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

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作者：

GDJ Watts，J Wymer，MJ Kovach，SG Mehta，S Mumm，D Darvish，A Pestronk，MP Whyte，VE Kimonis

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摘要：

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.

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关键词：

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