VCP mutations in familial and sporadic amyotrophic lateral sclerosis

Koppers, Max; Blitterswijk, Marka van; Vlam, Lotte; Rowicka, Paulina A.; Vught, Paul W.J. van; Groen, Ewout J N; Spliet, Wim G.M.; Engelen-Lee, Joo-Yeon; Schelhaas, Helenius J.; Visser, Marjolein; Kooi, Anneke J. van der; Pol, W‐Ludo van der; Pasterkamp, R. Jeroen; Veldink, Jan H.; Berg, Leonard H van den

doi:10.1016/j.neurobiolaging.2011.10.006

Cited by 114 publications

(90 citation statements)

References 28 publications

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“…Two of these mutations (R159C and R155C) have not previously been described in ALS, in contrast with R155H, R191Q, and I114V. 16,22 Each of these mutations was shown to comigrate with the disease in our families, with 2 exceptions: R191Q (FALS385) and I114V (FALS354). It is quite likely that R191Q can cause ALS, given that it was recently reported to comigrate with ALS within an Italian family with ALS.…”

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confidence: 57%

“…16 In contrast, I114V was identified in the proband in FALS354, whose affected parent died of ALS and whose unaffected parent carried the I114V mutation but was asymptomatic. It is possible that this is a nonpathogenic polymorphism as previously suggested 22 although, as noted above, it is not found in extensive databases covering several thousand control alleles. Lastly, R159C mutation was identified in 2 affected individuals (III:1 and III:4) in FALS007 but also in subject III:3, for whom no evidence of disease has been reported at age 68 years, which shows an incomplete penetrance for this mutation in this family.…”

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confidence: 89%

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Novel mutation in VCP gene causes atypical amyotrophic lateral sclerosis

González-Pérez

Cirulli²,

Drory³

et al. 2012

Neurology

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Objective: To identify the genetic variant that causes autosomal dominantly inherited motor neuron disease in a 4-generation Israeli-Arab family using genetic linkage and whole exome sequencing.Methods: Genetic linkage analysis was performed in this family using Illumina single nucleotide polymorphism chips. Whole exome sequencing was then undertaken on DNA samples from 2 affected family members using an Illumina 2000 HiSeq platform in pursuit of potentially pathogenic genetic variants that comigrate with the disease in this pedigree. Variants meeting these criteria were then screened in all affected individuals.Results: A novel mutation (p.R191G) in the valosin-containing protein (VCP) gene was identified in the index family. Direct sequencing of the VCP gene in a panel of DNA from 274 unrelated individuals with familial amyotrophic lateral sclerosis (FALS) revealed 5 additional mutations. Among them, 2 were previously identified in pedigrees with a constellation of inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD) and in FALS, and 2 other mutations (p.R159C and p.R155C) in IBMPFD alone. We did not detect VCP gene mutations in DNA from 178 cases of sporadic amyotrophic lateral sclerosis. Conclusions:We report a novel VCP mutation identified in an amyotrophic lateral sclerosis family (p.R191G) with atypical clinical features. In our experience, VCP mutations arise in approximately 1.5% of FALS cases. Our study supports the view that motor neuron disease is part of the clinical spectrum of VCP-associated disease.

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confidence: 57%

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confidence: 89%

Novel mutation in VCP gene causes atypical amyotrophic lateral sclerosis

González-Pérez

Cirulli²,

Drory³

et al. 2012

Neurology

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“…Next generation sequencing of Italian and US families identified VCP mutation as a cause of familial ALS, with other members of the affected kindreds showing other phenotypic manifestations of VCP mutation [52], although the ALS phenotype appears to be a very rare manifestation of VCP mutation with a limited contribution to ALS risk [26,57,108,126].…”

Section: Vcpmentioning

confidence: 99%

The genetics and neuropathology of amyotrophic lateral sclerosis

et al. 2012

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons leading to death from respiratory failure within about 3 years of symptom onset. A family history of ALS is obtained in about 5 % but the distinction between familial and apparently sporadic ALS is artificial and genetic factors play a role in all types. For several years, only one gene was known to have a role in ALS pathogenesis, SOD1. In the last few years there has been a rapid advance in our genetic knowledge of the causes of ALS, and the relationship of the genetic subtypes with pathological subtypes and clinical phenotype. Mutations in the gene for TDP-43 protein, TARDBP, highlight this, with pathology mimicking closely that found in other types of ALS, and a phenotypic spectrum that includes frontotemporal dementia. Mutations in the FUS gene, closely related to TDP-43, lead to a similar clinical phenotype but distinct pathology, so that the three pathological groups represented by SOD1, TARDBP, and FUS are distinct. In this review, we explore the genetic architecture of ALS, highlight some of the genes implicated in pathogenesis, and describe their phenotypic range and overlap with other diseases.

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“…Mutations in ubiquilin2 (UBQLN2), which encodes an ubiquitin-like protein, cause dominantly inherited chromosome X-linked ALS/FTD [50]. However, several studies failed to confirm the association of VCP [51][52][53][54][55][56] and UBQLN2 [57][58][59][60][61][62][63][64][65][66] with ALS/FTD, suggesting that mutations in these genes are not a common cause of ALS/FTD globally. Conversely, the presence of sequestosome (SQSTM1) mutations in 1-3.5% of ALS/FTD patients has been confirmed [67][68][69][70][71][72][73][74][75].…”

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confidence: 99%