Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0005940 (bone disease)
 7,459 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Paget's disease of bone (PDB) is a common metabolic bone disease of late onset with a strong genetic component. Rarely, PDB can occur as part of a syndrome in which the disease is accompanied by inclusion body myopathy and frontotemporal dementia (inclusion body myopathy, Paget's disease and frontotemporal dementia, IBMPFD). Recently, IBMPFD has been shown to be caused by mutations in Valosin-containing Protein (VCP), which is required for the proteasomal degradation of phosphorylated IkappaB-alpha, a necessary step in the activation of the transcription factor NF-kappaB. Here, we evaluated the role of VCP in the pathogenesis of typical PDB. We conducted mutation screening of VCP in 44 kindreds with familial Paget's disease recruited mainly through clinic referrals in the UK, Australia and New Zealand. We also performed an association study of VCP haplotypes in patients with PDB who did not have a family history of the disease (sporadic PDB). No mutations were found in VCP in three PDB families where there was evidence of allele sharing between affected subjects in the VCP critical region on chromosome 9p13. We failed to detect disease-associated mutations in any of the three exons previously reported to contain IBMPFD mutations in a further 41 PDB families. We found no evidence of allelic association between common VCP haplotypes in a case-control study of 179 sporadic PDB patients and 172 age- and sex-matched controls. Genetic variation in VCP does not appear to be a common cause of familial or sporadic PDB in the absence of myopathy and dementia.
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PMID:Evaluation of the role of Valosin-containing protein in the pathogenesis of familial and sporadic Paget's disease of bone. 1619 18

We report on an unusual family with an autosomal dominant limb-girdle type of myopathy and bone fragility. This family was previously reported by Henry et al. [1958] as autosomal dominant progressive limb girdle "muscular dystrophy" with propensity to fractures and defective healing of long bones. Clinical, biochemical, and radiological aspects were evaluated in eight living relatives in this family (three males and five females) and in eight deceased individuals. The average age-of-onset of the limb-girdle myopathy was 31 years occurring in 87% of affected individuals. The average age of onset of fractures was 24 years occurring in 88% of affected individuals. Biochemical analysis showed a mean alkaline phosphatase (ALP) of 64 U/L (normal 30-120) and borderline high creatine kinase (CK) of 213 U/L (normal 4-220). Radiographs revealed coarse trabeculation, patchy sclerosis, cortical thickening, and narrowing of the medullary cavity with an appearance not considered typical of Paget disease of bone (PDB) or of fibrous dysplasia. Results of nerve conduction studies were normal, and electromyograms and muscle biopsies documented non-specific myopathic changes. There is premature graying with thin hair, thin skin, hernias and the affected individuals appear older than their chronological age, and three members had a clotting disorder. Linkage analysis for markers for the chromosome 9p22.3-q12 locus indicated that the disorder in this family does not segregate with markers in the critical region of limb-girdle/inclusion body myopathy, PDB, and frontotemporal dementia (FTD) [IBMPFD, OMIM #605382]. Sequencing of Valosin-containing protein (VCP), the gene associated with IBMPFD, did not identify mutations. We have excluded linkage to the known loci for limb-girdle type of myopathy and bone disease and excluded several candidate genes. Elucidation of the novel molecular basis of this disorder may provide valuable links between bone, collagen and muscle, and targeted therapeutic options.
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PMID:Manifestations in a family with autosomal dominant bone fragility and limb-girdle myopathy. 1641 37

Frontotemporal dementia with inclusion body myopathy and Paget's disease of bone (IBMPFD) is a rare, autosomal dominant disorder caused by mutations in the gene valosin-containing protein (VCP). The CNS pathology is characterized by a novel pattern of ubiquitin pathology distinct from sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive inclusions without VCP mutations. Yet, the ubiquitin-positive inclusions in IBMPFD also stain for TAR DNA binding protein, a feature that links this rare disease with the pathology associated with the majority of sporadic FTD as well as disease resulting from different genetic alterations. VCP, a member of the AAA-ATPase gene family, associates with a plethora of protein adaptors to perform a variety of cellular processes including Golgi assembly/disassembly and regulation of the ubiquitin-proteasome system. However, the mechanism whereby mutations in VCP lead to CNS, muscle, and bone disease is largely unknown. In this report, we review current literature on IBMPFD, focusing on the pathology of the disease and the biology of VCP with respect to IBMPFD.
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PMID:Valosin-containing protein and the pathogenesis of frontotemporal dementia associated with inclusion body myopathy. 1745 94