IBMPFD related journal articles
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Trans Assoc Am Physicians. 1982;95:126-34.
A new familial disorder of combined lower motor neuron degeneration and skeletal disorganization.
Tucker WS Jr, Hubbard WH, Stryker TD, Morgan SW, Evans OB, Freemon FR, Theil GB.
A new familial disorder, inherited as an autosomal dominant trait and characterized by dual features of neurologic degeneration and skeletal disorganization, is reported. The neurologic disease is a degenerative process of lower motor neurons and develops in middle age with progressive muscle weakness and ends in respiratory failure and premature death. Clinical examination, electromyography, and muscle biopsy with histochemical stains are diagnostic. The skeletal disorganization resembles Paget’s disease of bone. It is characterized by polyostotic radiographic abnormalities, elevated serum alkaline phosphatase of bone origin, abnormal radioisotopic bone scan, elevated hydroxyprolinuria, and bone histology.
PMID:7182974 [PubMed – indexed for MEDLINE]
Nat Genet. 2004 Apr;36(4):377-81. Epub 2004 Mar 21.
Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein.
Watts GD, Wymer J, Kovach MJ, Mehta SG, Mumm S, Darvish D, Pestronk A, Whyte MP, Kimonis VE.
Division of Genetics, Children’s Hospital Boston, 300 Longwood Avenue, Harvard Medical School, Boston, Massachusetts 02115, USA.
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 approximately 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.
PMID:15034582 [PubMed – indexed for MEDLINE]
J Cell Biol. 2009 December 14; 187(6): 875–888. PMCID: PMC2806317
Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease
Jeong-Sun Ju,1 Rodrigo A. Fuentealba,1 Sara E. Miller,1 Erin Jackson,3 David Piwnica-Worms,2,3,4,5Robert H. Baloh,1,2 and Conrad C. Weihl1,2
1Department of Neurology, 2Hope Center for Neurological Disorders, 3Molecular Imaging Center,4Department of Radiology, and 5Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110
Corresponding author. Correspondence to Conrad C. Weihl: Email: firstname.lastname@example.org
Mutations in valosin-containing protein (VCP) cause inclusion body myopathy (IBM), Paget’s disease of the bone, and frontotemporal dementia (IBMPFD). Patient muscle has degenerating fibers, rimmed vacuoles (RVs), and sarcoplasmic inclusions containing ubiquitin and TDP-43 (TARDNA-binding protein 43). In this study, we find that IBMPFD muscle also accumulates autophagosome-associated proteins, Map1-LC3 (LC3), and p62/sequestosome, which localize to RVs. To test whether VCP participates in autophagy, we silenced VCP or expressed adenosine triphosphatase–inactive VCP. Under basal conditions, loss of VCP activity results in autophagosome accumulation. After autophagic induction, these autophagosomes fail to mature into autolysosomes and degrade LC3. Similarly, IBMPFD mutant VCP expression in cells and animals leads to the accumulation of nondegradative autophagosomes that coalesce at RVs and fail to degrade aggregated proteins. Interestingly, TDP-43 accumulates in the cytosol upon autophagic inhibition, similar to that seen after IBMPFD mutant expression. These data implicate VCP in autophagy and suggest that impaired autophagy explains the pathology seen in IBMPFD muscle, including TDP-43 accumulation.
J Neurosci. 2010 Jun 2;30(22):7729-39.
TDP-43 mediates degeneration in a novel Drosophila model of disease caused by mutations in VCP/p97.
Ritson GP, Custer SK, Freibaum BD, Guinto JB, Geffel D, Moore J, Tang W, Winton MJ, Neumann M, Trojanowski JQ, Lee VM, Forman MS, Taylor JP.
Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia (IBMPFD) is a dominantly inherited degenerative disorder caused by mutations in the valosin-containing protein (VCP7) gene. VCP (p97 in mouse, TER94 in Drosophila melanogaster, and CDC48 in Saccharomyces cerevisiae) is a highly conserved AAA(+) (ATPases associated with multiple cellular activities) ATPase that regulates a wide array of cellular processes. The mechanism of IBMPFD pathogenesis is unknown. To elucidate the pathogenic mechanism, we developed and characterized a Drosophila model of IBMPFD (mutant-VCP-related degeneration). Based on genetic screening of this model, we identified three RNA-binding proteins that dominantly suppressed degeneration; one of these was TBPH, the Drosophila homolog of TAR (trans-activating response region) DNA-binding protein 43 (TDP-43). Here we demonstrate that VCP and TDP-43 interact genetically and that disease-causing mutations in VCP lead to redistribution of TDP-43 to the cytoplasm in vitro and in vivo, replicating the major pathology observed in IBMPFD and other TDP-43 proteinopathies. We also demonstrate that TDP-43 redistribution from the nucleus to the cytoplasm is sufficient to induce cytotoxicity. Furthermore, we determined that a pathogenic mutation in TDP-43 promotes redistribution to the cytoplasm and enhances the genetic interaction with VCP. Together, our results show that degeneration associated with VCP mutations is mediated in part by toxic gain of function of TDP-43 in the cytoplasm. We suggest that these findings are likely relevant to the pathogenic mechanism of a broad array of TDP-43 proteinopathies, including frontotemporal lobar degeneration and amyotrophic lateral sclerosis.
PMID:20519548 [PubMed – indexed for MEDLINE]
Hum Mol Genet. 2010 May 1;19(9):1741-55. Epub 2010 Feb 10.
Transgenic mice expressing mutant forms VCP/p97 recapitulate the full spectrum of IBMPFD including degeneration in muscle, brain and bone.
Custer SK, Neumann M, Lu H, Wright AC, Taylor JP.
Department of Developmental Neurobiology, St. Jude Children’s Research, Hospital, Memphis, TN 38105, USA.
Inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia (IBMPFD) is a dominantly inherited degenerative disorder caused by mutations in the valosin-containing protein (VCP) gene. VCP (p97 in mouse, TER94 in Drosophila melanogaster and CDC48 in Saccharomyces cerevisiae) is a highly conserved AAA(+)-ATPase that regulates a wide array of cellular processes. The mechanism of IBMPFD pathogenesis is unknown. Towards elucidating the pathogenic mechanism we have developed and characterized transgenic mice with ubiquitous expression of wild-type and disease-causing versions of human VCP/p97. Here, we report that mice expressing VCP/p97 harboring the mutations R155H or A232E develop pathology that is limited to muscle, brain and bone, recapitulating the spectrum of disease in humans with IBMPFD. The mice exhibit progressive muscle weakness and pathological examination of muscle shows classic characteristics of inclusion body myopathy including rimmed vacuoles and TDP-43 pathology. The mice exhibit abnormalities in behavioral testing and pathological examination of the brain shows widespread TDP-43 pathology. Furthermore, radiological examination of the skeleton reveals that mutant mice develop severe osteopenia accompanied by focal lytic and sclerotic lesions in vertebrae and femur. In vitro studies indicate that mutant VCP causes inappropriate activation of the NF-kappaB signaling cascade, which could contribute to the mechanism of pathogenesis in multiple tissues including muscle, bone and brain.
PMID:20147319 [PubMed – indexed for MEDLINE]