Familial Paget Disease and SQSTM1 Mutations in New Zealand

• Published in: Calcified tissue international Vol. 89; no. 3; pp. 258 - 264
• Main Authors: Cundy, Tim, Naot, Dorit, Bava, Usha, Musson, David, Tong, Pak Cheung, Bolland, Mark
• Format: Journal Article
• Language: English
• Published: New York Springer-Verlag 01.09.2011; Springer Nature B.V
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adult; Aged; Aged, 80 and over; Biochemistry; Biomedical and Life Sciences; Bone density; Cell Biology; Endocrinology; Family Health - statistics & numerical data; Female; Gene Frequency; Genetic disorders; Genetic Predisposition to Disease; Genotype; Genotype & phenotype; Humans; Life Sciences; Male; Middle Aged; Mutation; New Zealand - epidemiology; Original Research; Orthopedics; Osteitis Deformans - epidemiology; Osteitis Deformans - genetics; Pedigree; Point Mutation - physiology; Population genetics; Sequestosome-1 Protein; Severity of Illness Index; New Zealand; New Zealand; Paget disease of bone; Family history; Sequestosome 1
• ISSN: 0171-967X; 1432-0827; 1432-0827
• DOI: 10.1007/s00223-011-9514-0

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.