Familial Paget Disease and <Emphasis Type="Italic">SQSTM1</Emphasis> Mutations in New Zealand |
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Authors: | Tim Cundy Dorit Naot Usha Bava David Musson Pak Cheung Tong Mark Bolland |
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Institution: | (1) Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand |
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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. |
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