* 601023
VALOSIN-CONTAINING PROTEIN; VCP
Alternative titles; symbols
CDC48, YEAST, HOMOLOG OF
p97
HGNC Approved Gene Symbol: VCP
Cytogenetic location: 9p13.3 Genomic coordinates (GRCh38): 9:35,056,063-35,072,741 (from NCBI)
Gene-Phenotype Relationships
| Location | Phenotype | Phenotype MIM number |
Inheritance | Phenotype mapping key |
|---|---|---|---|---|
| 9p13.3 | Amyotrophic lateral sclerosis 14, with or without frontotemporal dementia | 613954 | 3 | |
| Charcot-Marie-Tooth disease, type 2Y | 616687 | Autosomal dominant | 3 | |
| Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia 1 | 167320 | Autosomal dominant | 3 |
TEXT
Description
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).
Cloning and Expression
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.
Biochemical Features
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.
Gene Structure
Johnson et al. (2010) noted that the VCP gene contains 17 exons.
Mapping
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).
Gene Function
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 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, comprised 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.
Molecular Genetics
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.
Amyotrophic Lateral Sclerosis 14 with or without Frontotemporal Dementia
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 amyotrophic lateral sclerosis-14 (ALS14; 613954) with or without frontotemporal dementia. 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.
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), R159G (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.
Genotype/Phenotype Correlations
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.
Animal Model
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.
ALLELIC VARIANTS 11 Selected Examples):
.0001 INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA
In 7 of 13 families with autosomal dominant IBMPFD (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 (ALS14; 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.
.0002 INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA
In 2 of 13 families with autosomal dominant IBMPFD (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.
.0003 INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA
In 1 of 13 families with autosomal dominant IBMPFD (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).
.0004 INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA
In 1 of 13 families with autosomal dominant IBMPFD (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.
.0005 INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA
In 1 of 13 families with autosomal dominant IBMPFD (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).
.0006 INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA
In 1 of 13 families with autosomal dominant IBMPFD (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 amyotrophic lateral sclerosis-14 (ALS14; 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 reminiscent of FSHD1 (158900). 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.
.0007 INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA
In 4 affected sibs of an Austrian family with autosomal dominant inclusion body myopathy and Paget disease but without dementia (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.
.0008 AMYOTROPHIC LATERAL SCLEROSIS 14 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA
In affected members of a family with ALS14 with or without frontotemporal dementia (613954), Johnson et al. (2010) identified a heterozygous 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.
.0009 AMYOTROPHIC LATERAL SCLEROSIS 14 WITHOUT FRONTOTEMPORAL DEMENTIA
In a patient with ALS14 without frontotemporal dementia (613954), Johnson et al. (2010) identified a heterozygous 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.
.0010 CHARCOT-MARIE-TOOTH DISEASE, TYPE 2Y
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.
.0011 CHARCOT-MARIE-TOOTH DISEASE, TYPE 2Y
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.
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Ada Hamosh - updated : 09/14/2016
Cassandra L. Kniffin - updated : 12/10/2015
Ada Hamosh - updated : 6/24/2015
Ada Hamosh - updated : 12/3/2014
Ada Hamosh - updated : 12/2/2014
Cassandra L. Kniffin - updated : 1/6/2014
Cassandra L. Kniffin - updated : 12/17/2013
Patricia A. Hartz - updated : 5/31/2013
Cassandra L. Kniffin - updated : 4/25/2012
Cassandra L. Kniffin - updated : 12/8/2011
George E. Tiller - updated : 12/1/2011
Cassandra L. Kniffin - updated : 5/5/2011
Cassandra L. Kniffin - updated : 12/21/2009
Patricia A. Hartz - updated : 11/10/2009
Cassandra L. Kniffin - updated : 10/29/2009
Cassandra L. Kniffin - updated : 4/23/2009
Cassandra L. Kniffin - updated : 3/23/2009
Ada Hamosh - updated : 1/24/2008
Cassandra L. Kniffin - updated : 2/5/2007
Patricia A. Hartz - updated : 1/4/2007
Ada Hamosh - updated : 3/8/2005
Ada Hamosh - updated : 7/22/2004
Ada Hamosh - updated : 4/2/2004
Paul J. Converse - updated : 1/28/2002
Ada Hamosh - updated : 1/2/2002
Victor A. McKusick - updated : 10/14/1997
carol : 06/21/2017
carol : 06/21/2017
carol : 06/20/2017
alopez : 09/14/2016
carol : 06/24/2016
carol : 12/16/2015
carol : 12/15/2015
ckniffin : 12/10/2015
alopez : 6/24/2015
carol : 5/7/2015
carol : 2/4/2015
mgross : 1/22/2015
alopez : 12/3/2014
alopez : 12/2/2014
carol : 1/7/2014
ckniffin : 1/6/2014
carol : 12/19/2013
mcolton : 12/18/2013
ckniffin : 12/17/2013
mgross : 9/17/2013
carol : 7/26/2013
mgross : 5/31/2013
carol : 4/26/2012
ckniffin : 4/25/2012
carol : 12/16/2011
ckniffin : 12/8/2011
ckniffin : 12/8/2011
alopez : 12/5/2011
terry : 12/1/2011
carol : 7/6/2011
terry : 6/3/2011
carol : 6/1/2011
wwang : 5/18/2011
ckniffin : 5/5/2011
carol : 7/30/2010
wwang : 1/14/2010
ckniffin : 12/21/2009
terry : 12/1/2009
mgross : 11/10/2009
wwang : 11/5/2009
ckniffin : 10/29/2009
ckniffin : 10/29/2009
wwang : 5/13/2009
ckniffin : 4/23/2009
wwang : 4/7/2009
ckniffin : 3/23/2009
alopez : 2/5/2008
alopez : 2/5/2008
terry : 1/24/2008
carol : 5/10/2007
wwang : 2/9/2007
ckniffin : 2/5/2007
mgross : 1/4/2007
wwang : 8/9/2006
alopez : 3/8/2005
carol : 1/13/2005
terry : 11/3/2004
alopez : 7/23/2004
terry : 7/22/2004
alopez : 4/6/2004
terry : 4/2/2004
mgross : 1/28/2002
alopez : 1/8/2002
terry : 1/2/2002
mgross : 3/21/2000
mark : 10/17/1997
terry : 10/14/1997
terry : 7/28/1997
mark : 4/8/1997
terry : 3/26/1996
mark : 1/30/1996