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Genetic Epidemiology of Paget’s Disease of Bone in Italy: sequestosome1/p62 Gene Mutational Test and Haplotype Analysis at 5q35 in a Large Representative Series of Sporadic and Familial Italian Cases of Paget’s Disease of Bone

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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 CGTG-H2 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 CGTG-H2 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 population.

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Acknowledgments

This 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 M.L.B). 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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Authors and Affiliations

  1. Department of Internal Medicine, University of Florence, Florence, Italy

    Alberto Falchetti, Francesca Marini, Laura Masi, Chiara Cepollaro & Maria Luisa Brandi

  2. Department of Internal Medicine, University of Turin, Turin, Italy

    Marco Di Stefano, Simona Bergui & Giancarlo Isaia

  3. Center for Metabolic Bone Disease, Division of Endocrinology, Istituto Auxologico Italiano, Milan, Italy

    Sergio Ortolani

  4. Ospedale Maggiore, Policlinico, Milan, Italy

    Massimo Fabio Ulivieri

  5. Rheumatology Unit, Nuovo Ospedale S. Giovanni di Dio, Florence, Italy

    Maurizio Benucci

  6. Rheumatology Unit, University of Pisa, Pisa, Italy

    Ombretta Di Munno

  7. Department of Rheumathology, University of Verona, Valeggio Hospital, Verona, Italy

    Maurizio Rossini & Silvano Adami

  8. Rheumatology Unit, University Federico II, Naples, Naples, Italy

    Antonio Del Puente

  9. Unit of Genetic Diagnosis, Careggi Hospital, Florence, Italy

    Francesca Torricelli

  10. DeGene Spin-off, University of Florence, Florence, Italy

    Maria Luisa Brandi

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  1. Alberto Falchetti
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Correspondence to Maria Luisa Brandi.

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Falchetti, A., Di Stefano, M., Marini, F. et al. Genetic Epidemiology of Paget’s Disease of Bone in Italy: sequestosome1/p62 Gene Mutational Test and Haplotype Analysis at 5q35 in a Large Representative Series of Sporadic and Familial Italian Cases of Paget’s Disease of Bone. Calcif Tissue Int 84, 20–37 (2009). https://doi.org/10.1007/s00223-008-9192-8

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