Familial Paget's disease in The Netherlands: Occurrence, identification of new mutations in the sequestosome 1 gene, and their clinical associations

Abstract

Objective. To estimate the occurrence of familial Paget's disease of bone in The Netherlands, to examine the prevalence of mutations of the sequestosome 1 gene (SQSTM1) in identified families, and to assess potential genotype-phenotype associations.Methods. We performed a case-control study of patients with Paget's disease and a mutation analysis of the SQSTM1 gene of index patients with familial disease and of the relatives of those with a mutation. Serum alkaline phosphatase (AP) activity was assessed, and bone scintigraphy was performed.Results. Five percent of patients had at least 1 first-degree relative with the disease, compared with 0.5% of the controls (relative risk 10; 95% confidence interval 1.3-75.6). In 38.9% of patients with familial disease, heterozygous mutations in the SQSTM1 gene were identified. These were the previously described P392L mutation, which was present in 22.2% of patients, and 3 new mutations, S399P, G425R, M404T, 9 of which were present in 3 different families. All mutations were located in the ubiquitin-associated domain of the gene. There was a relationship between serum AP activity, as a marker of the disease, and the presence or absence of the G425R and P392L mutations, the subject's age, and the presence of Paget's disease. Conclusion.Our data provide further evidence of a causal role of SQSTM1 gene mutations in the pathogenesis of Paget's disease and allow the design of a strategy based on measurements of serum AP activity and age for investigating asymptomatic relatives of patients with familial Paget's disease of bone.

Genetic variation in the TNFRSF11A gene encoding RANK is associated with susceptibility to Paget's disease of bone

“…The Dutch population used as a replication cohort was partially described in Eekhoff and colleagues (47) and Chung and colleagues. (50) Seventy-eight PDB patients without SQSTM1 …”

“…(34,42,43) To date, 23 SQSTM1 mutations have been found in 28.3% of patients with familial PDB and 7.5% of those with sporadic PDB. (37,42,(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60) Furthermore, in most cases, the same missense mutation was identified (C1215T, P392L). This missense mutation turned out to be due to a founder effect over several populations.…”

SQSTM1 gene analysis and gene-environment interaction in Paget's disease of bone

“…The same P392L mutation was identified subsequently in familial and sporadic PDB subjects from different countries. (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) Currently, at least 20 further mutations in the SQSTM1 gene have been identified, all of which are clustered within or near the ubiquitin-associated (UBA) domain of the protein and lead to increased NFkB signaling and enhanced bone resorption. In some but not all patient samples, truncating mutations (where all or part of the UBA domain is deleted) were associated with a more severe phenotype than missense mutations.…”

Genetic aspects of the Paget’s disease of bone: concerns on the introduction of DNA‐based tests in the clinical practice. Advantages and disadvantages of its application

“…Incomplete penetrance of PDB limits the application of SQSTM1 ⁄ p62 mutational analysis to the clinical practice Affected individuals from a PDB family with a known germline SQSTM1 ⁄ p62 mutation have not such a mutation [53,54,86] Asymptomatic mutant carriers from a PDB family with a known germline SQSTM1 ⁄ p62 mutation have not developed PDB despite their age over 55 years [21] Asymptomatic mutant carriers from a PDB family with a known germline SQSTM1 ⁄ p62 mutation have not developed PDB because they have not yet reached an age be deemed compatible for its clinical expression [21,86,87] Genetic heterogeneity of PDB and ⁄ or the presence of still unknown modifier genes able to control the clinical expression of the PDB in those subjects with the germline mutation in SQSTM1 ⁄ p62 gene [21,86];…”