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TY - JOUR AU - Watts, Giles D J AU - Wymer, Jill AU - Kovach, Margaret J AU - Mehta, Sarju G AU - Mumm, Steven AU - Darvish, Daniel AU - Pestronk, Alan AU - Whyte, Michael P AU - Kimonis, Virginia E PY - 2004 DA - 2004/04/01 TI - Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein JO - Nature Genetics SP - 377 EP - 381 VL - 36 IS - 4 AB - 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. SN - 1546-1718 UR - https://doi.org/10.1038/ng1332 DO - 10.1038/ng1332 ID - Watts2004 ER -