Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein.
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.
Watts
Giles D J
GD
Division of Genetics, Children's Hospital Boston, 300 Longwood Avenue, Harvard Medical School, Boston, Massachusetts 02115, USA.
Wymer
Jill
J
Kovach
Margaret J
MJ
Mehta
Sarju G
SG
Mumm
Steven
S
Darvish
Daniel
D
Pestronk
Alan
A
Whyte
Michael P
MP
Kimonis
Virginia E
VE
D000251:Adenosine Triphosphatases; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D002874:Chromosome Mapping; D002899:Chromosomes, Human, Pair 9; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009135:Muscular Diseases / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation; D010001:Osteitis Deformans / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D000074405:Valosin Containing Protein
D018797:Cell Cycle Proteins; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein