Mechanisms of disease: genetics of Paget's disease of bone and related disorders.
Paget's disease of bone (PDB) is a common disorder in which focal abnormalities of increased bone turnover lead to complications such as bone pain, deformity, pathological fractures, and deafness. PDB has a strong genetic component and several susceptibility loci for the disease have been identified by genome-wide scans. Mutations that predispose individuals to PDB and related disorders have been identified in four genes. The rare PDB-like syndromes of familial expansile osteolysis, early-onset familial PDB, and expansile skeletal hyperphosphatasia are caused by insertion mutations in TNFRSF11A, which encodes receptor activator of nuclear factor (NF)kappaB (RANK)-a critical regulator of osteoclast function. Inactivating mutations in TNFRSF11B, which encodes osteoprotegerin (a decoy receptor for RANK ligand) cause idiopathic hyperphosphatasia, and polymorphisms in this gene seem to increase the risk for classical PDB. Mutations of the sequestosome 1 gene (SQSTM1), which encodes an important scaffold protein in the NFkappaB pathway, are a common cause of classical PDB. The rare syndrome of hereditary inclusion body myopathy, PDB, and fronto-temporal dementia is caused by mutations in the valosin-containing protein (VCP) gene. This gene encodes VCP, which has a role in targeting the inhibitor of NFkappaB for degradation by the proteasome. Several additional genes for PDB remain to be discovered, and it seems likely that they will also involve the RANK-NFkappaB signaling pathway or components of the proteasomal processing of this pathway, underscoring the critical importance of this signaling pathway in bone metabolism and bone disease.
Daroszewska
Anna
A
University of Edinburgh, UK.
Ralston
Stuart H
SH
D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases; D002352:Carrier Proteins / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D019656:Loss of Heterozygosity; D008562:Membrane Glycoproteins / Q000235:genetics; D018979:Myositis, Inclusion Body / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics; D010001:Osteitis Deformans / Q000235:genetics*; D010014:Osteolysis / Q000235:genetics; D053244:Osteoprotegerin; D011110:Polymorphism, Genetic; D011506:Proteins / Q000235:genetics; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D000071456:Sequestosome-1 Protein; D000074405:Valosin Containing Protein
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053244:Osteoprotegerin; D011506:Proteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein