Novel valosin-containing protein mutations associated with multisystem proteinopathy

Al-Tahan, Sejad; Al-Obeidi, Ebaa; Yoshioka, Hiroshi; Lakatos, Anita; Weiss, Lan; Grafe, Marjorie R.; Palmio, Johanna; Wicklund, M.; Harati, Yadollah; Omizo, Molly; Udd, Bjarne; Kimonis, Virginia

doi:10.1016/j.nmd.2018.04.007

Cited by 20 publications

(23 citation statements)

References 72 publications

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“…In the original report, six different disease-causing mutations in VCP were identified. However, at the time of writing, 45 different pathogenic VCP mutations have now been identified in patients with MSP (Table 4) [58]. Whilst mutations have been identified throughout the gene, the majority are situated in exons 3-5 which encode the N-terminal domain which is involved in ubiquitin binding and binding of co-factors essential for VCP's function.…”

Section: Geneticsmentioning

confidence: 99%

Rare Inherited forms of Paget’s Disease and Related Syndromes

Ralston

Taylor

2019

Calcif Tissue Int

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Several rare inherited disorders have been described that show phenotypic overlap with Paget's disease of bone (PDB) and in which PDB is a component of a multisystem disorder affecting muscle and the central nervous system. These conditions are the subject of this review article. Insertion mutations within exon 1 of the TNFRSF11A gene, encoding the Receptor Activator of Nuclear Factor Kappa B (RANK) cause severe, PDB-like disorders including Familial Expansile Osteolysis, Early-onset familial PDB and Expansile Skeletal Flyperphosphatasia. The mutations interfere with normal processing of RANK and cause osteoclast activation through activation of nuclear factor kappa B (NFκB) independent of RANK Ligand stimulation. Recessive, loss of function mutations in the TNFRSF11B gene, which encodes osteoprotegerin, cause juvenile PDB and here the bone disease is due to unopposed activation of RANK by RANKL. Multisystem proteinopathy is a disorder characterised by myopathy and neurodegeneration in which PDB is often an integral component. It may be caused by mutations in several genes including VCP, HNRNPA1, HNRNPA2B1, SQSTM1, MATR3, and TIA1, some of which are involved in classical PDB. The mechanisms of osteoclast activation in these conditions is less clear but may involve NFκB activation through sequestration of IκB. The evidence base for management of these disorders is somewhat limited due to the fact they are extremely rare. Bisphosphonates have been successfully used to gain control of elevated bone remodeling but as yet, no effective treatment exists for the treatment of the muscle and neurological manifestations of MSP syndromes.

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Section: Geneticsmentioning

confidence: 99%

Rare Inherited forms of Paget’s Disease and Related Syndromes

Ralston

Taylor

2019

Calcif Tissue Int

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“…Many studied reported that more than 50 missense mutations in gene coding VCP is causative in many neurodegenerative diseases characterised by ALS, FTD, IBM, CMT2Y, and PBD ( Al-Tahan et al, 2018 ). Approximately 9% of patients with VCP mutations had ALS phenotype, 4% with Parkinson's disease, and 2% has been diagnosed with Alzheimer's ( Al-Obeidi et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Protein network analysis to prioritize key genes in amyotrophic lateral sclerosis

Kumar

Haider

2022

IBRO Neuroscience Reports

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Amyotrophic Lateral Sclerosis (ALS) is a fatal disease, progressive nature characterizes by loss of both upper and lower motor neuron functions. One of the major challenge is to understand the mechanism of ALS multifactorial nature. We aimed to explore some key genes related to ALS through bioinformatics methods for its therapeutic intervention. Here, we applied a systems biology approach involving experimentally validated 148 ALS-associated proteins and construct ALS protein-protein interaction network (ALS-PPIN). The network was further statistically analysed and identified bottleneck-hubs. The network is also subjected to identify modules which could have similar functions. The interaction between the modules and bottleneck-hubs provides the functional regulatory role of the ALS mechanism. The ALS-PPIN demonstrated a hierarchical scale-free nature. We identified 17 bottleneck-hubs, in which CDC5L , SNW1, TP53, SOD1, and VCP were the high degree nodes (hubs) in ALS-PPIN. CDC5L was found to control highly cluster modules and play a vital role in the stability of the overall network followed by SNW1 , TP53, SOD1, and VCP . HSPA5 and HSPA8 acting as a common connector for CDC5L and TP53 bottleneck-hubs. The functional and disease association analysis showed ALS has a strong correlation with mRNA processing, protein deubiquitination, and neoplasms, nervous system, immune system disease classes. In the future, biochemical investigation of the observed bottleneck-hubs and their interacting partners could provide a further understanding of their role in the pathophysiology of ALS.

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“…We performed a literature review on the clinical and genetic characteristics of previously reported ALS‐VCP cases (Table S1), 2,4–7,16,23–33 and illustrated mutation sites in VCP associated with ALS, IBMPFD, and other phenotypes (Figure S1). 2–5,7,16,20–86 A total of 59 cases have been reported, with the disease typically developing in patients in their 40s–50s, and 14 of the 33 cases survived without artificial respiration for more than five years. Given that the epidemiological studies of general ALS suggest that the peak prevalence is observed in patients in their 70s–80s, and that the median survival time is two to four years, 87–91 the ALS‐VCP cases might be characterized by relatively early disease onset and slow disease progression.…”

Section: Discussionmentioning

confidence: 99%

An autopsy report of a familial amyotrophic lateral sclerosis case carrying VCP Arg487His mutation with a unique TDP‐43 proteinopathy

Matsubara

Izumi

Oda³

et al. 2021

Neuropathology

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We here report an autopsy case of familial amyotrophic lateral sclerosis (ALS) with p.Arg487His mutation in the valosin-containing protein (VCP) gene (VCP), in which upper motor neurons (UMNs) were predominantly involved. Moreover, our patient developed symptoms of frontotemporal dementia later in life and pathologically exhibited numerous phosphorylated transactivation response DNAbinding protein of 43 kDa (p-TDP-43)-positive neuronal cytoplasmic inclusions and short dystrophic neurites with a few lentiform neuronal intranuclear inclusions, sharing the features of frontotemporal lobar degeneration with TDP-43 pathology type A pattern. A review of previous reports of ALS with VCP mutations suggests that our case is unique in terms of its UMN-predominant lesion pattern and distribution of p-TDP-43 pathology. Thus, this case report effectively expands the clinical and pathological phenotype of ALS in patients with a VCP mutation.

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Novel valosin-containing protein mutations associated with multisystem proteinopathy

Cited by 20 publications

References 72 publications

Rare Inherited forms of Paget’s Disease and Related Syndromes

Rare Inherited forms of Paget’s Disease and Related Syndromes

Protein network analysis to prioritize key genes in amyotrophic lateral sclerosis

An autopsy report of a familial amyotrophic lateral sclerosis case carrying VCP Arg487His mutation with a unique TDP‐43 proteinopathy

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