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Ann N Y Acad Sci. 2011 Dec;1240:53-60. doi: 10.1111/j.1749-6632.2011.06228.x.

Genetic determinants of Paget's disease of bone.

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Rheumatic Diseases Unit, Molecular Medicine Centre, University of Edinburgh, United Kingdom.


Paget's disease is a common skeletal disorder with a strong genetic component, which is characterized by focal increases in disorganized bone remodeling, predominantly affecting the axial skeleton. Current evidence suggests that classical Paget's disease of bone (PDB) is caused by a combination of rare alleles of large effect size that cause autosomal dominant inheritance of the disease and more common alleles of smaller effect size. Mutations of SQSTM1 are the most common cause of classical PDB, occurring in about 10% of patients. The causal mutations cluster in the ubiquitin-associated domain and impair its ability to bind ubiquitin. Other loci that predispose to PDB have recently been identified by genome-wide association studies, which have identified variants at seven loci that predispose to the disease. These increase the risk of PDB individually by 1.3- to 1.7-fold, but have combined effects that account for about 86% of the population-attributable risk of PDB in SQSTM1 negative patients.

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