VCP mutations in familial and sporadic amyotrophic lateral sclerosis

Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
Neurobiology of aging (Impact Factor: 5.01). 11/2011; 33(4):837.e7-13. DOI: 10.1016/j.neurobiolaging.2011.10.006
Source: PubMed


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.

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    • "c Dejesus et al. [21] (1 SALS for All Exons + 112 SALS for Exon 5; 407 Controls for I151V). d Koppers et al. [22] (93 FALS from 80 Families for all Exons; 377 SALS for all Exons + 377 SALS for Exon 4 and 5+ 58 SALS-FTD for All Exons; 713 Controls for R159H, 685 for T330T, 674 for L414L and I479I, 662 for A528A, 594 for L661L and 695 for the rest of Exons). e Tiloca et al. [23] (166 FALS+ 14 FALS/FTD for all Exons, 285 Controls for Q568Q). "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease causing loss of motor neurons in the spinal cord, brain stem and cerebral cortex. Mutations in the Valosin containing protein (VCP) gene have recently been identified in Familial ALS (FALS) patients, accounting for ~1% of all FALS cases. In order to study the frequency of VCP mutations in UK FALS patients, we have screened the exons known to harbour mutations together with 3' and 5' UTR sequences. No coding changes were identified in this UK cohort and no common polymorphisms were associated with FALS. However, we identified an imperfect hexanucleotide expansion (8 repeats), c.-221_-220insCTGCCACTGCCACTGCCG, in the 5'UTR of a FALS case and a 7-repeat hexanucleotide repeat in a Sporadic ALS case (SALS) that were not present in 219 UK controls. Subsequent screening of sequence data from 1844 controls (1000 genomes Phase 3) revealed the presence of the 7-repeat (0.3%) and a single individual with an 8-repeat containing a homogeneous insert [CTGCCG]3 but no individuals with the heterogeneous insert found in FALS ([CTGCCA]2[CTGCCG]). Two novel single base pair substitutions, c.-360G>C and c.2421+94C>T, were found in FALS cases in the 5' and 3' UTRs respectively. The hexanucleotide expansion and c.-360G>C were predicted to be pathogenic and were found in FALS cases harbouring C9orf72 expansions. The SALS case with a 7 repeat lacked a C9orf72 expansion. We conclude that VCP mutations are not a major cause of FALS in the UK population although novel rare variations in the 5' UTR of the VCP gene may be pathogenic. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of the Neurological Sciences 01/2015; 349(1-2). DOI:10.1016/j.jns.2015.01.021 · 2.47 Impact Factor
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    • "The TARDBP gene encoding TDP-43 lies on chromosome 1p36.2. The TDP-43 protein con‐ sists of 414 amino acids and is highly conserved among species [7]. The expression pattern is almost ubiquitous with high levels during development. "

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    • "Accumulation of mis-folded or abnormal proteins into compact or skein-like ubiquitinpositive inclusions is a hallmark of ALS. TDP-43 has been shown to be a major constituent of these inclusions and is a common feature for both fALS and sALS (Neumann et al. 2006; Sreedharan et al. 2008). Normally, TDP-43 is predominantly present in the nucleus, but in the presence of TDP-43-positive inclusions, loss of nuclear TDP-43 is seen (Neumann et al. 2006). "
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    ABSTRACT: This review article is focused on the research progress made utilizing the wobbler mouse as animal model for human motor neuron diseases, especially the amyotrophic lateral sclerosis (ALS). The wobbler mouse develops progressive degeneration of upper and lower motor neurons and shows striking similarities to ALS. The cellular effects of the wobbler mutation, cellular transport defects, neurofilament aggregation, neuronal hyperexcitability and neuroinflammation closely resemble human ALS. Now, 57 years after the first report on the wobbler mouse we summarize the progress made in understanding the disease mechanism and testing various therapeutic approaches and discuss the relevance of these advances for human ALS. The identification of the causative mutation linking the wobbler mutation to a vesicle transport factor and the research focussed on the cellular basis and the therapeutic treatment of the wobbler motor neuron degeneration has shed new light on the molecular pathology of the disease and might contribute to the understanding the complexity of ALS.
    MGG Molecular & General Genetics 03/2013; 288(5-6). DOI:10.1007/s00438-013-0741-0 · 2.73 Impact Factor
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