title: 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.
authors: Department of Medicine, University of Auckland, New Zealand. t.cundy@auckland.ac.nz
authors: Tim
authors: T
authors: Cundy
authors: Dorit
authors: D
authors: Naot
authors: Usha
authors: U
authors: Bava
authors: David
authors: D
authors: Musson
authors: Pak Cheung
authors: PC
authors: Tong
authors: Mark
authors: M
authors: Bolland
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005192:Family Health / Q000706:statistics & numerical data; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009520:New Zealand / Q000453:epidemiology; D010001:Osteitis Deformans / Q000453:epidemiology / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation / Q000502:physiology; D000071456:Sequestosome-1 Protein; D012720:Severity of Illness Index
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein