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- Title
Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein.
- Authors
Watts, Giles D. J.; Wymer, Jill; Kovach, Margaret J.; Mehta, Sarju G.; Mumm, Steven; Darvish, Daniel; Pestronk, Alan; Whyte, Michael P.; Kimonis, Virginia E.
- 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 ~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.
- Subjects
INCLUSION body myositis; MUSCLE diseases; OSTEITIS deformans; DEMENTIA; CHROMOSOME abnormalities; EXONS (Genetics); CELL cycle; MEMBRANE fusion
- Publication
Nature Genetics, 2004, Vol 36, Issue 4, p377
- ISSN
1061-4036
- Publication type
Article
- DOI
10.1038/ng1332