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ABSTRACT: The exact pathway leading to neuron death and muscle atrophy in amyotrophic lateral sclerosis (ALS) has not yet been elucidated. Gene expression profile of spinal cord, blood and muscle could provide signalling pathways and systemic alterations useful for future biomarker development. In our study we compared whole genome expression profiles of lumbar spinal cord with peripheral blood and tibialis anterior muscle in 16 mutant SOD1-G93A mice and 15 wild-type littermates. In SOD1-G93A mice, 11 genes were significantly differentially expressed in spinal cord, and 16 genes in blood, while much larger transcriptional changes were noted in muscle (1745 genes significant; six overlapping with spinal cord (0.3%)) probably due to muscle atrophy. Overlap with spinal cord was enriched for significant genes in blood (six of 16 overlapping with spinal cord (37.5%)). Three genes were significantly down-regulated in all three tissues, and were closely related to mitochondrial function. Furthermore, clustering the significant genes in spinal cord and in blood, but not in muscle, could identify the SOD1-G93A mice. We conclude that blood gene expression profile overlapped with profile of spinal cord, allowing differentiation of SOD1-G93A mice from wild-type littermates. Blood gene expression profiling may be a promising biomarker for ALS patients.
Amyotrophic lateral sclerosis and frontotemporal degeneration. 01/2013;
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ABSTRACT: The exact pathogenic cascade leading to motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is unknown. Gene expression profiles of ALS-affected spinal cord and motor neurons have been well established in mice and man. We provide a meta-analysis of the reported significant gene lists of gene expression studies in ALS, and compare results between mouse models and human post mortem tissue. In total, 12 articles met inclusion criteria. Twenty-nine genes were found to be differentially expressed at least twice in studies using human post mortem tissue, enriched for the functions 'immune response', 'apoptosis' and 'protein metabolism'. In mouse studies, 86 genes were reported at least two times and were enriched for 'immune response', 'lysosome', 'metal ion binding' and 'mitochondrion'. Next, all differentially expressed genes from the mouse studies were translated to human homologous genes. Seventy-four differentially expressed genes in mouse tissue were also found to be differentially expressed in human tissue. In conclusion, evidence was found for shared dysfunction in protein turnover in the ubiquitin-proteasome system. Differential expression of Cathepsin B and D, GFAP and SERPINA3 was repeatedly found to be significant in both the mouse model and ALS patients.
Amyotrophic lateral sclerosis and frontotemporal degeneration. 01/2013;
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ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that causes progressive muscle weakness, eventually resulting in death because of respiratory failure. Genetic variants are thought to predispose to the disease. A recent, large, genome-wide association study identified 2 loci that increase susceptibility to ALS. These 2 loci on chromosomes 9 and 19 consist of 4 genes: UNC13a, IFNK, MOBKL2b, and C9ORF72. A hexanucleotide repeat expansion in the noncoding region of C9ORF72 was recently identified as the cause of chromosome 9-linked ALS-FTD (frontotemporal dementia). In this study, our aim was to determine whether the coding regions of these genes harbor rare, nonsynonymous variants that play a role in ALS pathogenesis. In DNA from 1019 sporadic ALS patients and 1103 control subjects of Dutch descent, we performed a mutation screening analysis in the coding region of these 4 genes by resequencing the exons. A total of 16 amino acid-changing rare variations were identified, 11 in UNC13a and 5 on chromosome 9. Some of these were unique to ALS, but were detected in a single patient. None of the genes showed significant enrichment of rare variants in the coding sequence. Rare variants in the coding region of UNC13a, IFNK, MOBKL2b, and C9ORF72 are unlikely to be a genetic cause of ALS.
Neurobiology of aging 11/2012; · 5.94 Impact Factor
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ABSTRACT: Recently, repeat expansions in several genes have been shown to cause or be associated with amyotrophic lateral sclerosis (ALS). It has been demonstrated that an intronic hexanucleotide repeat expansion in C9ORF72 is a major cause of both familial (approximately 40%) and sporadic (approximately 5%) ALS, as well as frontotemporal dementia (FTD). In addition, a CAG-repeat expansion in exon 1 of ATXN2, otherwise known to cause spinocerebellar ataxia type 2, has been identified as a major risk factor for sporadic ALS. Intermediate repeat expansions in the fragile X mental retardation 1 (FMR1) gene (55-200 repeats) are known to cause fragile X-associated premature ovarian insufficiency [(FX)POI; female carriers] or fragile X-associated tremor/ataxia syndrome (FXTAS; male carriers) by CGG-mediated RNA toxicity. The present investigation involves screening FMR1 repeat length in 742 sporadic ALS patients and 792 matched controls. Our conclusion is that FMR1 repeat expansions are not associated with ALS.
Neurobiology of aging 04/2012; 33(8):1852.e1-3. · 5.94 Impact Factor
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Frank P Diekstra,
Christiaan G J Saris,
Wouter van Rheenen,
Lude Franke,
Ritsert C Jansen,
Michael A van Es,
Paul W J van Vught,
Hylke M Blauw, Ewout J N Groen,
Steve Horvath, [......],
Orla Hardiman,
John E Landers,
Robert H Brown,
Aleksey Shatunov,
Christopher E Shaw,
P Nigel Leigh,
Ammar Al-Chalabi,
Roel A Ophoff,
Leonard H van den Berg,
Jan H Veldink
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ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease characterized by loss of upper and lower motor neurons. ALS is considered to be a complex trait and genome-wide association studies (GWAS) have implicated a few susceptibility loci. However, many more causal loci remain to be discovered. Since it has been shown that genetic variants associated with complex traits are more likely to be eQTLs than frequency-matched variants from GWAS platforms, we conducted a two-stage genome-wide screening for eQTLs associated with ALS. In addition, we applied an eQTL analysis to finemap association loci. Expression profiles using peripheral blood of 323 sporadic ALS patients and 413 controls were mapped to genome-wide genotyping data. Subsequently, data from a two-stage GWAS (3,568 patients and 10,163 controls) were used to prioritize eQTLs identified in the first stage (162 ALS, 207 controls). These prioritized eQTLs were carried forward to the second sample with both gene-expression and genotyping data (161 ALS, 206 controls). Replicated eQTL SNPs were then tested for association in the second-stage GWAS data to find SNPs associated with disease, that survived correction for multiple testing. We thus identified twelve cis eQTLs with nominally significant associations in the second-stage GWAS data. Eight SNP-transcript pairs of highest significance (lowest p = 1.27 × 10(-51)) withstood multiple-testing correction in the second stage and modulated CYP27A1 gene expression. Additionally, we show that C9orf72 appears to be the only gene in the 9p21.2 locus that is regulated in cis, showing the potential of this approach in identifying causative genes in association loci in ALS. This study has identified candidate genes for sporadic ALS, most notably CYP27A1. Mutations in CYP27A1 are causal to cerebrotendinous xanthomatosis which can present as a clinical mimic of ALS with progressive upper motor neuron loss, making it a plausible susceptibility gene for ALS.
PLoS ONE 01/2012; 7(4):e35333. · 4.09 Impact Factor
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Michael A van Es,
Helenius J Schelhaas,
Paul W J van Vught,
Nicola Ticozzi,
Peter M Andersen, Ewout J N Groen,
Claudia Schulte,
Hylke M Blauw,
Max Koppers,
Frank P Diekstra, [......],
Thomas Gasser,
Albert C Ludolph,
Wim Robberecht,
Roel A Ophoff,
Jan H Veldink,
R Jeroen Pasterkamp,
Paul I W de Bakker,
John E Landers,
Bart P van de Warrenburg,
Leonard H van den Berg
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ABSTRACT: Several studies have suggested an increased frequency of variants in the gene encoding angiogenin (ANG) in patients with amyotrophic lateral sclerosis (ALS). Interestingly, a few ALS patients carrying ANG variants also showed signs of Parkinson disease (PD). Furthermore, relatives of ALS patients have an increased risk to develop PD, and the prevalence of concomitant motor neuron disease in PD is higher than expected based on chance occurrence. We therefore investigated whether ANG variants could predispose to both ALS and PD.
We reviewed all previous studies on ANG in ALS and performed sequence experiments on additional samples, which allowed us to analyze data from 6,471 ALS patients and 7,668 controls from 15 centers (13 from Europe and 2 from the USA). We sequenced DNA samples from 3,146 PD patients from 6 centers (5 from Europe and 1 from the USA). Statistical analysis was performed using the variable threshold test, and the Mantel-Haenszel procedure was used to estimate odds ratios.
Analysis of sequence data from 17,258 individuals demonstrated a significantly higher frequency of ANG variants in both ALS and PD patients compared to control subjects (p = 9.3 × 10(-6) for ALS and p = 4.3 × 10(-5) for PD). The odds ratio for any ANG variant in patients versus controls was 9.2 for ALS and 6.7 for PD.
The data from this multicenter study demonstrate that there is a strong association between PD, ALS, and ANG variants. ANG is a genetic link between ALS and PD.
Annals of Neurology 12/2011; 70(6):964-73. · 11.09 Impact Factor
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Max Koppers,
Marka M van Blitterswijk,
Lotte Vlam,
Paulina A Rowicka,
Paul W J van Vught, Ewout J N Groen,
Wim G M Spliet,
JooYeon Engelen-Lee,
Helenius J Schelhaas,
Marianne de Visser,
Anneke J van der Kooi,
W-Ludo van der Pol,
R Jeroen Pasterkamp,
Jan H Veldink,
Leonard H van den Berg
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ABSTRACT: Mutations in the valosin-containing protein (VCP) gene were recently reported to be the cause of 1%-2% of familial amyotrophic lateral sclerosis (ALS) cases. VCP mutations are known to cause inclusion body myopathy (IBM) with Paget's disease (PDB) and frontotemporal dementia (FTD). The presence of VCP mutations in patients with sporadic ALS, sporadic ALS-FTD, and progressive muscular atrophy (PMA), a known clinical mimic of inclusion body myopathy, is not known. To determine the identity and frequency of VCP mutations we screened a cohort of 93 familial ALS, 754 sporadic ALS, 58 sporadic ALS-FTD, and 264 progressive muscular atrophy patients for mutations in the VCP gene. Two nonsynonymous mutations were detected; 1 known mutation (p.R159H) in a patient with familial ALS with several family members suffering from FTD, and 1 mutation (p.I114V) in a patient with sporadic ALS. Conservation analysis and protein prediction software indicate the p.I114V mutation to be a rare benign polymorphism. VCP mutations are a rare cause of familial ALS. The role of VCP mutations in sporadic ALS, if present, appears limited.
Neurobiology of aging 11/2011; 33(4):837.e7-13. · 5.94 Impact Factor
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Hylke M Blauw,
Ammar Al-Chalabi,
Peter M Andersen,
Paul W J van Vught,
Frank P Diekstra,
Michael A van Es,
Christiaan G J Saris, Ewout J N Groen,
Wouter van Rheenen,
Max Koppers, [......],
Dan Rujescu,
Claudia Schulte,
Thomas Gasser,
Robert H Brown,
John E Landers,
Wim Robberecht,
Albert C Ludolph,
Roel A Ophoff,
Jan H Veldink,
Leonard H van den Berg
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ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease selectively affecting motor neurons in the brain and spinal cord. Recent genome-wide association studies (GWASs) have identified several common variants which increase disease susceptibility. In contrast, rare copy-number variants (CNVs), which have been associated with several neuropsychiatric traits, have not been studied for ALS in well-powered study populations. To examine the role of rare CNVs in ALS susceptibility, we conducted a CNV association study including over 19,000 individuals. In a genome-wide screen of 1875 cases and 8731 controls, we did not find evidence for a difference in global CNV burden between cases and controls. In our association analyses, we identified two loci that met our criteria for follow-up: the DPP6 locus (OR = 3.59, P = 6.6 × 10(-3)), which has already been implicated in ALS pathogenesis, and the 15q11.2 locus, containing NIPA1 (OR = 12.46, P = 9.3 × 10(-5)), the gene causing hereditary spastic paraparesis type 6 (HSP 6). We tested these loci in a replication cohort of 2559 cases and 5887 controls. Again, results were suggestive of association, but did not meet our criteria for independent replication: DPP6 locus: OR = 1.92, P = 0.097, pooled results: OR = 2.64, P = 1.4 × 10(-3); NIPA1: OR = 3.23, P = 0.041, pooled results: OR = 6.20, P = 2.2 × 10(-5)). Our results highlight DPP6 and NIPA1 as candidates for more in-depth studies. Unlike other complex neurological and psychiatric traits, rare CNVs with high effect size do not play a major role in ALS pathogenesis.
Human Molecular Genetics 10/2010; 19(20):4091-9. · 7.64 Impact Factor
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Ewout J N Groen,
Michael A van Es,
Paul W J van Vught,
Wim G M Spliet,
Jooyeon van Engelen-Lee,
Marianne de Visser,
John H J Wokke,
Helenius J Schelhaas,
Roel A Ophoff,
Katsumi Fumoto,
R Jeroen Pasterkamp,
Dennis Dooijes,
Edwin Cuppen,
Jan H Veldink,
Leonard H van den Berg
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ABSTRACT: To assess the frequency of FUS mutations in 52 probands with familial amyotrophic lateral sclerosis (FALS) and to provide careful documentation of clinical characteristics.
FUS mutation analysis was performed using capillary sequencing on all coding regions of the gene in a cohort of patients with FALS. The clinical characteristics of patients carrying FUS mutations were described in detail.
Three university hospitals in the Netherlands (referral centers for neuromuscular diseases).
Fifty-two probands from unrelated pedigrees with FALS.
FUS mutations.
We identified 3 mutations in 4 of 52 probands. We observed 2 previously identified mutations (p.Arg521Cys and p.Arg521His) and 1 novel mutation (p.Ser462Phe). In addition, a p.Gln210His polymorphism was identified in 1 proband and 3 healthy control subjects. Phenotypic analysis demonstrated that patients may lack upper motor neuron signs, which was confirmed at autopsy, and disease survival was short (<36 months for 8 of 10 patients).
We discovered FUS mutations in Dutch patients with FALS and the occurrence of benign variations in the gene. Therefore, caution is warranted when interpreting results in a clinical setting. Although the phenotype associated with FUS mutations is variable, most patients predominantly demonstrate loss of lower motor neurons and have short disease survival.
Archives of neurology 02/2010; 67(2):224-30. · 6.31 Impact Factor
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Michael A van Es,
Jan H Veldink,
Christiaan G J Saris,
Hylke M Blauw,
Paul W J van Vught,
Anna Birve,
Robin Lemmens,
Helenius J Schelhaas, Ewout J N Groen,
Mark H B Huisman, [......],
Judith Melki,
P Nigel Leigh,
Christopher E Shaw,
John E Landers,
Ammar Al-Chalabi,
Robert H Brown,
Wim Robberecht,
Peter M Andersen,
Roel A Ophoff,
Leonard H van den Berg
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ABSTRACT: We conducted a genome-wide association study among 2,323 individuals with sporadic amyotrophic lateral sclerosis (ALS) and 9,013 control subjects and evaluated all SNPs with
Nature Genetics 09/2009; 41(10):1083-1087. · 35.53 Impact Factor
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Michael A van Es,
Jan H Veldink,
Christiaan G J Saris,
Hylke M Blauw,
Paul W J van Vught,
Anna Birve,
Robin Lemmens,
Helenius J Schelhaas, Ewout J N Groen,
Mark H B Huisman, [......],
Judith Melki,
P Nigel Leigh,
Christopher E Shaw,
John E Landers,
Ammar Al-Chalabi,
Robert H Brown,
Wim Robberecht,
Peter M Andersen,
Roel A Ophoff,
Leonard H van den Berg
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ABSTRACT: We conducted a genome-wide association study among 2,323 individuals with sporadic amyotrophic lateral sclerosis (ALS) and 9,013 control subjects and evaluated all SNPs with P < 1.0 x 10(-4) in a second, independent cohort of 2,532 affected individuals and 5,940 controls. Analysis of the genome-wide data revealed genome-wide significance for one SNP, rs12608932, with P = 1.30 x 10(-9). This SNP showed robust replication in the second cohort (P = 1.86 x 10(-6)), and a combined analysis over the two stages yielded P = 2.53 x 10(-14). The rs12608932 SNP is located at 19p13.3 and maps to a haplotype block within the boundaries of UNC13A, which regulates the release of neurotransmitters such as glutamate at neuromuscular synapses. Follow-up of additional SNPs showed genome-wide significance for two further SNPs (rs2814707, with P = 7.45 x 10(-9), and rs3849942, with P = 1.01 x 10(-8)) in the combined analysis of both stages. These SNPs are located at chromosome 9p21.2, in a linkage region for familial ALS with frontotemporal dementia found previously in several large pedigrees.
Nature Genetics 09/2009; 41(10):1083-7. · 35.53 Impact Factor
