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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

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 , exter...

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Published in:Calcified tissue international 2009, Vol.84 (1), p.20-37
Main Authors: Falchetti, Alberto, Di Stefano, Marco, Marini, Francesca, Ortolani, Sergio, Ulivieri, Massimo Fabio, Bergui, Simona, Masi, Laura, Cepollaro, Chiara, Benucci, Maurizio, Di Munno, Ombretta, Rossini, Maurizio, Adami, Silvano, Del Puente, Antonio, Isaia, Giancarlo, Torricelli, Francesca, Brandi, Maria Luisa
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cited_by cdi_FETCH-LOGICAL-c400t-49f113b780339393ca69e7cd06b2157541ca3dc6d63c4e68ebee8cddeadfb62e3
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container_title Calcified tissue international
container_volume 84
creator Falchetti, Alberto
Di Stefano, Marco
Marini, Francesca
Ortolani, Sergio
Ulivieri, Massimo Fabio
Bergui, Simona
Masi, Laura
Cepollaro, Chiara
Benucci, Maurizio
Di Munno, Ombretta
Rossini, Maurizio
Adami, Silvano
Del Puente, Antonio
Isaia, Giancarlo
Torricelli, Francesca
Brandi, Maria Luisa
description 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.
doi_str_mv 10.1007/s00223-008-9192-8
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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.</abstract><cop>New York</cop><pub>Springer-Verlag</pub><pmid>19067022</pmid><doi>10.1007/s00223-008-9192-8</doi><tpages>18</tpages></addata></record>
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ispartof Calcified tissue international, 2009, Vol.84 (1), p.20-37
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subjects Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - physiology
Aged
Aged, 80 and over
Biochemistry
Biogeography
Biomedical and Life Sciences
Bone diseases
Cell Biology
Chromosomes, Human, Pair 5 - genetics
DNA Mutational Analysis
Endocrinology
Epidemiology
Exons
Female
Founder Effect
Genetic disorders
Genetic Predisposition to Disease
Genetic Testing
Genotype
Haplotypes - genetics
Humans
Introns
Italy - epidemiology
Life Sciences
Male
Middle Aged
Molecular Epidemiology
Mutation
Orthopedics
Osteitis Deformans - epidemiology
Osteitis Deformans - genetics
Pedigree
Phenotype
Polymorphism, Single Nucleotide
Sequestosome-1 Protein
title 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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