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

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 valosincontaining 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.Hereditary inclusion body myopathy (IBM) associated with PDB and frontotemporal dementia (FTD), or IBMPFD, is a rare, complex and ultimately lethal autosomal dominant disorder (OMIM 605382; ref. 1). IBMPFD features adult-onset proximal and distal muscle weakness (clinically resembling limb girdle muscular dystrophy), early-onset PDB in most cases and 'premature' FTD 2 . Although the disorder was mapped to chromosome 9p21-p12, the genetic basis was not known.Within 13 families (12 from the United States and 1 from Canada, Fig. 1 and Supplementary Fig. 1 online), 82% of individuals had myopathy, 49% had PDB and 30% had early-onset FTD. The mean age of presentation was 42 years for both IBM and PDB, whereas FTD typically presented at age 53 years. In IBMPFD myopathic muscle and PDB osteoclasts, inclusions appear similar, suggestive of disruptions in the same pathological pathway.Haplotype analysis of the families with IBMPFD identified two ancestral, disease-associated haplotypes, distinguishing families 1, 3, 7 and 16 (group A) from families 2 and 5 (group B), both groups of Northern European ancestry ( Table 1

The phenotypic variability of amyotrophic lateral sclerosis

“…Mutations in VCP, HNRNPA2B1 and HNRNPA1 can induce ALS and/or FTLD combined with inclusion body myositis and bone abnormalities, such as those seen in Paget disease. 72,73 These phenotypes again demonstrate the multisystemic character of ALS.…”

Giant cell tumor occurring in familial Paget's disease of bone: Report of clinical characteristics and linkage analysis of a large pedigree

“…(23)(24)(25) As shown in Table 4, genome-wide screening allowed us to identify five possible candidate regions containing putative genes predisposing to PDB on chromosomes 8 (39 Mb between rs278559 and rs2280871), 5 (50 Mb between rs12514992 and rs17597145; 15 Mb between rs353287 and rs10462946), 6 (56 Mb from 6pter), 20 (2 Mb near the SNP rs11905231), and 1 (47 Mb between rs12142090 and rs6702754). Assuming a dominant model and a 100% penetrance, parametric analysis resulted in Table 3.…”

Genetic analysis of SIGMAR1 as a cause of familial ALS with dementia

“…Mutations in the TARDBP gene encoding the TDP-43 protein, 5,6 and the FUS/TLS gene encoding the FUS protein 7,8 been identified in both ALS and FTLD patients, while mutations in ALS cases recently reported in VCP, 9 a gene in which mutations were previously associated with FTLD. 10 Furthermore, neurons of ALS and FTLD patients both display a nuclear clearing and cytoplasmic sequestration of normal cellular TDP-43 or FUS proteins, 11 which are encoded by genes that, when mutated, are estimated to account for up to 5-10% of all ALS cases. 6,7 Twelve families linked to a locus on chromosome 9p have been reported to have members with either MND or FTLD, while a few members displayed both phenotypes.…”