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

Arthritis Rheum. 2004 May;50(5):1650-4. doi: 10.1002/art.20224.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins / genetics*
  • Case-Control Studies
  • DNA Mutational Analysis
  • Family Health
  • Genotype
  • Humans
  • Netherlands / epidemiology
  • Osteitis Deformans / epidemiology*
  • Osteitis Deformans / genetics*
  • Phenotype
  • Point Mutation
  • Prevalence
  • Proteins*
  • Sequestosome-1 Protein

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Proteins
  • SQSTM1 protein, human
  • Sequestosome-1 Protein