SQSTM1 and Paget's disease of bone

Abstract. Mutations in the Sequestosome 1 gene (SQSTM1; also known as p62) have recently been identified as the cause of 5q35-linked Paget’s disease of bone (PDB). All of the mutations identified to date affect the ubiquitin-associated (UBA) domain of SQSTM1, a region of the protein that binds noncovalently to ubiquitin. In this review we consider the possible functional significance of the SQSTM1-ubiquitin interaction, and consequences of the SQSTM1 UBA domain mutations. Clarification of the in vivo roles of SQSTM1 in bone-cell function will be central to improving our understanding of the molecular pathogenesis of PDB and related conditions.