ReviewValosin-containing protein disease: Inclusion body myopathy with Paget’s disease of the bone and fronto-temporal dementia
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).
References (88)
- et al.
Clinical delineation and localization to chromosome 9p13.3–p12 of a unique dominant disorder in four families: hereditary inclusion body myopathy, Paget disease of bone, and frontotemporal dementia
Mol Genet Metab
(2001) - et al.
Clinical and molecular studies in a unique family with autosomal dominant limb-girdle muscular dystrophy and Paget disease of bone
Genet Med
(2000) - et al.
Frontotemporal dementia
Lancet Neurol
(2005) - et al.
Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease
Cell
(1998) - et al.
Molecular perspectives on p97-VCP: progress in understanding its structure and diverse biological functions
J Struct Biol
(2004) - et al.
p97: The cell’s molecular purgatory?
Mol Cell
(2006) - et al.
UBXD7 binds multiple ubiquitin ligases and implicates p97 in HIF1alpha turnover
Cell
(2008) - et al.
Involvement of valosin-containing protein, an ATPase Co-purified with IkappaBalpha and 26 S proteasome, in ubiquitin–proteasome-mediated degradation of IkappaBalpha
J Biol Chem
(1998) - et al.
Dominant-negative effect of mutant valosin-containing protein in aggresome formation
FEBS Lett
(2006) - et al.
Physical and functional interaction between Dorfin and Valosin-containing protein that are colocalized in ubiquitylated inclusions in neurodegenerative disorders
J Biol Chem
(2004)