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Several rare disorders have also been described that show phenotypic overlap with PDB. Genome-wide searches have identified several susceptibility loci for PDB and PDB-like disorders, and mutations that cause these disorders have now been identified in four genes, all of which are involved in the RANK-NF-\u03baB signaling pathway. Mutations in SQSTM1, which encodes an important scaffold protein in this pathway, have been found to be a common cause of classical PDB. Thus far, all disease-causing mutations in SQSTM1 affect the ubiquitin-associated (UBA) domain of the gene product and cause loss of ubiquitin binding. The rare PDB-like disorders of familial expansile osteolysis, early-onset familial PDB, and expansile skeletal hyperphosphatasia are caused by duplication mutations in exon 1 of the TNFRSF11A gene, which encodes the RANK receptor. This gene does not seem to be involved in the pathogenesis of classical PDB. Inactivating mutations in the TNFRSF11B gene, which encodes osteoprotegerin, cause juvenile PDB, and TNFRSF11B polymorphisms seem to increase the risk of classical PDB. The rare syndrome of hereditary inclusion body myopathy, PDB, and frontotemporal dementia (IBMPFD) is caused by mutations in the VCP gene, which is involved in regulating I-\u03baB degradation by the proteasome. The disease-causing mutations in VCP cluster in and around a domain involved in ubiquitin binding. Whereas SQSTM1 has emerged as an important gene for classical PDB, most kindreds with familial PDB do not carry SQSTM1 mutations, indicating that additional genes for PDB remain to be discovered. In light of the molecular defects that have been identified thus far, it seems likely that these genes will also be involved in the RANK-NF-\u03baB signaling pathway or its interactions with the ubiquitin-proteasome system.<\/jats:p>","DOI":"10.1359\/jbmr.06s206","type":"journal-article","created":{"date-parts":[[2007,1,17]],"date-time":"2007-01-17T21:41:47Z","timestamp":1169070107000},"page":"P31-P37","source":"Crossref","is-referenced-by-count":43,"title":["Contribution of Genetic Factors to the Pathogenesis of Paget's Disease of Bone and Related Disorders"],"prefix":"10.1093","volume":"21","author":[{"given":"Gavin JA","family":"Lucas","sequence":"first","affiliation":[{"name":"Rheumatic Diseases Unit, Molecular Medicine Centre, University of Edinburgh, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Daroszewska","sequence":"additional","affiliation":[{"name":"Rheumatic Diseases Unit, Molecular Medicine Centre, University of Edinburgh, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart H","family":"Ralston","sequence":"additional","affiliation":[{"name":"Rheumatic Diseases Unit, Molecular Medicine Centre, University of Edinburgh, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,12,4]]},"reference":[{"key":"2024013019364998900_bib1","volume-title":"Pathophysiology and Treatment of Paget's Disease of Bone","author":"Kanis","year":"1992"},{"key":"2024013019364998900_bib2","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1136\/jech.37.3.226","article-title":"A family study of Paget's disease of bone","volume":"37","author":"Sofaer","year":"1983","journal-title":"J Epidemiol Community Health"},{"key":"2024013019364998900_bib3","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1002\/jbmr.5650060511","article-title":"Familial aggregation of Paget's disease of bone","volume":"6","author":"Siris","year":"1991","journal-title":"J Bone Miner Res"},{"key":"2024013019364998900_bib4","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/S8756-3282(00)00278-7","article-title":"Familial Paget's disease of Bone: Patterns of inheritance and frequency of linkage to chromosome 18q","volume":"26","author":"Hocking","year":"2000","journal-title":"Bone"},{"key":"2024013019364998900_bib5","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1302\/0301-620X.70B2.3346299","article-title":"Familial expansile osteolysis. 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