title: The multiple faces of valosin-containing protein-associated diseases: inclusion body myopathy with Paget's disease of bone, frontotemporal dementia, and amyotrophic lateral sclerosis.
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.
authors: Department of Pediatrics, Division of Genetics and Metabolism, 2501 Hewitt Hall, University of California-Irvine, 2501 Hewitt Hall, Irvine, CA 92696, USA.
authors: Angèle
authors: A
authors: Nalbandian
authors: Sandra
authors: S
authors: Donkervoort
authors: Eric
authors: E
authors: Dec
authors: Mallikarjun
authors: M
authors: Badadani
authors: Veeral
authors: V
authors: Katheria
authors: Prachi
authors: P
authors: Rana
authors: Christopher
authors: C
authors: Nguyen
authors: Jogeshwar
authors: J
authors: Mukherjee
authors: Vincent
authors: V
authors: Caiozzo
authors: Barbara
authors: B
authors: Martin
authors: Giles D
authors: GD
authors: Watts
authors: Jouni
authors: J
authors: Vesa
authors: Charles
authors: C
authors: Smith
authors: Virginia E
authors: VE
authors: Kimonis
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D001343:Autophagy; D018797:Cell Cycle Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D056726:Genetic Association Studies; D006801:Humans; D009154:Mutation; D018979:Myositis, Inclusion Body / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D010001:Osteitis Deformans / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse