Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein

By Giles D. J. Watts, J. Wymer, M. J. Kovach, S. Mehta, S. Mumm, D. Darvish, A. Pestronk, M. Whyte, V. Kimonis. Nature Genetics, 2004

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Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD) is a dominant progressive disorder that maps to chromosome 9p21.1–p12. We investigated 13 families with IBMPFD linked to chromosome 9 using a candidate-gene approach. We found six missense mutations in the gene encoding valosin-containing protein (VCP, a member of the AAA-ATPase superfamily) exclusively in all 61 affected individuals. Haplotype analysis indicated that descent from two founders in two separate North American kindreds accounted for IBMPFD in ∼50% of affected families. VCP is associated with a variety of cellular activities, including cell cycle control, membrane fusion and the ubiquitin-proteasome degradation pathway. Identification of VCP as causing IBMPFD has important implications for other inclusion-body diseases, including myopathies, dementias and Paget disease of bone (PDB), as it may define a new common pathological ubiquitin-based pathway.

Subfields: Cell Biology, Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/83382b08cd5732faca742ea4af02ae658f315635

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Citations in the corpus

Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system (2012, background): “As stated above, p97 missense mutations cause the degenerative late-onset disorder IBMPFD that affects various tissue”
Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration (2007, background): “mosome 9p [4, 5, 20, 55, 56, 57, 68, 75, 77], and the novel (TDP-43) proteinopathy, which is present in most cases of FTLD-U with or without MND [3, 16, 21, 61].”
Exome sequencing reveals VCP mutations as a cause of familial ALS (2010, positive): “This particular mutation has been previously described as the cause of an unusual syndrome characterized clinically by the triad of Inclusion Body Myopathy with early-onset Paget disease of the bone and Frontotemporal Dementia (IBMPFD) (Watts et al., 2004), and characterized pathologically by the pr”
Converging mechanisms in ALS and FTD: Disrupted RNA and protein homeostasis (2013, positive): “ALS-and FTD-Linked Mutations in Vasolin-Containing Protein Mutations in vasolin-containing protein (VCP) were originally identified as causative of inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMFTD) (Watts et al., 2004) and later in ALS (Johnson et al., 2010).”
Cellular strategies for controlling protein aggregation (2010, background): “VCP mutations are linked to inclusion body myopathy with early-onset Paget's disease and frontotemporal dementia (IBMPFD) and loss of VCP function in mammalian cells leads to the accumulation of insoluble ubiquitylated protein”
Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. (2011, background): “…diagnosis of bvFTD is critical, as it has implications for heritability (Hutton et al., 1998; Poorkaj et al., 1998; Spillantini et al., 1998; Watts et al., 2004; Skibinski et al., 2005; Baker et al., 2006; Cruts et al., 2006; Kumar-Singh and Van Broeckhoven, 2007), prognosis (Rascovsky et…”
The roles of intracellular protein-degradation pathways in neurodegeneration (2006, background): “Mutations in CDC48/p97 (also known as valosin-containing protein) cause a dominantly inherited disease known as inclusion-body myopathy with Paget's disease of bone and frontotemporal dementia, which is also characterized by cytoplasmic and nuclear aggregates in muscle and brain tissue”