DiagnosisClinical DiagnosisThe diagnosis of inclusion body or nonspecific myopathy associated with Paget disease of bone with or without frontotemporal dementia (IBMPFD) is established by the combination of the following:Myopathy that is usually proximal, progressive, and adult-onset: Serum CK concentration is normal to mildly elevated (mean: 195 U/L; range: 40-1145 U/L; normal range: 20-222 U/L). EMG (electromyogram) shows myopathic changes, and occasionally neuropathic changes including acute and chronic denervation. Skeletal muscle pathology is typically nonspecific. Light microscopy of muscle biopsy reveals nonspecific changes: variability in fiber size, type I fiber predominance, and atrophic and hypertrophic fibers. Fibers may contain single or multiple vacuoles. Rimmed vacuoles and cytoplasmic VCP (valosin-containing protein) and ubiquitin-positive inclusions visible in some fibers are characteristic of inclusion body myopathy. The inclusions appear with time and can be observed at a later stage of the disease in some individuals. In advanced cases, severe degenerative muscle changes and fatty replacement of muscle fibers may be noted. Inflammatory cells are absent. Electron microscopy may show nonspecific cytoplasmic changes. The characteristic inclusions composed of randomly oriented tubulofilaments, roughly 15-21 nm in diameter, are seen in muscle nuclei and in cytoplasm. In one family, atrophic and vacuolated muscle fibers containing abundant cytoplasmic-paired helical filaments with epitopes of phosphorylated tau, congophilia, abnormal accumulation of β-amyloid precursor protein (βAPP) epitopes, and accumulation of apolipoprotein E (ApoE) were observed [Alvarez et al 1998]. Paget disease of bone (PDB), suspected in individuals with spine or hip pain, bony tenderness, reduced height, pathologic fractures, long-bone or cranial-bone deformity, or hearing loss resulting from eighth-nerve compression by calvarial bony overgrowth. The diagnosis of PDB can be established with the following findings: Elevated serum alkaline phosphatase (ALP) concentration (mean: 359 U/L; range: 58-1724 U/L; normal range: 30-130 U/L) Elevated urine concentrations of pyridinoline (PYD) and deoxypyridinoline (DPD): Mean PYD: 153 IU/L (normal: 31.1 IU/L) Mean DPD: 40 IU/L (normal: 6.8 IU/L)
Note: The DPD/PYD ratio is not significantly different between affected persons (0.291) and normal controls (0.214).Bone findings – either of the following: Skeletal radiographs reveal diagnostic changes of coarse trabeculation; cortical thickening; and spotty sclerosis in the skull, pelvis, spine, and scapula that later becomes widespread. Radiographic findings of PDB are typically present ten to 15 years before the diagnosis of PDB can be made based on clinical findings.Radionuclide scan shows focally increased bony uptake (a more sensitive indicator of PDB than skeletal radiographs). Frontotemporal dementia (FTD), diagnosed by comprehensive neuropsychological assessment that reveals behavioral alteration (e.g., personal/social unawareness, perseveration, disinhibition), early expressive or receptive language dysfunction, and relative preservation of memory, orientation, and praxis [Miller et al 1997]: Imaging studies reveal atrophy of anterior temporal and frontal lobes. Molecular Genetic TestingGene. VCP, encoding valosin-containing protein (VCP), a member of the AAA-ATPase superfamily, is the only gene in which mutations are known to cause inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD). Note:In the majority of families with IBMPFD that link to 9p, VCP mutations have been identified.In families with isolated PDB that link to 9p, VCP mutations have not been identified [Lucas et al 2006]. Evidence for locus heterogeneity. Several families that meet diagnostic criteria for IBMPFD have not had an identifiable VCP mutation and have not shown linkage to 9p21.2 [Authors, unpublished data], suggesting genetic heterogeneity for this disorder [Waggoner et al 2002]. Testing Sequence analysis. A VCP mutation has been identified in all families with IBMPFD that have shown linkage to 9p (see Table 2 for specific mutations identified) [Author, personal observation]. Targeted mutation analysis. Using a panel of the ten known mutations*, a mutation was identified in 27/37 (70%) of probands [Author, personal observation].
*Known mutations: p.Arg93Cys, p.Arg95Gly, p.Arg191Gln, p.Arg155Cys, p.Arg155Pro, p.Arg159His, p.Ala232Glu, p.Leu198Trp, p.Asn387HisTable 1. Summary of Molecular Genetic Testing Used in Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal DementiaView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityVCPSequence analysisSequence variants 2~100% 3Clinical 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. In families who meet diagnostic criteria for IBMPFD and show linkage to 9p21.1-p12Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy To confirm/establish the diagnosis in a proband. Evaluation strategy to establish the cause of IBMPFD in an affected person includes the following:Clinical evaluation. A thorough medical history, neurologic history, and physical examination focusing on features associated with IBMPFD. Comprehensive testing should include electrophysiologic testing of muscle; muscle biopsy for histologic examination for rimmed vacuoles and inclusions; laboratory testing for serum creatinine phosphokinase (CK) concentration; serum alkaline phosphatase (ALP) concentration, and urine concentrations of pyridinoline (PYD) and deoxypyridinoline (DPD); skeletal radiographs and bone scan; and, if clinically indicated, neuropsychological testing. Family history. A three-generation family history with attention to other relatives with possible IBMPFD. Documentation of relevant findings in family members can be accomplished either through direct examination of those individuals or through review of their medical records including neuroimaging, neuropathology, neurologic examination, and results of molecular genetic testing.Confirmation of the diagnosis in a proband. Detection of a mutation in VCP is the only way to confirm the clinical diagnosis of IBMPFD. VCP molecular genetic testing should be accompanied by formal genetic counseling. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersOther phenotypes associated with mutations in VCP include isolated:Proximal limb-girdle myopathy Paget disease of bone Dementia Familial amyotropic lateral sclerosis (ALS). At this point, additional research is necessary to establish whether VCP mutations cause familial ALS without other manifestations and, if so, the frequency of VCP mutations in familial ALS.}

Natural HistoryInclusion body myopathy associated with Paget disease of bone (PDB) and/or frontotemporal dementia (IBMPFD) is characterized by adult-onset proximal and distal muscle weakness (clinically resembling a limb-girdle muscular dystrophy syndrome), early-onset PDB in most cases, and premature frontotemporal dementia (FTD). The association of inclusion body myopathy and frontotemporal dementia was established by Kovach et al [2001] among 49 affected individuals from the original family described by Kimonis et al [2000] and three other unrelated families. The phenotype has been expanded based on findings in affected individuals from 27 families from North and South America and Europe who harbor VCP missense mutations [Haubenberger et al 2005, Schroder et al 2005, Guyant-Marechal et al 2006, Hübbers et al 2007, Kimonis et al 2008].Kimonis et al [2008] reviewed the clinical variability among 29 individuals from nine families, in whom the diagnosis was confirmed by the presence of a VCP mutation. In those individuals, diagnoses that had been considered before the diagnosis of IBMPFD was established by molecular genetic testing included the following: limb-girdle muscular dystrophy (LGMD) (11 persons); scapuloperoneal muscular dystrophy (SPMD) (8); amyotrophic lateral sclerosis (ALS) (3); spinal muscular atrophy (SMA) (2); diabetic neuropathy (2); inclusion body myositis (1); multiple sclerosis (1); polymyositis (1); facioscapulohumeral (FSH) muscular dystrophy (1); and distal myopathy / oculopharyngeal muscular dystrophy / myofibrillar myopathy (1). The remaining individuals were diagnosed with a nonspecific myopathy. Several persons had more than one diagnosis made over the course of their illness. Myopathy. In families studied thus far, 92% of affected individuals had proximal limb-girdle weakness. Diagnosis was at a mean age of 42 years (range: 3-61 years; typically 20s-40s). Muscle weakness is usually proximal, involving the hip and shoulder girdle muscles; however, several individuals have had initial weakness of the distal muscles of the hands and feet. Affected individuals experience difficulty walking upstairs and raising the arms above the shoulders. The gait is typically waddling and the stance lordotic. Weakness progresses and other limb and respiratory muscle groups become involved over time. Many affected individuals become wheelchair bound. Death typically occurs in the 50s-60s from progressive respiratory and cardiac failure. Dilated cardiomyopathy. In several individuals in the first family originally reported by Kimonis et al [2000] with limb-girdle myopathy and Paget disease of bone, cardiac failure and cardiomyopathy were noted in the later stages of the disease. Hübbers et al [2007] reported dilated cardiomyopathy in a woman with the common mutation characterized by ubiquitin-positive cytoplasmic aggregates and nuclear inclusions. See Dilated Cardiomyopathy Overview. Paget disease of bone (PDB). In families studied thus far, 51% of affected individuals had PDB. Mean age at diagnosis was 42 years (range: 31-61 years). PDB was occasionally asymptomatic, but was diagnosed based on the serum concentration of alkaline phosphatase; therefore, it may be underdiagnosed. PDB involves focal areas of increased bone turnover that lead to complications such as bone pain, localized painful enlargement and deformity of the long bones, pathologic fractures (rare), and deafness. PDB typically manifests as spine and/or hip pain.Frontotemporal dementia. FTD is a degenerative condition of the frontal and anterior temporal lobes that differs from the dementia seen in disorders such as Alzheimer disease (see Alzheimer Disease Overview), Pick disease, and Creutzfeldt-Jakob disease (see Prion Diseases). The areas of the brain affected by FTD control reasoning, personality, movement, speech, social graces, and language; memory is preserved. Among those studied, features were consistent with frontotemporal dementia. In the early stages, dysnomia, dyscalculia, comprehension deficits, and paraphasic errors were evident. Adjusting for aphasia, episodic memory is minimally impaired in the early stages. Progressive aphasia with inability to speak, auditory comprehension deficits for even one-step commands, alexia, and agraphia are noted. In families studied thus far, approximately 30% of affected individuals had frontotemporal dementia. Mean age at diagnosis of dementia was 55 years (range: 42-61 years). Several individuals were in advanced stages of dementia when diagnosed with IBMPFD. Amyotropic lateral sclerosis (ALS). Published data indicate that up to 10% of individuals with VCP-confirmed IBMPFD had a previous diagnosis of ALS [Kimonis et al 2008].Recently five unrelated families with autosomal dominant familial amyotropic lateral sclerosis (ALS) were found to have a mutation in VCP [Johnson et al 2010]. These individuals had limb-onset motor neuron findings with unequivocal upper and lower motor signs affecting all four limbs and bulbar musculature that progressed to quadriparesis and disability. Electrophysiologic studies demonstrated widespread changes of ongoing denervation and chronic reinnervation consistent with ALS. Serum concentration of alkaline phosphatase was within normal limits, thereby excluding concomitant Paget disease. The parent of one proband died at age 58 years with dementia, parkinsonism, Paget disease, and upper-limb muscle weakness, findings that strongly suggest IBMPFD. In another individual with a VCP mutation and diagnosis of ALS, neuropsychological testing performed within one year of symptom onset suggested mild frontal lobe dysfunction. Kumar et al [2010] reported an individual with IBMPFD from an Australian family with a novel VCP mutation (p.Arg155Leu) in whom the clinical findings of muscle wasting, fasciculations, and upper-motor neuron signs on physical examination and neurogenic (rather than myopathic) changes on EMG strongly suggested the diagnosis of ALS.Other phenotypic features including hepatic steatosis, cataracts, sensory-motor axonal neuropathy, pyramidal tract dysfunction, sphincter disturbance, and sensorineural hearing loss have been reported [Haubenberger et al 2005, Guyant-Marechal et al 2006, Hübbers et al 2007, Djamshidian et al 2009, Miller et al 2009, Kumar et al 2010].Neuropathology. VCP-related disease represents a novel class of neurodegenerative diseases called TDP-43 proteinopathies. A systematic analysis of the neuropathologic changes in eight persons with IBMPFD and VCP mutations revealed a novel pattern of ubiquitin pathology characterized by ubiquitin-positive neuronal intranuclear inclusions, dystrophic neuritis, and rare intracytoplasmic inclusions. The ubiquitin pathology was abundant in the neocortex, less robust in limbic and subcortical nuclei, and absent in the dentate gyrus. Only rare inclusions were detected with antibodies to VCP and TDP-43 [Forman et al 2006, Neumann et al 2007]. These findings support the hypothesis that neuropathologic changes associated with VCP mutations result from impairment of ubiquitin-based degradation pathways. In a study of ubiquitin and TDP-43 immunohistochemistry on 193 individuals with familial and simplex (i.e., a single occurrence in a family) frontotemporal lobar degeneration (FTLD) with or without motor neuron disease, including five with familial FTD caused by a VCP mutation, Cairns et al [2007] determined that TDP-43 is a major component of the pathologic inclusions in familial FTD caused by mutations in VCP. Specifically, persons with a VCP mutation had exclusively type 4 FTLD-U (ubiquitin-positive, tau-negative frontotemporal lobar degeneration) pathology, distinguished by numerous neuronal intranuclear inclusions, infrequent neuronal cytoplasmic inclusions, and dystrophic neurites in neocortical areas with relative sparing of the hippocampus.Van der Zee et al [2009] published autopsy data on three individuals in two VCP mutation-positive families from Belgium that was consistent with FTLD-TDP type 4 pathology, showing numerous ubiquitin-immunoreactive, intranuclear inclusions, and dystrophic neuritis staining positive for TDP-43 protein.

Genotype-Phenotype CorrelationsClinical, radiologic, biochemical, and mutation data were analyzed in 103 individuals from 14 families: Individuals with the p.Arg155Cys mutation had an earlier age of onset of IBM (p=0.01) and those with the p.Arg155His mutation had a later onset of PDB (p<0.05) compared to the others [Watts et al 2007]. A mutation in the main catalytic D1 ATPase domain of VCP (p.Ala232Glu) essential for hexamer formation was found in a single family with a more aggressive type of disease. Because of the range of phenotypes associated with mutations in VCP, several studies have looked at modifier genes: From a database of 231 members of 15 families, 174 had APOE genotype available for regression analysis. Analysis of the data suggests a potential link between APOE e4 genotype and the frontotemporal dementia found in IBMPFD [Mehta et al 2007]. No association between frontotemporal dementia and microtubule associated protein tau (MAPT) H2 haplotype was observed (p=0.5) [Author, personal observation].

Differential DiagnosisThe differential diagnosis of inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD) includes the following disorders: Limb-girdle muscular dystrophy (LGMD). Because the muscle biopsy is nonspecific in the majority of individuals with IBMPFD, the disorder has been labeled as an LGMD. Inclusion body myopathy type 2 (IBM2). IBM2 is characterized by adult-onset, slowly progressive distal muscle weakness that begins with gait disturbance and foot drop secondary to anterior tibialis muscle weakness. Weakness eventually includes the hand and thigh muscles, but commonly spares the quadriceps muscles, even in advanced disease. Affected individuals are usually wheelchair bound approximately 20 years after onset. If quadriceps sparing is incomplete, loss of ambulation tends to occur earlier. Muscle histopathology typically shows rimmed vacuoles and characteristic filamentous inclusions. GNE, encoding the bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, is the only gene in which mutations are known to cause IBM2. Inheritance is autosomal recessive [Eisenberg et al 2001]. Sporadic inclusion-body myositis (sIBM) is the most common acquired muscle disease in individuals of European heritage over age 50 years. Pathologically it is characterized by inflammatory, degenerative, and mitochondrial changes that interact in an as-yet-unknown manner to cause progressive muscle degeneration and weakness. The cause is unknown, but it is thought to involve a complex interplay between environmental factors, genetic susceptibility, and aging [Askanas & Engel 2002]. Facioscapulohumeral muscular dystrophy (FSHD) FSHD typically presents before age 20 years with weakness of the facial muscles and the stabilizers of the scapula or the dorsiflexors of the foot. Severity is variable. Weakness is slowly progressive and approximately 20% of affected individuals eventually require a wheelchair. Life expectancy is not shortened. Inheritance is autosomal dominant. Scapuloperoneal myopathy (SPM) (also known as scapuloperoneal muscular dystrophy (SPMD) or scapuloperoneal syndrome, myopathic type). Scapuloperoneal syndromes are heterogeneous. They are characterized by weakness in the distribution of the shoulder girdle and peroneal muscles. Scapuloperoneal myopathy can resemble FSHD clinically. The locus for SPMD has been assigned to 12q [Wilhelmsen et al 1996]. Amyotrophic lateral sclerosis (ALS). Because of asymmetric involvement and association of both distal and proximal muscle groups, individuals with IBMPFD have been misdiagnosed as having ALS. Published data indicate that up to 10% of individuals with VCP-confirmed IBMPFD had a previous diagnosis of ALS [Kimonis et al 2008]. Furthermore, recent studies indicate that VCP mutations cause ALS, broadening the phenotype of IBMPFD to include motor neuron degeneration [Johnson et al 2010]. Paget disease of bone (PDB). Genetic heterogeneity is found [Cody et al 1997, Hocking et al 2002, Laurin et al 2002]. Germline mutations of the gene encoding sequestosome 1 have been implicated in Paget disease of bone. A mutation hot spot (p.Pro392Leu) was identified in the ubiquitin-associated domain (UBA) that accounts for 16% of simplex cases (i.e., a single occurrence in a family) and 46% of familial cases in the French Canadian population. Frontotemporal dementia (FTD) causes a substantial proportion of primary degenerative dementia occurring before age 65 years [Chow et al 1999]. (See CHMP2B-Related Frontotemporal Dementia, GRN-Related Frontotemporal Dementia.)Frontotemporal dementia with parkinsonism-17 (FTDP-17) is a presenile dementia affecting the frontal and temporal cortex and some subcortical nuclei. Clinical presentation is variable. Individuals may present with slowly progressive behavioral changes, language disturbances, and/or extrapyramidal signs. Some present with rigidity, bradykinesia, supranuclear palsy, and saccadic eye movement disorders. Symptoms usually start between ages 40 and 60 years, but may occur earlier or later. Disease duration is usually between five and ten years, but occasionally may be up to 20 to 30 years. The disease progresses over a few years into a profound dementia with mutism. MAPT, encoding microtubule-associated protein tau, is the only gene in which mutations are known to cause FTDP-17. Inheritance is autosomal dominant [Hutton et al 1998]. Alzheimer disease. Imaging studies in IBMPFD reveal atrophy of anterior temporal and frontal lobes. By contrast, more widespread atrophy or perfusion deficits, for example involving parietal lobes, are more compatible with Alzheimer disease. Other DisordersAutosomal dominant limb-girdle myopathy and bone fragility, associated with progressive myopathy of a limb-girdle distribution, bone fragility, poor healing of long bones, premature graying with thin hair, thin skin, hernias, and clotting disorders that may resemble IBMPFD, has been described in a single family [Mehta et al 2006]. Skeletal radiographs demonstrate coarse trabeculation, patchy sclerosis, cortical thickening, and narrowing of medullary cavities. A genome-wide scan mapped the disorder to chromosome 9p21-p22, the region in which diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH) also maps, suggesting possible allelic heterogeneity [Watts et al 2005]. Waggoner et al [2002] reported a ten-member family with autosomal dominant PDB and a scapuloperoneal type of muscular dystrophy. Molecular analyses excluded all known loci for Paget disease of bone, scapuloperoneal muscular dystrophy (SPMD), facioscapulohumeral muscular dystrophy (FSHD), amyotrophic lateral sclerosis (ALS), Bethlem myopathy, two forms of autosomal dominant limb-girdle muscular dystrophy (LGMD), and the critical region for LGMD or HIBM/PDB on chromosome 9p21.1-q12. A genome-wide search identified linkage to chromosome 16q 22.3-q24.1 [Watts et al 2007], a locus known to contain a quantitative trait locus (QTL) [Ralston et al 2005].Nasu Hakola disease (also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, or PLOSL) is a presenile dementia associated with loss of myelin, basal ganglia calcification, and bone cysts. It is caused by recessively inherited mutations in the two genes TREM2 and DAP12 which encode subunits of a cell membrane-associated receptor complex [Paloneva et al 2002].Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD), the following evaluations are recommended: Assessment of muscle strength, muscle wasting and tendon reflexes. EMG and/or muscle biopsy may be necessary. Baseline pulmonary function studies Cardiac evaluation by echocardiogram and ECG Blood alkaline phosphatase, urine pyridinoline studies and, if indicated, skeletal x-ray or bone scan studies to evaluate distribution and severity of Paget disease of the bone Baseline neuropsychological studies of behavior and mental status Treatment of ManifestationsIndividuals benefit from care by a multidisciplinary team that includes: a neurologist, endocrinologist with expertise in Paget disease, specially trained nurses, pulmonologist, speech therapist, physical therapist, occupational therapist, respiratory therapist, nutritionist, psychologist, social worker, and geneticist/genetic counselor.Myopathy. Management should be tailored to the individual. A general approach to appropriate management can prolong survival and improve quality of life. This general approach is based on the typical progression and complications of individuals with LGMD as described by McDonald et al [1995] and Bushby [1999]. Weight control to avoid obesity Physical therapy and stretching exercises to promote mobility and prevent contractures Occupational therapy and use of mechanical aids such as canes, walkers, orthotics, and wheelchairs as needed for ambulation and mobility Surgical intervention as needed for orthopedic complications such as foot deformity and scoliosis Use of respiratory aids when indicated Social and emotional support and stimulation to maximize a sense of social involvement and productivity and to reduce the sense of social isolation common in individuals with these disorders [Eggers & Zatz 1998] Assisted living arrangements as necessitated by muscle weakness and/or dementia Paget disease of bone. Treatment with the following potent bisphosphonates can reduce the alkaline phosphatase concentration and relieve pain and disability: Actonel^®/risedronate Fosamax^®/alendronate Aredia^®/pamidronate SurveillanceAt periodic intervals: Echocardiogram and EKG to monitor for evidence of cardiomyopathy Pulmonary function studies Alkaline phosphatase, skeletal x-rays, and bone scans for monitoring of the PDB if symptomatic and for monitoring of therapy Monitoring of behavior and mental status Agents/Circumstances to AvoidIndividuals and their families should be educated about safety precautions and environmental modification in the home and at work.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDVCP9p13​.3Transitional endoplasmic reticulum ATPaseAlzheimer Disease & Frontotemporal Dementia Mutation Database
alsod/VCP genetic mutations
VCP homepage - Leiden Muscular Dystrophy pagesVCPData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia (View All in OMIM) View in own window 167320INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA; IBMPFD 601023VALOSIN-CONTAINING PROTEIN; VCPNormal allelic variants. VCP has 17 exons. Pathologic allelic variants. Mutations in the 39 families reported to date are summarized in Table 2 and Table 3 (pdf).Table 2. Selected Pathologic VCP Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.277C>Tp.Arg93CysNM_007126​.3
NP_009057​.1c.283C>Gp.Arg95Glyc.463C>Tp.Arg155Cysc.464G>Ap.Arg155Hisc.464G>Cp.Arg155Proc.476G>Ap.Arg159Hisc.572G>Ap.Arg191Glnc.593T>Gp.Leu198Trpc.695C>Ap.Ala232Gluc.1159A>Cp.Asn387HisSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). Normal gene product. The 97-kd transitional endoplasmic reticulum ATPase (also known as the valosin-containing protein) is a member of the type II AAA ATPases (ATPases associated with a variety of activities), characterized by the presence of two conserved ATPase domains, also called AAA domains. Similar to other AAA proteins, it is an enzymatic machine catalyzing ATP hydrolysis to generate energy and using the energy to perform mechanical work in cells. Transitional endoplasmic reticulum ATPase is involved in an unusually wide variety of functions and is associated with distinct and crucial cell protein pathways, namely cell cycle control homotypic membrane fusion, nuclear envelope reconstruction, postmitotic organelle reassembly, and ubiquitin-dependent protein degradation [Rabouille et al 1998, Hetzer et al 2001, Rabinovich et al 2002]. Transitional endoplasmic reticulum ATPase forms a homohexamer and binds to several different adapter proteins, enabling it to target specific substrates for degradation [Kondo et al 1997, Meyer et al 2000]. Transitional endoplasmic reticulum ATPase plays a critical role in the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway during the "quality control process" that selectively eliminates aberrant proteins in the secretory pathway [Jarosch et al 2002]. This pathway also targets destruction of protein substrates dislocated from the ER to the cytosol, where ubiquitination and degradation occur by the 26S proteasome [Dai & Li 2001]. Abnormal gene product. VCP mutations in families with IBMPFD cluster in the N-terminal CDC48 domain, involved in ubiquitin binding [Dai & Li 2001, Rape et al 2001]. This highly structured domain forms two distinct regions — the double ψ barrel (amino acids 25-106) and the four-stranded β barrel (amino acids 112-186) — connected by a short linker region (amino acids 107-111). Transitional endoplasmic reticulum ATPase forms a homohexamer in which the D1/D2 domains bind in a head-to-tail ring [Zhang et al 2000], allowing the N-terminal domain to undergo conformational changes without affecting the stability of the homohexamer ring structure.IBMPFD-causing missense mutations in VCP encode amino acids that disrupt either the double ψ barrel (p.Arg93Cys, p.Arg95Gly/Cys), the four-stranded β barrel (p.Arg155Cys/His/Pro, p.Arg159His), or the flexible linker (p.Arg191Gln). Hence, the affected ubiquitin-binding domain may possibly impair N-terminal domain binding of specific partner proteins. Most of the mutated residues are adjacent and potentially interact with each other (p.Arg155-p.Asn387, p.Arg159-p.Ala232 and p.Arg191-p.Leu198), suggesting that these residues may have a similar and specific function within the homohexamer. Halawani et al [2009] revealed that proteins encoded by VCP mutations p.Arg155Prp and p.Ala232Glu form hexameric ring-shaped structures, exhibiting an approximately threefold increase in ATPase activity and displayed increased sensitivity to heat-induced upregulation of ATPase activity compared to wild type. Protein fluorescence analysis showed conformational differences in the D2 rings and increased the proteolytic susceptibility of both proteins from the VCP mutations. It was suggested that proteins encoded by VCP mutations p.Arg155Pro and p.Ala232Glu possess structural defects that may compromise the mechanism of VCP activity within large multiprotein complexes.Growing evidence implicates transitional endoplasmic reticulum ATPase in neuronal degeneration. Several in vitro studies, using neuronally differentiated mammalian cell lines, show that mutations encoding the D2 domain of VCP are associated with polyubiquitinated proteins that accumulate in nuclear and membrane cellular fractions and induce cytoplasmic vacuoles. Transitional endoplasmic reticulum ATPase also binds to expanded polyglutamine (poly-Q) protein aggregates. The poly-Q binding domain of human transitional endoplasmic reticulum ATPase maps to amino acid residues 142-200, encompassing a region of the N domain and linker (N domain to D1) domain. Recently transitional endoplasmic reticulum ATPase has been associated with the degradation of aggregate-prone proteins, a process principally mediated by autophagy. Proteins encoded by mutated VCP were shown to lead to accumulation of autophagic structures in patient and transgenic animal tissue, likely due to a defect in transitional endoplasmic reticulum ATPase-mediated autophagosome maturation [Ju & Weihl 2010].Animal models for IBMPFD (pdf)