Abstract
Mutations of the p62/Sequestosome 1 gene (p62/SQSTM1) account for both sporadic and familial forms of Paget's disease of bone (PDB). We originally described a methionine→valine substitution at codon 404 (M404V) of exon 8, in the ubiquitin protein-binding domain of p62/SQSTM1 gene in an Italian PDB patient. The collection of data from the patient's pedigree provided evidence for a familial form of PDB. Extension of the genetic analysis to other relatives in this family demonstrated segregation of the M404V mutation with the polyostotic PDB phenotype and provided the identification of six asymptomatic gene carriers. DNA for mutational analysis of the exon 8 coding sequence was obtained from 22 subjects, 4 PDB patients and 18 clinically unaffected members. Of the five clinically ascertained affected members of the family, four possessed the M404V mutation and exhibited the polyostotic form of PDB, except one patient with a single X-ray-assessed skeletal localization and one with a polyostotic disease who had died several years before the DNA analysis. By both reconstitution and mutational analysis of the pedigree, six unaffected subjects were shown to bear the M404V mutation, representing potential asymptomatic gene carriers whose circulating levels of alkaline phosphatase were recently assessed as still within the normal range. Taken together, these results support a genotype–phenotype correlation between the M404V mutation in the p62/SQSTM1 gene and a polyostotic form of PDB in this family. The high penetrance of the PDB trait in this family together with the study of the asymptomatic gene carriers will allow us to confirm the proposed genotype–phenotype correlation and to evaluate the potential use of mutational analysis of the p62/SQSTM1 gene in the early detection of relatives at risk for PDB.
Highlights
Paget's disease of bone (PDB; Online Mendelian Inheritance in Man (OMIM) entry no. 602080) is a metabolic bone disease characterized by accelerated bone resorption followed by the deposition of dense, chaotic bone matrix, affecting up to 3% of individuals of Caucasian ancestry above the age of 55 years [1]
In a recent paper we described an M404V mutation in the ubiquitin-binding-associated domain (UBA) of the p62/SQSTM1 gene in an Italian population of patients affected by PDB [5]
DNA analysis for the p62/SQSTM1 gene mutation was performed in all affected familial members and in several unaffected subjects, to evaluate the segregation of the M404V mutation with the PDB phenotype and to detect potentially asymptomatic gene carriers. Through this analysis we identified both a familial form of PDB, in which the M404V mutation segregates with a polyostotic phenotype of the disorder, and several asymptomatic gene carriers
Summary
Paget's disease of bone (PDB; Online Mendelian Inheritance in Man (OMIM) entry no. 602080) is a metabolic bone disease characterized by accelerated bone resorption followed by the deposition of dense, chaotic bone matrix, affecting up to 3% of individuals of Caucasian ancestry above the age of 55 years [1]. In a recent paper we described an M404V mutation in the UBA of the p62/SQSTM1 gene in an Italian population of patients affected by PDB [5]. AP = alkaline phosphatase; NFκB = nuclear factor κB; PCR = polymerase chain reaction; PDB = Paget's disease of bone; RANK = receptor activator of nuclear factor κB; TNF = tumour necrosis factor; UBA domain = ubiquitin-binding-associated domain.
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