Article

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: 5.94). 11/2011; 33(4):837.e7-13. DOI: 10.1016/j.neurobiolaging.2011.10.006
Source: PubMed

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.

0 Bookmarks
 · 
167 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Considerable progress has been made in unraveling the genetic etiology of amyotrophic lateral sclerosis (ALS), the most common form of adult-onset motor neuron disease and the third most common neurodegenerative disease overall. Here we review genes implicated in the pathogenesis of motor neuron degeneration and how this new information is changing the way we think about this fatal disorder. Specifically, we summarize current literature of the major genes underlying ALS, SOD1, TARDBP, FUS, OPTN, VCP, UBQLN2, C9ORF72 and PFN1, and evaluate the information being gleaned from genome-wide association studies. We also outline emerging themes in ALS research, such as next-generation sequencing approaches to identify de novo mutations, the genetic convergence of familial and sporadic ALS, the proposed oligogenic basis for the disease, and how each new genetic discovery is broadening the phenotype associated with the clinical entity we know as ALS.
    Nature Neuroscience 01/2014; 17(1):17-23. · 15.25 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The GGGGCC repeat expansion in the C9orf72 gene was recently identified as a major cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in white populations. To estimate the frequency of hexanucleotide repeats in patients with ALS and FTD from mainland China, we screened for C9orf72 in a cohort of 128 patients and 150 control subjects using the repeat-primed polymerase chain reaction method. We observed pathogenic repeat expansions in a family with ALS-FTD and in a patient with sporadic FTD. In the family with ALS-FTD, the proband and the 2 asymptomatic siblings exhibited C9orf72 repeat expansions, and the clinical feature of the proband was characterized by pure motor syndrome with no cognitive impairment. The patient with sporadic FTD presented primarily with deteriorating behavior and mental status. Genotype analysis revealed that the proband shared the previously reported 20-single nucleotide polymorphism risk haplotype, whereas the patient with sporadic FTD carried all single nucleotide polymorphisms except rs2814707-A. To our knowledge, this study is the first to report 2 C9orf72 mutation patients in mainland China, and they shared the similar risk haplotype identified in white populations, suggesting that ALS and FTD associated with C9orf72 mutation was probably derived from a single founder.
    Neurobiology of aging 10/2013; · 5.94 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective Amyotrophic lateral sclerosis (ALS) is associated with frontotemporal dementia (FTD) in 14% of cases. Five percent report a family history of ALS, and other ALS patients report a family history of other neurodegenerative diseases. The objective of this study was to conduct a family aggregation study of ALS, and neurodegenerative and neuropsychiatric conditions in ALS kindreds and matched healthy controls. The aim was to determine the true rate of familial ALS and the recurrence risk of ALS in family members, and to identify kindreds with increased aggregation of neurodegenerative and neuropsychiatric disease in the context of the recently described expanded hexanucleotide repeat in C9orf72. MethodsA prospective, population-based, case–control family aggregation study was conducted. Family history information was collected through questionnaires and interviews from ALS patients and matched controls. Cause of death was verified with death certification. The recurrence rate of ALS and the risk in family members of other neurodegenerative and neuropsychiatric disease was calculated using the relative risk (lambda) and cumulative risk using Kaplan–Meier analysis. ResultsMedical histories from 9,684 first- and second-degree relatives of 172 ALS probands and 192 controls were obtained. Cause of death was verified in 2,494 cases. Sixteen percent (n = 27) of ALS patients had a family history of ALS. The lifetime hazard ratio (HR) of developing ALS among first- and second-degree relatives was 34.3 (p < 0.0001) in relatives of ALS patients with the C9orf72 repeat expansion, and 2.3 (p = 0.019) in relatives of ALS patients without the expansion. The relatives of ALS patients also had an increased HR of developing a psychotic illness (HR = 4.7, p = 0.004, 95% confidence interval [CI] = 1.6–12.3) and of suicide (HR = 5.6, p < 0.0001, 95% CI = 2.4–12.9) InterpretationThe true rate of familial ALS in Ireland is 16%. There is an overlap between ALS, FTD, and neuropsychiatric disease that is pronounced in kindreds with the C9orf72 repeat expansion, but is also present in kindreds of those without the C9orf72 expanded repeat. Ann Neurol 2013;74:699–708
    Annals of Neurology 11/2013; 74(5). · 11.19 Impact Factor