 gene (SOD1+) and compare their neurometabolic ratios to patients with ALS and healthy controls.Methods: A cross-sectional study of (1)H-MRS of the cervical spine was performed on 24 presymptomatic SOD1+ volunteers, 29 healthy controls, and 23 patients with ALS. All presymptomatic subjects had no symptoms of disease, normal forced vital capacity, and normal electromyographic examination. Relative concentrations of choline (Cho), creatine (Cr), myo-inositol (Myo), and N-acetylasparate (NAA) were determined.Results: NAA/Cr and NAA/Myo rations are reduced in both SOD1+ subjects (39.7%, p = 0.001 and 18.0%, p = 0.02) and patients with ALS (41.2%, p < 0.001 and 24.0%, p = 0.01) compared to controls. Myo/Cr is reduced (10.3%, p = 0.02) in SOD1+ subjects compared to controls, but no difference was found between patients with ALS and controls. By contrast, NAA/Cho is reduced in patients with ALS (24.0%, p = 0.002), but not in presymptomatic SOD1+ subjects compared to controls.Conclusions: Changes in neurometabolite ratios in the cervical spinal cord are evident in presymptomatic SOD1+ individuals in advance of symptoms and clinical or electromyographic changes in this population resemble changes observed in patients with clinically apparent ALS. This suggest that neurometabolic changed occur early in the course of the disease process.
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| 19. |
- Chiang, Huei-Hsin, et al.
(författare)
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Novel TARDBP mutations in Nordic ALS patients
- 2012
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Ingår i: Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1434-5161 .- 1435-232X. ; 57:5, s. 316-319
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a neurodegenerative syndrome primarily affecting the upper and lower motor neurons. A characteristic neuropathological finding in ALS patients is neuronal inclusions positive for TAR DNA-binding protein 43 (TDP-43). Subsequently, mutations in the gene encoding TDP-43, TARDBP, proved to be involved in the development of ALS. We thus sequenced TARDBP in 177 Nordic ALS patients and found two previously reported (p.A90V and p.S379P) and two novel (p.G357R and p.R361T) missense variations in three familial ALS patients. The p.A90V and p.G357R variations were detected in the same patient and p.R361T was present in a family with both ALS and frontotemporal dementia-ALS. None of the missense variations were present in 200 neurologically healthy controls. However, p.A90V has also been reported in healthy individuals by others. Thus, the data suggest that these variations are rare and p.G357R, p.R361T and p.S379P are likely pathogenic but further functional characterization is needed to prove their pathogenicity. The mutation frequency in TARDBP in Nordic ALS patients was 1.7%. The ALS cohort was highly selected for a positive family history suggesting that mutations in TARDBP generally are a rare cause of ALS in Nordic countries.
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| 20. |
- Czell, D., et al.
(författare)
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Phenotypes in Swiss Patients with Familial ALS Carrying TARDBP Mutations
- 2013
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Ingår i: Neurodegenerative Diseases. - : S. Karger AG. - 1660-2854 .- 1660-2862. ; 12:3, s. 150-155
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Tidskriftsartikel (refereegranskat)abstract
- Background: Recently, mutations in the TARDBP gene encoding the TAR DNA-binding protein 43 (TDP-43) have been identified in some familial annyotrophic lateral sclerosis (ALS) and sporadic ALS patients. The phenotype and frequency of TARDBP mutation carriers reportedly varies greatly among European populations. Objective: To define the phenotypic spectrum of TARDBP mutations and their frequency in a Swiss population. Methods: A total of 225 patients diagnosed with ALS (182 sporadic cases, 43 familial cases) were screened for TARDBP mutations. All patients were carefully examined and interviewed for a familial predisposition. Except for 1 patient who was followed at the University of Geneva, all patients were followed at the Kantonsspital St. Gallen. Results: 43 patients (19.5%) had a definite family history for ALS. A TARDBP mutation was identified in 4 of these (9.3%). Two female ALS patients carried the p.Asn352Ser mutation. Both had limb onset and a slowly progressive course of the disease. A novel mutation (p.Gly376Asp) was identified in a 44-year-old female patient. Survival amongst affected family members varied between 6 and 18 months. The patient and also the other siblings affected with ALS had an accessory nipple. A fourth male patient carried the p.Ala-90Val mutation. None of the patients had overt cognitive impairment. TARDBP mutations were not found among patients with sporadic forms of ALS. Conclusion: In this Swiss population, the frequency of familial ALS is higher than reported earlier in other populations. The novel p.Gly376Asp TARDBP mutation is associated with rapid disease progression and may be associated with an accessory nipple while the p.Asn352Ser mutation is associated with slow disease progression.
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