Autosomal dominant inclusion body myopathy, Paget disease of bone, and frontotemporal dementia.
Autosomal dominant proximal limb girdle or inclusion body myopathy, associated with Paget disease of bone and frontotemporal dementia (IBMPFD) is a recently described disorder that maps to chromosome 9p21.1-p12. We refined the critical locus and identified the gene as the Valosin Containing Protein (VCP) gene, a member of the AAA-ATPase superfamily using a candidate gene approach. Six missense mutations were found to co-segregate with affected individuals only, two of these representing mutation hot spots. We report the clinical and molecular findings in 99 individuals in 13 families. VCP is associated with a variety of cellular activities, including the control of cell cycle, membrane fusion, and the ubiquitin-proteasome degradation pathway. Previous studies have associated VCP mutants in cell lines with vacuole formation and aggregate formation. Identification of VCP as the gene causing IBMPFD has important implications for understanding the pathogenesis of neurodegenerative disorders.
Kimonis
Virginia E
VE
Division of Genetics, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA. virginia.kimonis@childrens.harvard.edu
Watts
Giles D J
GD
D000251:Adenosine Triphosphatases; D000293:Adolescent; D000328:Adult; D018797:Cell Cycle Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D018979:Myositis, Inclusion Body / Q000235:genetics* / Q000473:pathology; D010001:Osteitis Deformans / Q000235:genetics* / Q000473:pathology; D020774:Pick Disease of the Brain / Q000235:genetics* / Q000473:pathology; D000074405:Valosin Containing Protein
D018797:Cell Cycle Proteins; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein