Review
Valosin-containing protein disease: Inclusion body myopathy with Paget’s disease of the bone and fronto-temporal dementia

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Abstract

Mutations in valosin-containing protein (VCP) cause inclusion body myopathy (IBM) associated with Paget’s disease of the bone (PDB) and fronto-temporal dementia (FTD) or IBMPFD. Although IBMPFD is a multisystem disorder, muscle weakness is the presenting symptom in greater than half of patients and an isolated symptom in 30%. Patients with the full spectrum of the disease make up only 12% of those affected; therefore it is important to consider and recognize IBMPFD in a neuromuscular clinic. The current review describes the skeletal muscle phenotype and common muscle histochemical features in IBMPFD. In addition to myopathic features; vacuolar changes and tubulofilamentous inclusions are found in a subset of patients. The most consistent findings are VCP, ubiquitin and TAR DNA-binding protein 43 (TDP-43) positive inclusions. VCP is 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 protein degradation. Although the role of VCP in skeletal muscle is currently unknown, it is clear that VCP mutations lead to the accumulation of ubiquitinated inclusions and protein aggregates in patient tissue, transgenic animals and in vitro systems. We suggest that IBMPFD is novel type of protein surplus myopathy. Instead of accumulating a poorly degraded and aggregated mutant protein as seen in some myofibrillar and nemaline myopathies, VCP mutations disrupt its normal role in protein homeostasis resulting in the accumulation of ubiquitinated and aggregated proteins that are deleterious to skeletal muscle.

Introduction

IBMPFD is an autosomal dominantly inherited disorder with variable penetrance of three predominant phenotypic features [1]. (1) 90% of patients develop disabling weakness with a mean onset of 45 years of age at this same mean age (2) 51% of affected patients have osteolytic lesions consistent with PDB. Finally (3) 32% develop a typical FTD manifested by prominent language and behavior dysfunction with a mean onset of 54-years-old [2]. Other phenotypic features have been reported as well, including dilated cardiomyopathy, hepatic fibrosis, cataracts and sensory-motor axonal neuropathy [3], [4], [5]. How common these features are in affected patients is not known.

Familial syndromes phenotypically similar to IBMPFD had been described prior to the identification of VCP as the causative gene in 2004 [1]. Four previous reports described an autosomal dominant syndrome with weakness and PDB with and without dementia [6], [7], [8], [9]. Most notably, a multisystem myotonic disorder with fronto-temporal dementia was described that subsequently was recharacterized as IBMPFD once VCP gene testing was performed [3]. In addition, a family with lower motor neuron degeneration and PDB reported in 1982 by Tucker et al. [8] was found to have an R155P gene mutation in VCP [1]. Whether the two other previous syndromes were in fact IBMPFD remains unknown.

Section snippets

Clinical features of IBMPFD myopathy

Muscle weakness is an isolated symptom in ∼30% of patients and the presenting symptom in greater than half of patients with IBMPFD suggesting that IBMPFD may be commonly seen in a neuromuscular clinic without its other syndromic features [10]. Because of this, it is important for clinicians to take a careful family history of dementia and PDB in a patient with a suspected IBM. Patients can present with both proximal and distal muscle weakness. Commonly described patterns include proximal lower

Muscle pathology in IBMPFD

Reported muscle biopsy histopathology is consistent with IBM in a subset of patients [1], [3], [4], [5], [11], [12], [14]. These patients have histologic features consistent with IBM including ubiquitin positive and tubulofilamentous inclusions seen by EM [5], [11]. However, many patients have no rimmed vacuoles and have been characterized as a non-specific myopathy [13]. A recent review of 49 patients from nine different families noted that of the 18 patients with muscle biopsies performed

Overlapping pathology with fronto-temporal dementia (FTD)

Patients with VCP dementia have prominent ubiquitin positive intranuclear neuronal inclusions classifying it as a novel type of FTD [21], [22]. Rare intranuclear neuronal VCP inclusions are also present [21], [22]. FTDs are a group of neurodegenerative disorders associated with degeneration of the prefrontal and anterior temporal lobes. They are histopathologically distinguishable from other dementias due to the lack of Alzheimer disease type pathology [23]. Affected patients (∼50%) report a

The biology of VCP

VCP is a member of the AAA+ protein family [28]. Dysfunction in this family of proteins is associated with many inherited diseases including hereditary spastic paraparesis due to mutations in the proteins spastin and paraplegin [29], [30] and juvenile onset generalized dystonia associated with mutations in torsinA [31]. The typical features of a AAA+ protein are one or two tandemly encoded AAA+ protein domains (two in the case of VCP) [28]. These domains are essential for ATP binding and

VCP in skeletal muscle

VCP is an abundant and ubiquitously distributed protein. It has been reported to be similarly expressed in most mammalian tissues [52] and targeted deletion of VCP in mice is embryonic lethal [53]. The normal role of VCP in mammalian skeletal muscle is not known. One study found that the localization of VCP in differentiated skeletal muscle tissue is intranuclear [19]. Our studies in addition to others, find VCP throughout the sarcoplasm but also perinuclear and within endomysial vessels in

IBMPFD mutant VCP

To date there have been thirteen unique IBMPFD mutations in VCP associated with eight different residues with an arginine at residue 155 having three different mutations each (Fig. 2) [13]. These residues cluster within the N and D1 domain interface (Fig. 2). This is a region that has been proposed to associate with ubiquitin and ubiquitin-like domain containing proteins [48], [50]. Most notably using NMR spectroscopy, it was shown that ubiquitin-like domain of the ERAD essential protein Npl4

IBMPFD a disorder of protein homeostasis

Fundamentally, VCP is involved in protein homeostasis or maintaining the proper balance between protein synthesis and protein degradation necessary for all cells [63]. This balance is disturbed in many disease states associated with protein accumulation [63]. VCP mutations may affect the normal function of VCP in protein homeostasis (Fig. 3). For example, VCP is necessary for the retrotranslocation of misfolded ER synthesized proteins [51]. A failure in this activity would result in defective

Conclusions

IBMPFD is an autosomal dominant multisystem disorder due to mutations in the multifunctional chaperone VCP [1]. Muscle weakness typically presents in the 3rd to 4th decade of life and is phenotypically heterogeneous with both proximal and distal weakness owing to the confusion in the diagnosis as being FSHD or LGMD. Muscle biopsies often show vacuoles in a subset of patients but more commonly have prominent ubiquitinated sarcoplasmic and myonuclear inclusions in association with VCP and TDP-43

Acknowledgements

This work was supported by research grants from the Muscular Dystrophy Association (CCW), NIH 5K08AG026271 (CCW) and NIH 1R01AG031867 (CCW).

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