Paget Disease of Bone :SQSTM1Mutation
Image Description
Note: A quick review of normal functioning of RANKL-mediated NF-κB signaling (discussed in the previous image) would be helpful in understanding this illustration.
SQSTM1 gene on chromosome 5q35.3 encodes a 440-amino acid scaffold protein called Sequestosome 1 (aka p62). The C-terminus of p62 contains a UBA domain that is required for binding to deubiquitinating enzyme CYLD - a negative regulator of RANK-NF-κB signaling pathway (and osteoclast activity).
In normal situation (wild type SQSTM1; left panel), CYLD binds to the UBA domain of p62 to form the RANK-TRAF6-p62-CYLD complex which allows it to deubiquitinate TRAF6. TRAF6 is inactivated and signaling further downstream of RANK is blocked. This downregulates osteoclast activity.
Deletions or missense mutations in SQSTM1 gene (right panel) that alter UBA domain impair the binding between CYLD and p62. This leads to increased TRAF6 ubiquitination, overactivation of RANKL-mediated NF-κB signaling and increased osteoclast activity.
SQSTM1 mutations have been found in 50% of familial cases and 5-10% of sporadic cases of Paget disease of bone (PDB). Patients with SQSTM1 mutation have severe PDB with early onset. SQSTM1 mutations have also been linked to neurodegenerative disorders like amyotrophic lateral sclerosis and frontotemporal lobal degeneration which may rarely coexist with PDB.
Reference: Ralston SH & Layfield R. Pathogenesis of Paget Disease of Bone. Calcif Tissue Int (2012) 91:97-113. Credit: Illustration created with BioRender.com
SQSTM1 gene on chromosome 5q35.3 encodes a 440-amino acid scaffold protein called Sequestosome 1 (aka p62). The C-terminus of p62 contains a UBA domain that is required for binding to deubiquitinating enzyme CYLD - a negative regulator of RANK-NF-κB signaling pathway (and osteoclast activity).
In normal situation (wild type SQSTM1; left panel), CYLD binds to the UBA domain of p62 to form the RANK-TRAF6-p62-CYLD complex which allows it to deubiquitinate TRAF6. TRAF6 is inactivated and signaling further downstream of RANK is blocked. This downregulates osteoclast activity.
Deletions or missense mutations in SQSTM1 gene (right panel) that alter UBA domain impair the binding between CYLD and p62. This leads to increased TRAF6 ubiquitination, overactivation of RANKL-mediated NF-κB signaling and increased osteoclast activity.
SQSTM1 mutations have been found in 50% of familial cases and 5-10% of sporadic cases of Paget disease of bone (PDB). Patients with SQSTM1 mutation have severe PDB with early onset. SQSTM1 mutations have also been linked to neurodegenerative disorders like amyotrophic lateral sclerosis and frontotemporal lobal degeneration which may rarely coexist with PDB.
Reference: Ralston SH & Layfield R. Pathogenesis of Paget Disease of Bone. Calcif Tissue Int (2012) 91:97-113. Credit: Illustration created with BioRender.com