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

Giles D J Watts, Jill Wymer, Margaret J Kovach, Sarju G Mehta, Steven Mumm, Daniel Darvish, Alan Pestronk, Michael P Whyte, Virginia E Kimonis

Research output: Contribution to journalArticlepeer-review

1039 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)377-81
Number of pages5
JournalNature Genetics
Volume36
Issue number4
DOIs
Publication statusPublished - Apr 2004

Keywords

  • Adenosine Triphosphatases
  • Cell Cycle Proteins
  • Chromosome Mapping
  • Chromosomes, Human, Pair 9
  • Female
  • Humans
  • Immunohistochemistry
  • Male
  • Muscular Diseases
  • Mutation
  • Osteitis Deformans
  • Pedigree

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