title: Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein.
abstract: 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.
authors.affiliation: Division of Genetics, Children's Hospital Boston, 300 Longwood Avenue, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Giles D J
authors.initials: GD
authors.lastname: Watts
authors.forename: Jill
authors.initials: J
authors.lastname: Wymer
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Kovach
authors.forename: Sarju G
authors.initials: SG
authors.lastname: Mehta
authors.forename: Steven
authors.initials: S
authors.lastname: Mumm
authors.forename: Daniel
authors.initials: D
authors.lastname: Darvish
authors.forename: Alan
authors.initials: A
authors.lastname: Pestronk
authors.forename: Michael P
authors.initials: MP
authors.lastname: Whyte
authors.forename: Virginia E
authors.initials: VE
authors.lastname: Kimonis
mesh_terms: D000251:Adenosine Triphosphatases; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D002874:Chromosome Mapping; D002899:Chromosomes, Human, Pair 9; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009135:Muscular Diseases / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation; D010001:Osteitis Deformans / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein