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Familial Paget Disease and SQSTM1 Mutations in 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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Acknowledgement

We thank the staff of the Centre for Genomics & Proteomics, DNA Sequencing Facility at the School of Biological Sciences, University of Auckland, for assistance with the sequencing and the Health Research Council of New Zealand for funding.

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Correspondence to Tim Cundy.

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The authors have stated that they have no conflict of interest.

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Cundy, T., Naot, D., Bava, U. et al. Familial Paget Disease and SQSTM1 Mutations in New Zealand. Calcif Tissue Int 89, 258–264 (2011). https://doi.org/10.1007/s00223-011-9514-0

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