215th ENMC International Workshop VCP-related multi-system proteinopathy (IBMPFD) 13–15 November 2015, Heemskerk, The Netherlands

Evangelista, Teresinha; Weihl, Conrad C.; Kimonis, Virginia; Lochmüller, Hanns

doi:10.1016/j.nmd.2016.05.017

Cited by 41 publications

(97 citation statements)

References 96 publications

(82 reference statements)

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“…Out of more than 20 different disease sites that have been reported to date in humans (Darvish et al, 2004; Mehta et al, 2013; Evangelista et al, 2016), 7 have been chosen for NMR analysis, Figure 2A. These include NTD residues R95 and R155 at the NTD-D1 interface, R191 and L198 in the NTD-D1 linker and the NTD-D1 interfacial residues A232, T262 and N387 in D1.…”

Section: Resultsmentioning

confidence: 99%

“…To date over 40 different IBMPFD disease mutations have been identified in 22 different positions throughout ND1Lp97 (Evangelista et al, 2016), of which 7 representative sites were studied here. From our dynamics studies a picture emerges whereby the NTDs of p97-ADP interconvert between up/down conformations that can be modulated by IBMPFD disease mutations.…”

Section: Discussionmentioning

confidence: 99%

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A Dynamic molecular basis for malfunction in disease mutants of p97/VCP

Schuetz

Kay

2016

eLife

111

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p97/VCP is an essential, abundant AAA+ ATPase that is conserved throughout eukaryotes, with central functions in diverse processes ranging from protein degradation to DNA damage repair and membrane fusion. p97 has been implicated in the etiology of degenerative diseases and in cancer. Using Nuclear Magnetic Resonance spectroscopy we reveal how disease-causing mutations in p97 deregulate dynamics of the N-terminal domain that binds adaptor proteins involved in controlling p97 function. Our results provide a molecular basis for understanding how malfunction occurs whereby mutations shift the ADP-bound form of the enzyme towards an ATP-like state in a manner that correlates with disease severity. This deregulation interferes with the two-pronged binding of an adaptor that affects p97 function in lysosomal degradation of substrates. Subtle structural changes propagate from mutation sites to regions distal in space, defining allosteric networks that facilitate inter-domain communication, with potential implications for modulation of enzyme activity by drug molecules.DOI: http://dx.doi.org/10.7554/eLife.20143.001

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Dynamic molecular basis for malfunction in disease mutants of p97/VCP

Schuetz

Kay

2016

eLife

111

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show abstract

Section: Discussionmentioning

confidence: 99%

“…Rare variants in the VCP gene may be more clinically important than is usually the case with other genes, because the protein appears to be intolerant to loss of function and missense mutations . For example, the I27V missense variant with an allele frequency of 0.05%, has been described several times as being potentially pathogenic and has been identified in PD . Moreover, immunohistochemical studies have demonstrated the presence of VCP in the peripheral portion of Lewy bodies, in Marinesco bodies that are seen in the nuclei of aged nigral neurons and in Lewy neurites in neuronal processes in PD, suggesting that the protein could be involved in the formation or degradation of various neuronal inclusions in neurodegenerative diseases such as a‐synucleinopathies …”

Section: Discussionmentioning

confidence: 99%

“…Valosin‐containing protein (VCP) is a hexameric AAA + ‐type ATPase with a central role in various cellular activities, including cell cycle control, membrane fusion and the ubiquitin‐proteasome degradation pathway. Mutations in the VCP gene have been associated with a variety of disorders, including distal myopathy with rimmed vacuoles, Paget's disease of the bone, frontotemporal dementia, amyotrophic lateral sclerosis (ALS), Charcot–Marie–Tooth disease type 2, cardiomyopathy and Parkinson's disease (PD) . Meige syndrome is a type of cranial dystonia with blepharospasm and oromandibular dystonia sometimes associated with complex movement of lower facial muscles, mouth, jaw, tongue, pharyngeal, and cervical muscles .…”

Section: Introductionmentioning

confidence: 99%

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Valosin‐containing protein‐related myopathy and Meige syndrome: Just a coincidence or not?

et al. 2019

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Provisional practice recommendation for the management of myopathy in VCP‐associated multisystem proteinopathy

Roy

Peck²,

Evangelista

et al. 2023

Ann Clin Transl Neurol

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Valosin-containing protein (VCP)-associated multisystem proteinopathy (MSP) is a rare genetic disorder with abnormalities in the autophagy pathway leading to various combinations of myopathy, bone diseases, and neurodegeneration. Ninety percent of patients with VCP-associated MSP have myopathy, but there is no consensus-based guideline. The goal of this working group was to develop a best practice set of provisional recommendations for VCP myopathy which can be easily implemented across the globe. As an initiative by Cure VCP Disease Inc., a patient advocacy organization, an online survey was initially conducted to identify the practice gaps in VCP myopathy. All prior published literature on VCP myopathy was reviewed to better understand the different aspects of management of VCP myopathy, and several working group sessions were conducted involving international experts to develop this provisional recommendation. VCP myopathy has a heterogeneous clinical phenotype and should be considered in patients with limb-girdle muscular dystrophy phenotype, or any myopathy with an autosomal dominant pattern of inheritance. Genetic testing is the only definitive way to diagnose VCP myopathy, and single-variant testing in the case of a known familial VCP variant, or multigene panel sequencing in undifferentiated cases can be considered. Muscle biopsy is important in cases of diagnostic uncertainty or lack of a definitive pathogenic genetic variant since rimmed vacuoles (present in ~40% cases) are considered a hallmark of VCP myopathy. Electrodiagnostic studies and 686

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215th ENMC International Workshop VCP-related multi-system proteinopathy (IBMPFD) 13–15 November 2015, Heemskerk, The Netherlands

Cited by 41 publications

References 96 publications

A Dynamic molecular basis for malfunction in disease mutants of p97/VCP

A Dynamic molecular basis for malfunction in disease mutants of p97/VCP

Valosin‐containing protein‐related myopathy and Meige syndrome: Just a coincidence or not?

Provisional practice recommendation for the management of myopathy in VCP‐associated multisystem proteinopathy

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