Genetic Epidemiology of Paget’s Disease of Bone in

Authors: Alberto Falchetti Marco Di Stefano Francesca Marini Sergio Ortolani Massimo Fabio Ulivieri Simona Bergui Laura Masi Chiara Cepollaro Maurizio Benucci Ombretta Di Munno Maurizio Rossini Silvano Adami Antonio Del Puente Giancarlo Isaia Francesca Torricelli Maria Luisa Brandi On Behalf of the GenePage Project

Publish Date: 2008/12/09

Volume: 84, Issue: 1, Pages: 20-37

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Abstract

Families affected by Paget’s disease of bone frequently harbor mutations in the SQSTM1/p62 gene In this multicentric study we collected 345 sporadic and 12 familial PDB cases throughout Italy identifying 12 different mutations 5 of which are newly reported and 3 D335E A381V and Y383X external to the UBA domain Subjects with truncating mutations E396X showed a significantly younger age at clinical diagnosis while the Y383X subjects had a higher average number of affected skeletal sites All the mutants exhibited the CGTGH2 haplotype In two pairs and one triad of unrelated Italian PDB families from different Italian regions we detected a common SQSTM1/p62 mutation for each P392L M404V and G425R group Since the CGTGH2 haplotype frequency was also high in normal subjects and genetic influence due to migratory fluxes of different ethnic groups exists in the Italian population to refine the search for a more geographically specific founder effect we extended the haplotype analysis in these families using polymorphic microsatellite repeat markers within and flanking the SQSTM1/p62 locus from chromosome 5q35 other than the exon 6 and 3′UTR polymorphisms All mutant carriers from two of the three M404V families and from the G425R families exhibited common extended chromosome 5q35 haplotypes IT01 and IT02 respectively which may be reflecting influences of past migrations This may be helpful in estimating the true rate of de novo mutations We confirm the data on the existence of both a mutational hotspot at the UBA domain of SQSTM1/p62 and a founder effect in the PDB populationThis paper was supported by the European Research Program Fifth Framework Program “Quality of Life and Management of Living Resources Research and Technological Development Program” on “Genetic Markers for Osteoporosis” by the Cofin MIUR PNR 2001–2003 FIRB by the Fondazione Ente Cassa di Risparmio di Firenze and by the Fondazione FIRMO to MLB F Marini is the recipient of a fellowship from the “Jacopo Ficai” grant of the Fondazione Ente Cassa di Risparmio di Firenze The authors are grateful to Mrs Debora Strigoli for her technical assistance to all colleagues and nurses dedicated to this project and in particular to all PDB patients and relatives Without their collaboration this study could not be performed This paper is published on behalf of the GenePage Project Department of Internal Medicine University of Florence Department of Internal Medicine University of Turin Center for Metabolic Bone Disease Division of Endocrinology Istituto Auxologico Italiano Milan Ospedale Maggiore Policlinico Milan Rheumatology Unit Ospedale Torregalli Florence Rheumatology Unit University of Pisa Department of Rheumathology University of Verona Rheumatology Unit University Federico II Naples Department of Clinical Medicine and Emerging Diseases University of Palermo Department of Medical and Surgical Sciences University of Padua Division Medicine I and Rheumatology Department of Medicine and Surgery University of Florence Unit of Rheumatology—ASL Pescara and Internal Medicine Unit Federico II University of Naples Italy

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