Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2011 Nov;45(3):522-31.
doi: 10.1007/s12031-011-9627-y. Epub 2011 Sep 3.

The multiple faces of valosin-containing protein-associated diseases: inclusion body myopathy with Paget's disease of bone, frontotemporal dementia, and amyotrophic lateral sclerosis

Angèle Nalbandian  1 , Sandra Donkervoort, Eric Dec, Mallikarjun Badadani, Veeral Katheria, Prachi Rana, Christopher Nguyen, Jogeshwar Mukherjee, Vincent Caiozzo, Barbara Martin, Giles D Watts, Jouni Vesa, Charles Smith, Virginia E Kimonis
Affiliations
Free article
Review

The multiple faces of valosin-containing protein-associated diseases: inclusion body myopathy with Paget's disease of bone, frontotemporal dementia, and amyotrophic lateral sclerosis

Angèle Nalbandian et al. J Mol Neurosci. 2011 Nov.
Free article

Abstract

Inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD) is a progressive, fatal genetic disorder with variable penetrance, predominantly affecting three main tissue types: muscle (IBM), bone (PDB), and brain (FTD). IBMPFD is caused by mutations in the ubiquitously expressed valosin-containing protein (VCP) gene, a member of the AAA-ATPase superfamily. The majority of individuals who develop IBM have progressive proximal muscle weakness. Muscle biopsies reveal rimmed vacuoles and inclusions that are ubiquitin- and TAR DNA binding protein-43 (TDP-43)-positive using immunohistochemistry. PDB, seen in half the individuals, is caused by overactive osteoclasts and is associated clinically with pain, elevated serum alkaline phosphatase, and X-ray findings of coarse trabeculation and sclerotic lesions. FTD diagnosed at a mean age of 55 years in a third of individuals is characterized clinically by comprehension deficits, dysnomia, dyscalculia, and social unawareness. Ubiquitin- and TDP-43-positive neuronal inclusions are also found in the brain. Genotype-phenotype correlations are difficult with marked intra-familial and inter-familial variations being seen. Varied phenotypes within families include frontotemporal dementia, amyotrophic lateral sclerosis, Parkinsonism, myotonia, cataracts, and anal incompetence, among others. Cellular and animal models indicate pathogenetic disturbances in IBMPFD tissues including altered protein degradation, autophagy pathway alterations, apoptosis, and mitochondrial dysfunction. Currently, mouse and drosophila models carrying VCP mutations provide insights into the human IBMPFD pathology and are useful as tools for preclinical studies and testing of therapeutic strategies. In this review, we will explore the pathogenesis and clinical phenotype of IBMPFD caused by VCP mutations.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Mol Cell. 2006 May 19;22(4):451-62 - PubMed
    1. J Neurol Neurosurg Psychiatry. 2009 May;80(5):583-4 - PubMed
    1. Mol Cell Biol. 2002 Jan;22(2):626-34 - PubMed
    1. J Neurol Neurosurg Psychiatry. 2008 Jan;79(1):6-11 - PubMed
    1. Traffic. 2002 Aug;3(8):530-6 - PubMed

Publication types

MeSH terms