Autosomal dominant myopathy, Paget disease of bone, and dementia constitute a unique disorder (MIM 605382). Here we describe the clinical, biochemical, radiological, and pathological characteristics of 49 affected (23 male, 26 female) individuals from four unrelated United States families. Among these affected individuals 90% have myopathy, 43% have Paget disease of bone, and 37% have premature frontotemporal dementia. EMG shows myopathic changes and muscle biopsy reveals nonspecific myopathic changes or blue-rimmed vacuoles. After candidate loci were excluded, a genome-wide screen in the large Illinois family showed linkage to chromosome 9 (maximum LOD score 3.64 with marker D9S301). Linkage analysis with a high density of chromosome 9 markers generated a maximum two-point LOD score of 9.29 for D9S1791, with a maximum multipoint LOD score of 12.24 between D9S304 and D9S1788. Subsequent evaluation of three additional families demonstrating similar clinical characteristics confirmed this locus, refined the critical region, and further delineated clinical features of this unique disorder. Hence, autosomal dominant inclusion body myopathy (HIBM), Paget disease of bone (PDB), and frontotemporal dementia (FTD) localizes to a 1.08–6.46 cM critical interval on 9p13.3–12 in the region of autosomal recessive IBM2.
"In addition, a member of the same family can have any combination of phenotypes. An illustrative example comes from one of the first families in which VCP mutations were identified – the five siblings each harbored different phenotypes: sibling 1 with muscle weakness and FTD, sibling 2 with PDB and FTD, sibling 3 with PDB and weakness, sibling 4 with isolated weakness and sibling 5 with weakness, PDB and FTD (Kovach et al., 2001). As more patients are identified with VCP mutations, the phenotypic spectrum continues to expand. "
[Show abstract][Hide abstract] ABSTRACT: The ATPase valosin-containing protein (VCP)/p97 has emerged as a central and important element of the ubiquitin system. Together with a network of cofactors, it regulates an ever-expanding range of processes that stretch into almost every aspect of cellular physiology. Its main role in proteostasis and key functions in signaling pathways are of relevance to degenerative diseases and genomic stability. In this Cell Science at a Glance and the accompanying poster, we give a brief overview of this complex system. In addition, we discuss the pathogenic basis for VCP/p97-associated diseases and then highlight in more detail new exciting links to the translational stress response and RNA biology that further underscore the significance of the VCP/p97 system.
"First of all, IBMPFD is a rare disorder, accounting for less than 1% of all patients with a familial form of FTD.5 Second, only a small group of all patients (12%) will ultimately exhibit the triad of cardinal symptoms that gave the disease its name: while 80-90% of all patients will have IBM and approximately half of them are diagnosed with PDB, only a third will develop ubiquitin-positive FTD.6 Moreover, the phenotypic expression of a mutation can vary so widely that carriers of the same mutation in a single affected family can have completely different symptoms: for example, one member might have PDB and FTD while his or her siblings might have only IBM.4 To complete the confusion, even two family members with IBM can exhibit a marked variability in the patterns of muscle weakness,7 or atypical features such as pyramidal tract dysfunction [mimicking spastic paraplegia or amyotrophic lateral sclerosis (ALS)], sensory motor axonal neuropathy, Parkinsonism, sensorineural hearing loss, cataract, cardiomyopathy, liver steatosis, sphincter disturbances, or erectile dysfunction.3,8,9,10 "
[Show abstract][Hide abstract] ABSTRACT: Inclusion-body myopathy with Paget's disease of the bone and frontotemporal dementia (IBMPFD) is a rare, late-onset autosomal disorder arising from missense mutations in a gene coding for valosin-containing protein.
We report the case of a man carrying the previously described p.Arg159His mutation, who had an unusual axonal sensorimotor neuropathy as the first clinical manifestation of IBMPFD, and for whom diagnosis only became clear 8 years later when the patient developed frontotemporal dementia.
Peripheral neuropathy is a rare manifestation of IBMPFD. This underdiagnosed disorder should be considered when a patient develops dementia or has signs of Paget's disease.
"The IBMPFD locus has been mapped to chromosome 9p21.1-p12 (Kovach et al., 2001). In 2004, this rare proteinopathy, affecting mainly muscle, brain and bone, was found to be associated with mutations in the p97/VCP gene (Watts et al., 2004). "
[Show abstract][Hide abstract] ABSTRACT: p97/VCP is a hexameric AAA type ATPase that functions in a variety of cellular processes such as endoplasmic reticulum associated degradation (ERAD), organelle biogenesis, autophagy and cell-cycle regulation. Inclusion body myopathy associated with Paget disease of the bone and frontotemporal dementia (IBMPFD) is an autosomal dominant disorder which has been attributed to mutations in p97/VCP. Several missense mutations affecting twelve different amino acids have been identified in IBMPFD patients and some of them were suggested to be involved in the observed pathology. Here, we analyzed the effect of all twelve p97/VCP variants on ERAD substrates and their cofactor binding abilities. While all mutants cause ERAD substrate accumulation, P137L mutant p97/VCP differs from other IBMPFD mutants by having a unique solubility profile and subcellular localization. Intriguingly, although almost all mutants exhibit enhanced p47 and Ufd1-Npl4 binding, the P137L mutation completely abolishes p97/VCP interactions with Ufd1, Npl4 and p47, while retaining its gp78 binding. While recombinant R155C mutant protein consistently interacts with both Ufd1 and VIM of gp78, P137L mutant protein lost binding ability to Ufd1 but not to VIM in vitro. The differential impairments in p97/VCP interactions with its functional partners and function should help our understanding of the molecular pathogenesis of IBMPFD.
The international journal of biochemistry & cell biology 01/2013; 45(4). DOI:10.1016/j.biocel.2013.01.006 · 4.05 Impact Factor
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