Mutations of SQSTM1 are associated with severity and clinical outcome in paget disease of bone

Abstract

Paget disease of bone (PDB) is a common disorder characterized by increased bone turnover at one of more sites throughout the skeleton. Genetic factors play an important role in the pathogenesis of PDB, and the most important predisposing gene is SQSTM1, which is mutated in about 10% of patients. Here we investigated the relationship between SQSTM1 mutation status, disease severity, and clinical outcome in 737 patients who took part in a randomized study of two different management strategies for the disease. Mutations of SQSTM1 were detected in 80 of 737 (10.9%) patients. Mutation carriers had an earlier age at diagnosis (59.4 AE11.5 versus 65.0 AE 10.4 years, p < .0001) and a greater number of affected bones (3.2 AE 1.2 versus 2.1 AE 1.2, p < .001) and more commonly required orthopedic surgery (26.2% versus 16.1%, p ¼ .024) and bisphosphonate therapy (86.3% versus 75.2%, p ¼ .01) than those without mutations. Quality of life, as assessed by the short-form-36 (SF36) physical summary score, was significantly reduced in carriers (34.0 AE 11.3 versus 37.1 AE 11.4, p ¼ .036). During the study, fractures were more common in carriers (12.5% versus 5.3%, p ¼ .011), although most of these occurred in unaffected bone. This study demonstrates that SQSTM1 mutations are strongly associated with disease severity and complications of PDB. Genetic testing for SQSTM1 mutations may be of value in identifying individuals at risk of developing severe disease, but further studies will be required to determine if a program of genetic testing and early intervention in these individuals would be cost-effective or be of benefit in preventing these complications. ß

Pathogenesis of Paget Disease of Bone

“…p62, as noted earlier, is an adaptor protein that binds ubiquitin and plays an important role in regulating NFjB signaling [69] as well as autophagy [70][71][72]. Current evidence suggests that mutations of SQSTM1 occur in 40-50 % of patients with a familial history of PDB and 2.5-10 % of ''sporadic'' PDB cases [60,65,66,73,74]. Virtually all of the PDB-causing mutations cluster in the UBA domain, and most prevent or A427D Yes Gennari et al [16] a Two different mutations were reported at the genomic level, which both resulted in the same amino acid change.…”

Giant cell tumor occurring in familial Paget's disease of bone: Report of clinical characteristics and linkage analysis of a large pedigree

“…(8) This gene encodes the p62/ sequestosome 1 protein, which acts as a scaffold protein in the NF-kB pathway as well as an intermediate protein in the proteosomal degradation of polyubiquitinated proteins. Even though patients with SQSTM1 mutations generally show an increased disease severity than SQSTM1-negative patients, (9,10) we recently identified SQSTM1-negative patients with a severe phenotype and the presence of peculiar phenotypic characteristics, including the occurrence of giant cell tumors (GCT) originating from affected skeletal sites. (9,11,12) This complication represents a very uncommon clinical feature of PDB (described in less than 100 cases worldwide), and mainly occurs in patients with severe polyostotic PDB.…”

Paget’s sarcoma of the patella

“…The protein product is p62 (sequestrome 1), which affects regulation of RANK L-mediated activation of NF-β, which has a major role in osteoclast function [3,40,[42][43][44][45][46]. Although there are some genotype phenotype relationships [45,46], the severity of the disease appears to be diminishing despite the presence of mutations and not all individuals with mutations get PDB [40]. Many genes are known or suspected to predispose to PDB, all of which are involved in the evolution and differentiation of osteoclasts.…”