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 language | English |
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Pages (from-to) | 377-81 |
Number of pages | 5 |
Journal | Nature Genetics |
Volume | 36 |
Issue number | 4 |
DOIs | |
Publication status | Published - Apr 2004 |
Keywords
- Adenosine Triphosphatases
- Cell Cycle Proteins
- Chromosome Mapping
- Chromosomes, Human, Pair 9
- Female
- Humans
- Immunohistochemistry
- Male
- Muscular Diseases
- Mutation
- Osteitis Deformans
- Pedigree