Alternative titles; symbols
HGNC Approved Gene Symbol: VCP
SNOMEDCT: 1187565005;
Cytogenetic location: 9p13.3 Genomic coordinates (GRCh38): 9:35,056,064-35,072,625 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9p13.3 | Charcot-Marie-Tooth disease, type 2Y | 616687 | Autosomal dominant | 3 |
| Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 | 613954 | Autosomal dominant | 3 | |
| Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia 1 | 167320 | Autosomal dominant | 3 |
The VCP gene encodes valosin-containing protein, a ubiquitously expressed multifunctional protein that is a member of the AAA+ (ATPase associated with various activities) protein family. It has been implicated in multiple cellular functions ranging from organelle biogenesis to ubiquitin-dependent protein degradation (summary by Weihl et al., 2009).
Clathrin is a structural protein found in coated pits and vesicles, organelles which are important in membrane trafficking functions such as endocytosis and Golgi sorting. A 100-kD protein, designated valosin-containing protein or VCP by early investigators, is a structural protein complexed with clathrin (see 118960). VCP is the homolog of yeast cdc48p, and is a member of a family that includes putative ATP-binding proteins involved in vesicle transport and fusion, 26S proteasome function, and assembly of peroxisomes (Pleasure et al., 1993). VCP was cloned from the pig (Koller and Brownstein, 1987) and mouse (Egerton et al., 1992). Druck et al. (1995) cloned a portion of the human cDNA.
Cloutier et al. (2013) stated that the deduced 806-amino acid VCP protein contains an N-terminal domain, followed by a linker region, an ATPase domain, a second linker region, a second ATPase domain, and a C-terminal domain. The N-terminal domain consists of a double-psi-barrel superfold and 4-stranded beta barrel, and each ATPase domain consists of Walker A and B motifs and a 4-alpha-helix bundle. VCP is extensively modified by phosphorylation and acetylation, as well as by lysine methylation.
Cryoelectron Microscopy
Banerjee et al. (2016) reported cryoelectron microscopy structures for ADP-bound, full-length, hexameric wildtype p97 in the presence and absence of an allosteric inhibitor at resolutions of 2.3 and 2.4 angstroms, respectively. Banerjee et al. (2016) also reported cryoelectron microscopy structures (at resolutions of approximately 3.3, 3.2, and 3.3 angstroms, respectively) for 3 distinct, coexisting functional states of p97 with occupancies of 0, 1, or 2 molecules of adenosine 5-prime-O-(3-thiotriphosphate) (ATP-gamma-S) per protomer. A large corkscrew-like change in molecular architecture, coupled with upward displacement of the N-terminal domain, is observed only when ATP-gamma-S is bound to both the D1 and D2 domains of the protomer. These cryoelectron microscopy structures established the sequence of nucleotide-driven structural changes in p97 at atomic resolution. They also enabled elucidation of the binding mode of an allosteric small-molecule inhibitor to p97 and illustrated how inhibitor binding at the interface between the D1 and D2 domains prevents propagation of the conformational changes necessary for p97 function.
Twomey et al. (2019) reported cryoelectron microscopy structures of the yeast Cdc48 ATPase in complex with Ufd1 (601754)/Npl4 (606590) and polyubiquitinated substrate. The structures showed that the Cdc48 complex initiates substrate processing by unfolding a ubiquitin molecule. The unfolded ubiquitin molecule binds to Npl4 and projects its N-terminal segment through both hexameric ATPase rings. Pore loops of the second ring form a staircase that acts as a conveyer belt to move the polypeptide through the central pore.
Cooney et al. (2019) reported a 3.7-angstrom-resolution structure of Cdc48 in complex with an adaptor protein and a native substrate. Cdc48 engages substrate by adopting a helical configuration of substrate-binding residues that extends through the central pore of both of the ATPase rings. Cooney et al. (2019) concluded that their findings indicated a unified hand-over-hand mechanism of protein translocation by Cdc48 and other AAA+ ATPases.
Johnson et al. (2010) noted that the VCP gene contains 17 exons.
Druck et al. (1995) used a partial human VCP cDNA to probe a panel of somatic cell hybrid DNAs and mapped the VCP gene to chromosome 9pter-q34.
By database analysis, Hoyle et al. (1997) identified a human expressed sequence tag (EST) that shares 80% identity with the mouse 3-prime untranslated region. They designed primers to this EST and amplified and sequenced a 127-bp product from total human DNA. This product detected 1 fragment only in a HindIII digest of total human DNA, indicating there is only 1 VCP sequence in the human genome. Using the 127-bp sequence to screen a human PAC library, followed by FISH analysis, they mapped the VCP gene to chromosome 9p13-p12. They mapped the mouse Vcp gene to mouse chromosome 4 and found a probable pseudogene on the mouse X chromosome.
The VCP gene maps to chromosome 9p13.3 (Johnson et al., 2010).
Ye et al. (2001) demonstrated that VCP (CDC48 in yeast and p97 in mammals) is required for the export of endoplasmic reticulum (ER) into the cytosol. Whereas CDC48/p97 was known to function in a complex with the cofactor p47 in membrane fusion, Ye et al. (2001) demonstrated that its role in ER protein export requires the interacting partners UFD1 (601754) and NPL4 (606590). The AAA ATPase interacts with substrates at the ER membrane and is needed to release them as polyubiquitinated species into the cytosol.
Zhang et al. (1999) created a substrate-trapping mutant of PTPH1 (176877) that interacted primarily with VCP in vitro but not in cells. A double mutant of PTPH1 had a marked reduction in phosphotyrosine content, specifically trapped VCP in vivo, and recognized the C-terminal tyrosines of VCP. Immunoblot analysis showed that wildtype PTPH1 specifically dephosphorylated VCP. Zhang et al. (1999) concluded that PTPH1 exerts its effects on cell growth through dephosphorylation of VCP and that tyrosine phosphorylation is an important regulator of VCP function.
Watts et al. (2004) summarized that VCP has been associated with several essential cell protein pathways including cell cycle, homotypic membrane fusion, nuclear envelope reconstruction, postmitotic Golgi reassembly, DNA damage response, suppressor of apoptosis, and ubiquitin-dependent protein degradation. Higashiyama et al. (2002) identified a fruit fly VCP loss-of-function mutant as a dominant suppressor of expanded polyglutamine-induced neuronal degeneration. The suppressive effects of the loss-of-function mutant did not seem to result from inhibition of polyglutamine aggregate formation but rather from the degree of loss of VCP function. This suggested that a gene dosage response for VCP expression is essential to its function in expanded polyglutamine-induced neuronal degeneration. In support of this idea, transgenic fruit flies in which VCP levels were elevated experienced severe apoptotic cell death, whereas homozygous VCP loss-of-function mutants were embryonic lethal.
Ye et al. (2004) found that VIMP (607918) recruits the p97 ATPase (VCP) and its cofactor, the UFD1/NPL4 complex, to the ER for retrotranslocation of misfolded proteins into the cytosol. They noted that all pathways of retrotranslocation appear to require the function of the p97 ATPase complex, which may provide the general driving force for the movement of proteins into the cytosol.
Using a library of endoribonuclease-prepared short interfering RNAs (esiRNAs), Kittler et al. (2004) identified 37 genes required for cell division, one of which was VCP. These 37 genes included several splicing factors for which knockdown generates mitotic spindle defects. In addition, a putative nuclear-export terminator was found to speed up cell proliferation and mitotic progression after knockdown.
Uchiyama et al. (2006) found that rodent p37 (610686) formed a complex with p97 in cytosol and localized to Golgi and ER. Small interfering RNA experiments in HeLa cells revealed that p37 was required for Golgi and ER biogenesis. Injection of anti-p37 antibodies into HeLa cells at different stages of the cell cycle showed that p37 was involved in Golgi and ER maintenance during interphase and in their reassembly at the end of mitosis. In an in vitro Golgi reassembly assay, the p97/p37 complex showed membrane fusion activity that required p115 (603344)-GM130 (GOLGA2; 602580) tethering and SNARE GS15 (BET1L; 615417). VCIP135 (VCPIP1) was also required, but its deubiquitinating activity was unnecessary for p97/p37-mediated activities.
Ramadan et al. (2007) showed that p97 stimulates nucleus reformation by inactivating the chromatin-associated kinase Aurora B (604970). During mitosis, Aurora B inhibits nucleus reformation by preventing chromosome decondensation and formation of the nuclear envelope membrane. During exit from mitosis, p97 binds to Aurora B after its ubiquitylation and extracts it from chromatin. This leads to inactivation of Aurora B on chromatin, thus allowing chromatin decondensation and nuclear envelope formation. Ramadan et al. (2007) concluded that their data revealed an essential pathway that regulates reformation of the nucleus after mitosis and defined ubiquitin-dependent protein extraction as a common mechanism of Cdc48/p97 activity also during nucleus formation.
Using a chromatin immunoprecipitation assay, Zhang et al. (2007) showed that ELF2 (619798) bound specifically to the 5-prime-flanking sequence of the VCP gene in MCF7 human breast cancer cells. Knockdown of ELF2 in MCF7 cells reduced VCP expression and cell viability. Immunohistochemical analysis revealed that ELF2 expression correlated with VCP expression and proliferative activity of cells in breast cancer specimens.
Using human cell lines, Mueller et al. (2008) identified several components of a protein complex required for retrotranslocation or dislocation of misfolded proteins from the ER lumen to the cytosol for proteasome-dependent degradation. These included SEL1L (602329), HRD1 (SYVN1; 608046), derlin-2 (DERL2; 610304), the ATPase p97, PDI (P4HB; 176790), BIP (HSPA5; 138120), calnexin (CANX; 114217), AUP1 (602434), UBXD8 (FAF2), UBC6E (UBE2J1; 616175), and OS9 (609677).
By affinity purification, SDS-PAGE, and mass spectrometry, Cloutier et al. (2013) found that METTL21D (615260) expressed in HEK293 cells interacted with endogenous VCP, ASPSCR1 (606236), and UBXN6 (611946). In vitro methylation assays showed that recombinant METTL21D methylated VCP, which was abrogated by mutation of lys315 in ATPase domain 1 of VCP. Methylation reduced the activity of VCP ATPase domain 1, but it had no effect on the activity of VCP ATPase domain 2. METTL21D did not methylate ASPSRC1 or UBXN6, but the presence of ASPSRC1, but not UBXN6, enhanced METTL21D-dependent VCP methylation.
In immunoprecipitation studies, Clemen et al. (2010) identified strumpellin (KIAA0196; 601657) as a binding partner with VCP. Strumpellin was detected in pathologic protein aggregates in muscle tissue derived from patients with IBMPFD1 (167320) as well as in various myofibrillar myopathies and in cortical neurons of a mouse model of Huntington disease (HD; 143100). These findings suggested that strumpellin, like VCP, may have a role in various protein aggregate diseases.
Maric et al. (2014) showed that the CMG helicase, composed of Cdc45 (603465)/Mcm (see MCM7, 600592)/GINS (see 610608), is ubiquitylated during the final stages of chromosome replication in S. cerevisiae, specifically on its Mcm7 subunit. The yeast F-box protein Dia2 is essential in vivo for ubiquitylation of CMG, and the SCF(Dia2) ubiquitin ligase (see 603134) is also required to ubiquitylate CMG in vitro on its Mcm7 subunit in extracts of S-phase yeast cells. Maric et al. (2014) concluded that their data identified 2 key features of helicase disassembly in budding yeast. First, there is an essential role for the F-box protein Dia2, which drives ubiquitylation of the CMG helicase on its Mcm7 subunit. Second, the Cdc48 segregase is required to break ubiquitylated CMG into its component parts. Once separated from GINS and Cdc45, the Mcm2-7 hexamer is less stable, so that all of the subunits of the CMG helicase are lost from the newly replicated DNA.
Moreno et al. (2014) presented evidence consistent with the idea that polyubiquitylation of a replisome component, MCM7, leads to its disassembly at the converging terminating forks due to the action of the p97/VCP/CDC48 protein remodeler. Using Xenopus laevis egg extract, the authors showed that blocking polyubiquitylation results in the prolonged association of the active helicase with replicating chromatin. The MCM7 subunit was the only component of the active helicase found to be polyubiquitylated during replication termination. The observed polyubiquitylation was followed by disassembly of the active helicase dependent on p97/VCP. Moreno et al. (2014) concluded that their data provided insight into the mechanism of replisome disassembly during eukaryotic DNA replication termination.
Olmos et al. (2015) demonstrated that the endosomal sorting complex required for transport-III (ESCRT-III) machinery localizes to sites of annular fusion in the forming nuclear envelope in human cells, and is necessary for proper postmitotic nucleocytoplasmic compartmentalization. The ESCRT-III component CHMP2A (610893) is directed to the forming nuclear envelope through binding to CHMP4B (610897), and provides an activity essential for nuclear envelope reformation. Localization also requires the p97 complex (see 601023) member UFD1 (601754). Olmos et al. (2015) concluded that their results described a novel role for the ESCRT machinery in cell division and demonstrated a conservation of the machineries involved in topologically equivalent mitotic membrane remodeling events.
Van Haaften-Visser et al. (2017) found that human VCP interacted with ANKZF1 (617541) in the cytoplasm of U2OS osteosarcoma cells and that the complex translocated toward mitochondria following H2O2-induced oxidative stress.
Yasuda et al. (2020) demonstrated that proteasome-containing nuclear foci form under acute hyperosmotic stress. These foci are transient structures that contain ubiquitylated proteins, VCP, and multiple proteasome-interacting proteins, which collectively constitute a proteolytic center. The major substrates for degradation by these foci were ribosomal proteins that failed to properly assemble. Notably, the proteasome foci exhibited properties of liquid droplets. RAD23B (600062), a substrate-shuttling factor for the proteasome, and ubiquitylated proteins were necessary for formation of proteasome foci. In mechanistic terms, a liquid-liquid phase separation was triggered by multivalent interactions of 2 ubiquitin-associated domains of RAD23B and ubiquitin chains consisting of 4 or more ubiquitin molecules. Yasuda et al. (2020) concluded that their results suggested that ubiquitin chain-dependent phase separation induces the formation of a nuclear proteolytic compartment that promotes proteasomal degradation.
In in vitro studies, Darwich et al. (2020) found that VCP normally acts as a disaggregase for polyubiquitinated phosphorylated pathologic tau fibrils derived from brains of patients with Alzheimer disease (see, e.g., AD, 104300). This function was ATP- and polyubiquitin-dependent.
By immunoprecipitation and mass spectrometry analyses in HEK293 cells, Fielden et al. (2020) identified p97 as an interacting partner of TOP1 (126420), a protein that regulates DNA topology to ensure efficient DNA replication and transcription. By interacting with TOP1, p97 functioned as a modulator of TOP1 cleavage complex (TOP1cc) repair, as p97 ATPase activity was needed to counteract TOP1cc accumulation in human cells. The authors identified TEX264 (620608) as a p97 cofactor. TEX264 simultaneously interacted with p97 and TOP1 to form a complex to bridge recruitment of p97 specifically to TOP1cc. TEX264 knockout caused substantial TOP1cc accumulation, which led to significantly delayed DNA damage repair. This phenotype was similar to that of TDP1 (607198) depletion, as TEX264 was epistatic with TDP1 and interacted with TDP1 to promote TOP1cc repair. TEX264 function in TOP1cc repair was mediated by sumoylation. TOP1 was sumoylated, and TEX264, which contains 2 putative SUMO-interacting motifs (SIMs) in its GyrI-like domain, bound to sumoylated TOP1 for its recruitment to TOP1cc. In addition, SPRTN (616086), a metalloprotease that proteolytically cleaves TOP1, contributed to TOP1cc repair. TEX264 associated with SPRTN at the nuclear periphery and acted at replication forks.
Inclusion Body Myopathy with Paget Disease of Bone and Frontotemporal Dementia
Watts et al. (2004) identified missense mutations in VCP as the cause of inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD; 167320). Ten of 13 families with this disorder had an amino acid change at arginine-155, either to histidine, proline, or cysteine. Arginine-155 of VCP was conserved in homologs through all species examined except in 2 C. elegans homologs, which had glutamine at that position. Arginine-191 was invariant in all species examined, and arginine-95 was substituted by histidine in only 2 species.
Watts et al. (2004) suggested that since patients with IBMPFD are viable with relatively late onset of disease, the mutations identified do not disrupt the cell cycle or apoptosis pathways. They proposed that mutations in VCP cause Paget disease of bone by compromising ubiquitin binding and target similar cellular pathways or proteins. They suggested that the progressive neuronal degeneration has to do with protein quality control and ubiquitin protein degradation pathways. Watts et al. (2004) concluded that because IBMPFD is a dominant progressive syndrome, the mutations they identified are probably relatively subtle, and aging, oxidative stress, and endoplasmic reticulum stress probably define a threshold at which the IBMPFD phenotype becomes manifest.
In vitro functional expression studies by Weihl et al. (2006) showed that cells transfected with the mutant R155H (601023.0001) and R95G (601023.0004) proteins developed a prominent increase in diffuse and aggregated ubiquitin conjugates and showed impaired function of endoplasmic reticulum-associated degradation (ERAD), as well as a distorted ER structure.
In human cells with IBMPFD-associated mutations, Ju et al. (2008) found that treatment with a proteasome inhibitor resulted in increased cell death and an increase in perinuclear ubiquitinated proteins, but no clear aggresomes, compared to wildtype. Expression of an aggregate protein in mutant cells did not result in proper formation of inclusion bodies or aggresomes. A similar lack of inclusion body formation was observed in mutant mouse muscle fibers in vivo. Further studies showed that mutant VCP trapped aggregated proteins but failed to release them to aggresomes or inclusion bodies. This was reversed upon coexpression with HDAC6 (300272), a VCP-binding protein that facilitates formation of aggresomes. Ju et al. (2008) concluded that mutations in the VCP gene impaired the proper clearance of aggregated proteins.
Frontotemporal Dementia and/or Amyotrophic Lateral Sclerosis 5
Using exome sequencing, Johnson et al. (2010) identified a heterozygous mutation in the VCP gene (R191Q; 601023.0006) in 4 affected members of an Italian family with frontotemporal dementia and/or amyotrophic lateral sclerosis-6 (FTDALS6; 613954). Screening of the VCP gene in 210 familial ALS cases and 78 autopsy-proven ALS cases identified 3 additional pathogenic VCP mutations (601023.0001, 601012.0008, and 601023.0009) in 4 patients. The findings expanded the phenotype associated with VCP mutations to include classic ALS.
In 3 unrelated adult Dutch patients with the behavioral variant of FTD without signs of myopathy or motor neuron disease (613954), Wong et al. (2018) identified heterozygous missense mutations in the VCP gene (R159S, 601023.0013, T262S, and M158V). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were not present in the gnomAD database. Functional studies of the variants were not performed. Postmortem examination of 2 patients (patients 2 and 3) showed prominent frontal atrophy with neuronal loss and gliosis, as well as neuronal intranuclear inclusions (NII), short dystrophic neurites (DN), and positive immunostaining for TDP43 and p62 (SQSTM1; 601530). A few hyperphosphorylated tau (MAPT; 157140) deposits without amyloid plaques were observed in 1 patient, and several amyloid plaques were observed in the other patient. Rare NII showed VCP-positive immunostaining. The pathologic findings were consistent with FTLD-TDP subtype D, although the severity and distribution of the pathologic findings varied somewhat between the 2 patients.
In 4 adult patients from 2 unrelated families with the behavioral variant of FTD without signs of myopathy, bone disease, or motor neuron disease, Darwich et al. (2020) identified the same heterozygous missense mutation in (D395G; 601023.0014). The substitution occurred at a conserved residue in the lid subdomain of the D1 ATPase domain. The mutation, which was found by targeted, whole-exome, or whole-genome sequencing, segregated with the disorder in both families. It was not present in the gnomAD database. Neuropathologic examination of 1 patient showed frontal atrophy, neuronal vacuolization, and abundant phosphorylated tau (MAPT; 157140) aggregates identical to neurofibrillary tangles (NFT) observed in patients with Alzheimer disease (see, e.g., AD, 104300). MAPT mutations were absent in both families. The distribution of the vacuoles and NFTs were inversely related: vacuoles were more prominent in the occipital cortex, which showed minimal neurodegeneration, whereas NFTs were more prominent in frontal regions and other areas that showed cerebral atrophy, neuronal loss, and reactive gliosis. TDP43 (605078), beta-amyloid (APP; 104760), SNCA (163890), and prion protein (PRNP; 176640) aggregates were not observed. The pathologic tau distribution was confirmed by brain imaging studies. In vitro functional expression studies showed that the D395G mutation resulted in decreased ATPase activity with a 30% reduction in maximum enzyme velocity compared to controls, which was consistent with a hypomorphic mutation. Additional in vitro studies showed that VCP normally acts as a disaggregase for polyubiquitinated phosphorylated pathologic tau fibrils derived from brains of patients with Alzheimer disease. Cells with the D395G mutation had increased intracellular tau aggregates, suggesting that this specific mutation impairs the turnover of pathologic tau aggregates, resulting in neurodegeneration. Transgenic mice expressing this mutation showed similar pathologic tau accumulation when seeded with AD-derived tau (see ANIMAL MODEL). Darwich et al. (2020) emphasized the distinct pathogenetic mechanism associated with this mutation, and named this disease 'vacuolar tauopathy' (VT).
Tyzack et al. (2019) examined motor neurons derived from 2 human induced pluripotent stem cell (iPSC) lines with different heterozygous VCP mutations (R155C, 601023.0002 and R191Q, 601023.0006) and identified a decrease in the nuclear to cytoplasmic localization of the FUS (137070) protein during motor neuron differentiation compared to controls. Tyzack et al. (2019) also identified a reduction in the nuclear to cytoplasmic localization of the FUS protein in motor neurons from the ventral spinal cord of transgenic mice with a heterozygous mutation in the VCP gene (A232E; 601023.0003). This reduction was not seen in mice with a SOD1 (147450) G93A mutation, where FUS remained in the nucleus. Tyzack et al. (2019) next identified evidence for nuclear to cytoplasmic FUS mislocalization in postmortem spinal cord tissue from individuals with sporadic ALS compared to controls. After identifying RNA binding targets of the FUS protein, Tyzack et al. (2019) found that the FUS protein bound extensively to an aberrantly retained intron 9 within the SFPQ (605199) transcript. This aberrant SFPQ transcript was increased in the human iPSC cell lines with the heterozygous VCP mutations compared to controls.
Harley et al. (2020) identified a decreased nuclear to cytoplasmic ratio of FUS in highly enriched spinal motor neurons that were derived from human iPSC cell lines with heterozygous VCP mutations. This mislocalization of FUS extended to the neuronal processes. Harley et al. (2020) hypothesized that the nuclear loss of the FUS protein may impair its role in pre-mRNA splicing and play a role in neurodegeneration.
Charcot-Marie-Tooth Disease Type 2Y
In 5 affected members of a family with autosomal dominant axonal Charcot-Marie-Tooth disease type 2Y (CMT2Y; 616687), Gonzalez et al. (2014) identified a heterozygous missense mutation in the VCP gene (E185K; 601023.0010). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. In vitro functional expression studies showed that the variant impaired autophagic function of VCP, leading to the accumulation of immature autophagosomes. ATPase function of the variant was normal.
Functional Effects of VCP Mutations
Cloutier et al. (2013) found that the R155H (601023.0001), R159H (601023.0007), and R191Q (601023.0006) mutations in VCP did not alter in vitro methylation of VCP by METTL21D. However, ASPSRC1 did not enhance methylation of VCP containing these mutations, as it did with wildtype VCP.
Mehta et al. (2013) analyzed clinical and biochemical markers from a database of 190 individuals from 27 families harboring 10 missense mutations in the VCP gene. Among these, 145 mutation carriers were symptomatic and 45 were presymptomatic. The most common clinical feature (in 91% of patients) was onset of myopathic weakness at a mean age of 43 years. Paget disease of the bone was found in 52% of patients at a mean age of 41 years. Frontotemporal dementia occurred in 30% of patients at a mean age of 55 years. Significant genotype-phenotype correlations were difficult to establish because of small numbers. However, patients with the R155C mutation (601023.0002) had a more severe phenotype with an earlier onset of myopathy and Paget disease, as well as decreased survival, compared to those with the R155H mutation (601023.0001). A diagnosis of ALS was found in at least 13 (8.9%) individuals from the 27 families, including 10 patients with the R155H mutation, and 5 (3%) patients were diagnosed with Parkinson disease.
Al-Obeidi et al. (2018) studied 231 individuals from 36 families carrying 15 different heterozygous VCP mutations. Of these individuals, 187 were clinically symptomatic and 44 were presymptomatic carriers. The cohort of patients were of various ethnicities, including European, Brazilian, Hispanic/Apache, and an African-American. Most (90%) of symptomatic patients presented with myopathy at a mean age of 43 years (range, 20-70 years). Paget disease of bone was identified in 42% of patients with a mean age at onset of 41 years (range, 23-65 years), and dementia was diagnosed in 29.4% of patients at a mean age of 55.9 years (range, 30-80 years). When possible to ascertain, the dementia included sociobehavioral and language changes, as well as loss of executive function. Sixteen (8.6%) of patients were diagnosed with ALS associated with upper and lower motor neuron degeneration. Some patients were diagnosed with Parkinson disease (3.8%) or Alzheimer disease (2.1%). Although VCP mutations are associated with a triad of symptoms, only 10% of patients had all 3 features of myopathy, bone disease, and dementia. After stratification by mutation type, there were no apparent genotype/phenotype correlations, although the R159C mutation was associated with a slightly later age at onset of myopathy (57 years) compared to other mutations. Functional studies of the variants were not performed. The authors emphasized the enormous phenotypic heterogeneity both between and within families.
Schiava et al. (2022) reported clinical and genetic data on 234 symptomatic patients (70% male) from 194 families from 24 countries with mutations in the VCP gene. Only 7 patients (2.9%) had the classic triad of myopathy, bone disease, and dementia. Muscle weakness affecting both proximal or distal muscles of the lower and/or upper limbs was the first symptom in 90.7% of patients and was present in all but 1 patient at last assessment. Paget disease of bone occurred in 28.2%, dysautonomia in 21.2%, lower motor neuron signs in 21.2%, and frontotemporal dementia in 14.3%. Of 57 identified variants, 4 (R155H, 601023.0001; R155C, 601023.0002; R159H, 601023.0007; and R93C) accounted for 54.7% of the patients. Exons 5 and 3 represented hotspots. All but one of the mutations were missense. No mutations were exclusively associated with specific mutations, but R155C, which occurred more frequently in females, showed a more severe phenotype with an earlier onset.
Weihl et al. (2007) found that transgenic mice overexpressing the R155H mutation became progressively weaker in a dose-dependent manner starting at 6 months of age. There was abnormal muscle pathology, with coarse internal architecture, vacuolation, and disorganized membrane morphology with reduced caveolin-3 (CAV3; 601253) expression at the sarcolemma. Even before animals displayed measurable weakness, there was an increase in ubiquitin-containing protein inclusions and high molecular weight ubiquitinated proteins. These findings suggested a dysregulation in protein degradation.
Custer et al. (2010) developed and characterized transgenic mice with ubiquitous expression of wildtype and disease-causing versions of human VCP/p97. Mice expressing VCP/p97 harboring the mutations R155H (601023.0001) or A232E (601023.0003) exhibited progressive muscle weakness, and developed inclusion body myopathy including rimmed vacuoles and TDP43 (605078) pathology. The brain showed widespread TDP43 pathology, and the skeleton exhibited severe osteopenia accompanied by focal lytic and sclerotic lesions in vertebrae and femur. In vitro studies indicated that mutant VCP caused inappropriate activation of the NF-kappa-B (see 164011) signaling cascade, which could contribute to the mechanism of pathogenesis in multiple tissues including muscle, bone, and brain.
Darwich et al. (2020) found that transgenic mice expressing the VCP D395G (601023.0014) mutation did not spontaneously develop a neurodegenerative phenotype and their brains did not show abnormal tau (MAPT; 157140) accumulation. However, when stimulated with pathologic tau derived from patients with Alzheimer disease (see, e.g., AD; 104300), transgenic mice had accumulation of pathologic tau aggregates in several brain regions. The findings suggested that neurons with this VCP mutation have increased susceptibility to pathologic tau aggregation under certain circumstances, resulting in downstream neurodegeneration.
Using mass spectroscopy analysis, Weiss et al. (2020) showed that ceramide levels were elevated in primary myoblasts from both mice homozygous for the Vcp R155H mutation and patients with VCP disease. Treatment with exogenous ceramide stimulated autophagy, a key feature of VCP disease pathology, in myoblasts from mice homozygous for the Vcp R155H mutation. Inhibition of ceramide biosynthesis mitigated VCP-associated autophagy and TDP43 pathology in patient myoblasts derived from induced pluripotent stem cells (iPSCs).
In 7 of 13 families with autosomal dominant inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD1; 167320), Watts et al. (2004) identified a G-to-A transition at nucleotide 464 of the VCP gene, resulting in an arg155-to-his substitution (R155H). This mutation appears to have arisen independently on several haplotype backgrounds.
Viassolo et al. (2008) identified heterozygosity for the R155H mutation in 3 affected members of an Italian family with IBMPFD. All 3 had progressive inclusion body myopathy and rapidly progressive severe dementia, but only 1 developed Paget disease.
In vitro functional expression studies by Weihl et al. (2006) showed that R155H-mutant protein properly assembled into a hexameric structure and showed normal ATPase activity. Cell transfected with the mutant protein showed a prominent increase in diffuse and aggregated ubiquitin conjugates and impaired function of endoplasmic reticulum-associated degradation (ERAD), as well as a distorted ER structure.
Johnson et al. (2010) identified heterozygosity for the R155H mutation, which they stated resulted from an 853G-A transition in exon 5, in a member of the family reported by Watts et al. (2004). However, the family member reported by Johnson et al. (2010) had classic ALS (FTDALS6; 613954) without evidence of Paget disease, myopathy, or frontotemporal dementia. Postmortem examination of this patient showed loss of brainstem and spinal cord motor neurons with Bunina bodies in surviving neurons, TDP43 (TARDBP; 605078)-positive immunostaining, and mild pallor of the lateral descending corticospinal tracts, all features consistent with diagnosis of ALS. The findings expanded the phenotype associated with VCP mutations, even within a single family.
In 2 of 13 families with autosomal dominant inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD1; 167320), Watts et al. (2004) identified a C-to-T transition at nucleotide 463 of the VCP gene, resulting in an arg155-to-cys substitution (R155C).
Kim et al. (2011) identified a heterozygous R155C mutation in 3 Korean sibs with IBMPFD. The proband developed progressive dementia presenting as fluent aphasia and language difficulties with onset at age 47. She never developed myopathy, but did develop asymptomatic Paget disease with increased serum alkaline phosphatase and lytic bone lesions on imaging. Her brother developed slowly progressive proximal muscle weakness at age 50, followed by frontotemporal dementia characterized initially by comprehension defects at age 54. He never had Paget disease, although serum alkaline phosphatase was increased. A second brother developed muscle weakness at age 47, followed by Paget disease at age 53, and dementia at age 61. Brain MRI in all patients showed asymmetric atrophy in the anterior inferior and lateral temporal lobes and inferior parietal lobule with ventricular dilatation on the affected side (2 on the left, 1 on the right). Two had glucose hypometabolism in the lateral temporal and inferior parietal areas, with less involvement of the anterior temporal and frontal lobes compared to those with typical semantic dementia.
In 1 of 13 families with autosomal dominant inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD1; 167320), Watts et al. (2004) identified a C-to-A transversion at nucleotide 695 of the VCP gene, resulting in an ala-to-glu change at codon 232 (A232E).
In 1 of 13 families with autosomal dominant inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD1; 167320), Watts et al. (2004) identified a C-to-G transversion at nucleotide 283 of the VCP gene, resulting in an arg-to-gly substitution at codon 95 (R95G).
In vitro functional expression studies by Weihl et al. (2006) showed that cells transfected with R95G-mutant protein developed a prominent increased in diffuse and aggregated ubiquitin conjugates and impaired function of endoplasmic reticulum-associated degradation (ERAD), as well as a distorted ER structure.
In 1 of 13 families with autosomal dominant inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD1; 167320), Watts et al. (2004) identified a G-to-C transversion at nucleotide 464 of the VCP gene, resulting in an arg-to-pro substitution at codon 155 (R155P). This family was originally reported by Tucker et al. (1982).
In 1 of 13 families with autosomal dominant inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD1; 167320), Watts et al. (2004) identified a G-to-C transversion at nucleotide 572 of the VCP gene, resulting in an arg-to-gln substitution at codon 191 (R191Q).
Using exome sequencing, Johnson et al. (2010) identified heterozygosity for the R191Q mutation in the VCP gene, which they stated resulted from a 961G-A transition in exon 5, in 4 affected members of an Italian family with frontotemporal dementia and/or amyotrophic lateral sclerosis-6 (FTDALS6; 613954). Affected individuals presented in adulthood with limb-onset motor neuron symptoms that rapidly progressed to involve all 4 limbs and the bulbar musculature, consistent with a classical ALS phenotype. All patients had unequivocal upper and lower motor signs, and none had evidence of Paget disease. One patient showed mild frontotemporal dementia. Autopsy material was not available. A parent of the proband had died at age 58 with dementia, parkinsonism, Paget disease, and upper limb weakness, suggesting IBMPFD. The findings indicated an expanded phenotypic spectrum for VCP mutations.
Sacconi et al. (2012) identified a heterozygous R191Q mutation in 2 unrelated men in their fifties who presented with a phenotype consistent with IBMPFD. One had scapuloperoneal weakness without facial involvement and increased serum creatine kinase. The second patient had facial weakness, shoulder and pelvic girdle weakness, and anterior foreleg weakness. Creatine kinase was increased 4-fold. Muscle biopsies of both patients showed mild dystrophic changes, but no inclusion bodies. EMG showed myopathic patterns. One patient was later found to have a mild dysexecutive syndrome, but neither had evidence of Paget disease.
In 4 affected sibs of an Austrian family with autosomal dominant inclusion body myopathy and Paget disease but without dementia (IBMPFD1; 167320), Haubenberger et al. (2005) identified a heterozygous 688G-A transition in exon 5 of the VCP gene, resulting in an arg159-to-his (R159H) substitution. The mutation occurred in a highly conserved region close to the codon 155 hotspot described by Watts et al. (2004) and was not present in 384 control chromosomes. None of the 4 affected sibs demonstrated frontotemporal dementia even though all were over 60 years of age. Haubenberger et al. (2005) noted that only approximately 30% of patients with VCP mutations develop dementia, illustrating phenotypic variability. In a follow-up of this family, van der Zee et al. (2009) noted that 1 patient had developed dementia at age 64. Van der Zee et al. (2009) also identified the R159H mutation in affected members of 2 unrelated Belgian families. In 1 family, patients presented with frontotemporal lobar degeneration only, whereas in the other family, patients developed frontotemporal lobar degeneration, Paget disease of the bone, or both without signs of inclusion body myopathy for any of the mutation carriers. Haplotype analysis showed that the 2 families and the Austrian family reported by Haubenberger et al. (2005) were unrelated. Autopsy data of 3 patients from the 2 Belgian families showed frontotemporal lobar degeneration with numerous ubiquitin-immunoreactive, intranuclear inclusions and dystrophic neurites staining positive for TDP43 (TARDBP; 605078) protein. Van der Zee et al. (2009) commented on the high degree of clinical heterogeneity and incomplete penetrance of the disorder in different families carrying the same mutation.
De Ridder et al. (2020) reported a 36-year-old Belgian man with onset of IBMPFD1 at age 29 years who carried a homozygous R159H mutation in the VCP gene. His 63-year-old father, who carried the mutation in heterozygous state, had a similar myopathic phenotype with later onset at age 58. His 60-year-old mother, who was also heterozygous for the mutation, was clinically unaffected. The proband presented with progressive proximal muscle weakness with possible neurogenic features and high serum creatine kinase; an asymptomatic Paget bone lesion was later identified. Neither patient had dementia. Functional studies of the variant were not performed, but proteomic analysis of skeletal muscle from the proband and his father, as well as from 3 additional patients with VCP-related myopathy, showed changes in upstream regulators involved in myogenesis, muscle regeneration, oxidative stress, endoplasmic reticulum stress, stress granules, and the unfolded protein response.
In affected members of a family with frontotemporal dementia and/or amyotrophic lateral sclerosis-6 (FTDALS6; 613954), Johnson et al. (2010) identified a heterozygous c.864C-G transversion in exon 5 of the VCP gene, resulting in an arg159-to-gly (R159G) substitution in a conserved residue. The mutation was not found in 3,138 control chromosomes, and a different pathogenic mutation had previously been reported in this codon (R159H; 601023.0007). Two patients had classic ALS with frontotemporal dementia, and a third obligate mutation carrier had Paget disease, followed by ALS without cognitive impairment.
In a patient with frontotemporal dementia and/or amyotrophic lateral sclerosis-6 (FTDALS6; 613954) without FTD, Johnson et al. (2010) identified a heterozygous c.2163G-A transition in exon 14 of the VCP gene, resulting in an asp592-to-asn (D592N) substitution in a residue directly adjacent to the central pore formed by the VCP hexamer. The mutation was not found in 3,138 control chromosomes. A maternal uncle had previously been diagnosed with ALS.
In 5 adult members of a family with autosomal dominant axonal Charcot-Marie-Tooth disease type 2Y (CMT2Y; 616687), Gonzalez et al. (2014) identified a heterozygous c.553C-T transition (c.553C-T, NM_007126.3) in the VCP gene, resulting in a glu185-to-lys (E185K) substitution at a highly conserved residue in the L1 linker domain between the N-domain and the D1 ATPase domain. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family and was not found in the Exome Variant Server database. In vitro functional expression studies showed that the variant impaired autophagic function of VCP, leading to the accumulation of immature autophagosomes. ATPase function of the variant was normal. Intrafamilial variation was striking: 1 patient had onset in early childhood and severe disability, whereas 3 other patients had onset after age 50 and a milder phenotype.
In a 60-year-old man of Dutch and Italian descent with autosomal dominant Charcot-Marie-Tooth disease type 2Y (CMT2Y; 616687), Jerath et al. (2015) identified a heterozygous c.290C-T transition in the VCP gene, resulting in a gly97-to-glu (G97E) substitution. The mutation was found by exome sequencing. In vitro functional expression studies showed that the mutant protein had increased ATPase activity compared to wildtype.
In 2 Brazilian brothers and their father with different clinical manifestations of VCP-related neurologic disease, Abrahao et al. (2016) identified a heterozygous c.271A-T transversion in exon 3 of the VCP gene, resulting in an asn91-to-tyr (N91Y) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with a neurologic phenotype in the family. The variant was not present in the Exome Variant Server or ExAC databases, or in 1000 control Brazilian exomes. Functional studies of the variant were not performed, but it was predicted to be pathogenic. The proband presented in his forties with proximal muscle weakness associated with dystrophic features, myofibrillar disorganization, and rimmed vacuoles on muscle biopsy, consistent with a diagnosis of inclusion body myopathy (IBMPFD1; 167320), but he had no signs of Paget disease or dementia. His affected brother presented in his late thirties with lower motor neuron-predominant amyotrophic lateral sclerosis (FTDALS6; 613954) without signs of Paget disease or frontotemporal dementia. Their father presented at age 66 with behavioral variant frontotemporal dementia (613954) without signs of Paget disease, myopathy, or ALS. The findings emphasized the extreme phenotypic variability associated with VCP mutations, even within the same family.
In a woman (patient 2) with frontotemporal dementia without amyotrophic lateral sclerosis (FTDALS6; 613954), Wong et al. (2018) identified a heterozygous c.475C-A transversion in exon 5 of the VCP gene, resulting in an arg159-to-ser (R159S) substitution in the CDC48 domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies of the variant were not performed. The patient had onset of symptoms consistent with the behavioral variant of FTD at age 56 and died at age 62. Neuropathologic examination showed prominent frontal atrophy with neuronal loss and gliosis, as well as neuronal intranuclear inclusions (NII), short dystrophic neurites (DN), and positive immunostaining for TDP43 and p62 (SQSTM1; 601530). Several amyloid plaques were also observed, and rare NII showed VCP-positive immunostaining. The pathologic findings were consistent with FTLD-TDP subtype D.
In 4 adult patients from 2 unrelated families with frontotemporal dementia without amyotrophic lateral sclerosis (FTDALS6; 613954), Darwich et al. (2020) identified a heterozygous c.1184A-G transition (c.1184A-G, NM_007126.5) in the VCP gene, resulting in an asp395-to-gly (D395G) substitution at a conserved residue in the lid subdomain of the D1 ATPase domain. The mutation, which was found by targeted, whole-exome, or whole-genome sequencing, segregated with the disorder in both families. It was not present in the gnomAD database. The patients presented with the behavioral variant of FTD and did not have signs of myopathy, bone disease, or motor neuron disease. Neuropathologic examination of 1 patient showed frontal atrophy, neuronal vacuolization, and abundant phosphorylated tau (MAPT; 157140) aggregates identical to neurofibrillary tangles (NFT) observed in patients with Alzheimer disease (see, e.g., AD; 104300). The distribution of the vacuoles and NFTs were inversely related: vacuoles were more prominent in the occipital cortex, which showed minimal neurodegeneration, whereas NFTs were more prominent in frontal regions and other areas that showed cerebral atrophy, neuronal loss, and reactive gliosis. TDP43 (605078), beta-amyloid (APP; 104760), SNCA (163890), and prion protein (PRNP; 176640) aggregates were not observed. The pathologic tau distribution was confirmed by brain imaging studies. In vitro functional expression studies showed that the D395G mutation resulted in decreased ATPase activity with a 30% reduction in maximum enzyme velocity compared to controls, which was consistent with a hypomorphic mutation. Additional in vitro studies showed that VCP normally acts as a disaggregase for polyubiquitinated phosphorylated pathologic tau fibrils derived from brains of patients with Alzheimer disease. Cells with the D395G mutation had increased intracellular tau aggregates, suggesting that this specific mutation impairs the turnover of pathologic tau aggregates, resulting in neurodegeneration. Darwich et al. (2020) named this disease 'vacuolar tauopathy' (VT).
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