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.
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.
authors.affiliation: Department of Internal Medicine, University of Florence, Florence, Italy. a.falchetti@dmi.unifi.it
authors.forename: Alberto
authors.initials: A
authors.lastname: Falchetti
authors.forename: Marco
authors.initials: M
authors.lastname: Di Stefano
authors.forename: Francesca
authors.initials: F
authors.lastname: Marini
authors.forename: Sergio
authors.initials: S
authors.lastname: Ortolani
authors.forename: Massimo Fabio
authors.initials: MF
authors.lastname: Ulivieri
authors.forename: Simona
authors.initials: S
authors.lastname: Bergui
authors.forename: Laura
authors.initials: L
authors.lastname: Masi
authors.forename: Chiara
authors.initials: C
authors.lastname: Cepollaro
authors.forename: Maurizio
authors.initials: M
authors.lastname: Benucci
authors.forename: Ombretta
authors.initials: O
authors.lastname: Di Munno
authors.forename: Maurizio
authors.initials: M
authors.lastname: Rossini
authors.forename: Silvano
authors.initials: S
authors.lastname: Adami
authors.forename: Antonio
authors.initials: A
authors.lastname: Del Puente
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Isaia
authors.forename: Francesca
authors.initials: F
authors.lastname: Torricelli
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Brandi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000502:physiology; D000368:Aged; D000369:Aged, 80 and over; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D018703:Founder Effect; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007438:Introns; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D017720:Molecular Epidemiology; D009154:Mutation; D010001:Osteitis Deformans / Q000453:epidemiology* / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D000071456:Sequestosome-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein