Familial Paget disease and SQSTM1 mutations in New Zealand

Abstract

Genetic factors play an important role in the pathogenesis of Paget disease of bone (PDB). SQSTM1 is the most important disease-associated gene identified to date. We investigated the relationship of family history, phenotype, and SQSTM1 mutation status in New Zealand (a country with a high prevalence of PDB) in patients with a family history and/or a severe phenotype. We studied 61 unrelated subjects with familial PDB. Family history was subclassified into three groups according to the closeness of the relationship. We also studied a fourth group of 19 unrelated patients defined by early onset and/or severe disease but no family history. The PDB phenotype was defined according to age, alkaline phosphatase activity, and disease extent on scintiscan at the time of diagnosis. Mutations in exon 8 of SQSTM1 were detected by screening of genomic DNA. Four different mutations were identified; the ubiquitous P392L mutation and the truncating mutation E396X accounted for 89% of cases. Overall 26% of patients with familial PBD in New Zealand had disease-associated mutations in the SQSTM1 gene. Mutations were most prevalent (60%) in those with a parent or sibling and at least one other relative affected (P < 0.002). The severity of the phenotype was significantly related to SQSTM1 mutation status but not the strength of the family history (P < 0.005). SQSTM1 mutations were found in 10.5% of patients with early onset and/or severe disease but no family history.