Genetic Determinants of Paget's Disease of Bone

Abstract

Purpose of review: To provide an overview of the role of genes and loci that predispose to Paget's disease of bone and related disorders.

Recent findings: Studies over the past ten years have seen major advances in knowledge on the role of genetic factors in Paget's disease of bone (PDB). Genome wide association studies have identified six loci that predispose to the disease whereas family based studies have identified a further eight genes that cause PDB. This brings the total number of genes and loci implicated in PDB to fourteen. Emerging evidence has shown that a number of these genes also predispose to multisystem proteinopathy syndromes where PDB is accompanied by neurodegeneration and myopathy due to the accumulation of abnormal protein aggregates, emphasising the importance of defects in autophagy in the pathogenesis of PDB. Genetic factors play a key role in the pathogenesis of PDB and the studies in this area have identified several genes previously not suspected to play a role in bone metabolism. Genetic testing coupled to targeted therapeutic intervention is being explored as a way of halting disease progression and improving outcome before irreversible skeletal damage has occurred.

Keywords: Paget's disease of bone; SQSTM1; genetics; multisystem proteinopathy; osteoclast.

Fig. 1

Genes implicated in Paget’s disease and related syndromes. Panel a shows some genes implicated in the pathogenesis of PDB which have effects on osteoclast differentiation and bone resorption. The gene products implicated in PDB are highlighted in red text. Panel b shows genes thought to affect intracellular signalling in osteoclasts and osteoclast precursors. The implicated gene products are highlighted in red and mostly affect the NFκB signalling pathway by interacting with SQSTM1 or genes that regulate signalling downstream of the RANK receptor. The ZNF678 gene encodes a transcription factor, but the exact mechanisms by which it predisposes to PDB are unclear. Abbreviations: c-fms - Colony Stimulating Factor 1 Receptor; M-CSF - Macrophage Colony Stimulating factor; RANK - Receptor Activator of Nuclear Factor Kappa B; RANKL - RANK Ligand; DC-STAMP - Dendritic Cell Specific Transmembrane Protein; OPG - Osteoprotegerin; RIN3 - Ras and Rab Interactor 3; IFN - Interferon; IFNR - Interferon Receptor; STAT - Signal Transducers and Activators of Transcription; TRAF 6 - Tumour Necrosis Factor Receptor Associated Factor 6; CYLD - Cylindromatosis; p62 - Sequestosome 1; aPKC - atypical Protein Kinase C; IKK - Inhibitor of Kappa B Kinase; IkB - Inhibitor of Kappa B; NFκB - Nuclear Factor Kappa B; OPTN - Optineurin, PFN1 - Profilin 1; NUP205 - Nucleoporin 205; ZNF687 - Zinc Finger Protein 687; Short Transmembrane Mitochondrial Protein 1.