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

• 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
• Format: Article
• Language: English
• 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
• ISSN: 0171-967X; 1432-0827
• DOI: 10.1007/s00223-008-9192-8

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.