Inclusion body myopathy and Paget disease is linked to a novel mutation in the
            <i>VCP</i>
            gene

Haubenberger, Dietrich; Bittner, Reginald E.; Rauch-Shorny, Sigrid; Zimprich, Friedrich; Mannhalter, Christine; Wagner, Ludwig; Mineva, I.; Vass, Karl; Auff, Eduard; Zimprich, Alexander

doi:10.1212/01.wnl.0000180407.15369.92

Cited by 104 publications

(75 citation statements)

References 8 publications

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“…As such, the term IBMPFD seems overly restrictive. IBMPFD-ALS is similarly cumbersome and probably inadequate given the rare, but well-described, involvement of other organ systems including cardiac, 13 hepatic, 14 visual, 14 auditory, 15 sensory, 16 and autonomic systems, 17 as well as emerging evidence that mutations in VCP may infrequently manifest as Parkinson disease, [18][19][20] hereditary spastic paraplegia, 21 or cerebellar ataxia. 22 Instead, we propose to change the name of this syndrome from IBMPFD to multisystem proteinopathy (MSP), using the nomenclature of MSP1 for disease caused by mutations in VCP, MSP2 when due to mutations in HNRNPA2B1, 5 MSP3 when caused by HNRNPA1 mutations, 5 and MSP4 when due to mutations in the as yet unidentified gene.…”

Section: Resultsmentioning

confidence: 99%

Motor neuron involvement in multisystem proteinopathy

et al. 2013

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Objective: To explore the putative connection between inclusion body myopathy, Paget disease, frontotemporal dementia (IBMPFD) and motor neuron disease (MND).Methods: Clinical, genetic, and EMG characterization of 17 patients from 8 IBMPFD families.Results: Limb weakness was the most common clinical manifestation (present in 15 patients, median onset age 38 years, range 25-52), with unequivocal evidence of upper motor neuron dysfunction in 3. EMG, abnormal in all 17, was purely neurogenic in 4, purely myopathic in 6, and mixed neurogenic/myopathic in 7. Cognitive/behavioral impairment was detected in at least 8. Mutations in VCP (R155H, R159G, R155C) were identified in 6 families, and in hnRNPA2B1 (D290V) in another family. The genetic cause in the eighth family has not yet been identified. Conclusion:Mutations in at least 4 genes may cause IBMPFD, and its phenotypic spectrum extends beyond IBM, Paget disease, and frontotemporal dementia (FTD). Weakness, the most common and disabling manifestation, may be caused by muscle disease or MND. The acronym IBMPFD is, therefore, insufficient to describe disorders due to VCP mutations or other recently identified IBMPFD-associated genes. Instead, we favor the descriptor multisystem proteinopathy (MSP), which encompasses both the extended clinical phenotype and the previously described prominent pathologic feature of protein aggregation in affected tissues. The nomenclature MSP1, MSP2, and MSP3 may be used for VCP-, HNRNPA2B1-, and HNRNPA1-associated disease, respectively. Genetic defects in MSP implicate a range of biological mechanisms including RNA processing and protein homeostasis, both with potential relevance to the pathobiology of more common MNDs such as amyotrophic lateral sclerosis (ALS) and providing an additional link between ALS and FTD. Neurology Inclusion body myopathy (IBM) with Paget disease and frontotemporal dementia (IBMPFD) is a rare multisystem degenerative disorder named after the organ systems originally recognized to be affected-muscle, bone, and brain. Mutations in the valosin-containing protein (VCP) gene were the first identified cause of IBMPFD, 1,2 but reports of families without linkage to chromosome 9 established the genetic heterogeneity of the disorder.3,4 It has recently emerged that mutations in the HNRNPA2B1 (chromosome 7) and HNRNPA1 (chromosome 12) genes account for some families with IBMPFD. 5 We first raised the possibility of a connection between IBMPFD and amyotrophic lateral sclerosis (ALS) after mutations in the VCP gene were identified in patients with familial ALS.6 Interestingly, the original report of IBMPFD 7 almost 30 years ago described it as a "familial disorder of combined lower motor neuron degeneration and skeletal disorganization"; the presence of fasciculations, EMG evidence of chronic reinnervation, and muscle biopsy showing grouped atrophy all pointing toward a primarily neurogenic process. This family was subsequently found to have an R155Q mutation in the VCP gene. 8 Since the original description, var...

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Section: Resultsmentioning

confidence: 99%

Motor neuron involvement in multisystem proteinopathy

et al. 2013

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“…The mutated amino acids include R93C, R95C R95G, R155C, R155H, R155P, G157R, R159H, R159C, R191Q, L198W, A232E, T262A, and N387H (35)(36)(37)(38)(39). Except for Thr-262, all other mutations were not observed at serine, threonine, tyrosine, or lysine.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, about a dozen missense mutations in the human VCP gene have been identified as causing inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD), an autosomal dominant inherited disease that affects multiple tissues, including muscle, bone, and the cerebral cortex (35)(36)(37)(38)(39). Although it is now known that VCP is critically involved in the pathogenesis of several types of human disorders, including neurodegeneration, the detailed molecular mechanisms mediated by VCP in neurodegenerative disorders remain to be elucidated.…”

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confidence: 99%

Valosin-containing Protein (VCP) in Novel Feedback Machinery between Abnormal Protein Accumulation and Transcriptional Suppression

Koike

Fukushi

Ichinohe

et al. 2010

Journal of Biological Chemistry

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Abnormal protein accumulation is often observed in human neurodegenerative disorders such as polyglutamine diseases and Parkinson disease. Genetic and biochemical analyses indicate that valosin-containing protein (VCP) is a crucial molecule in the pathogenesis of human neurodegenerative disorders. We report here that VCP was specifically modified in neuronal cells with abnormal protein accumulation; this modification caused the translocation of VCP into the nucleus. Modification-mimic forms of VCP induced transcriptional suppression with deacetylation of core histones, leading to cell atrophy and the decrease of de novo protein synthesis. Preventing VCP nuclear translocation in polyglutamine-expressing neuronal cells and Drosophila eyes mitigated neurite retraction and eye degenerations, respectively, concomitant with the recovery of core histone acetylation. This represents a novel feedback mechanism that regulates abnormal protein levels in the cytoplasm during physiological processes, as well as in pathological conditions such as abnormal protein accumulation in neurodegenerations.

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“…[2][3][4][5][6][7][8][9][10][11][12][13][14][15] Recently, a study using whole exome sequencing identified a VCP mutation (p.R191Q) in a family in which some individuals presented clinically with amyotrophic lateral sclerosis (ALS). The frequency of VCP mutations in familial ALS (FALS) patients is estimated at approximately 2%.…”

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confidence: 99%

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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Inclusion body myopathy and Paget disease is linked to a novel mutation in the VCP gene

Cited by 104 publications

References 8 publications

Motor neuron involvement in multisystem proteinopathy

Motor neuron involvement in multisystem proteinopathy

Valosin-containing Protein (VCP) in Novel Feedback Machinery between Abnormal Protein Accumulation and Transcriptional Suppression

Novel mutation in VCP gene causes atypical amyotrophic lateral sclerosis

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