Familial Paget's disease in The Netherlands: occurrence, identification of new mutations in the sequestosome 1 gene, and their clinical associations.
Arthritis Rheum
; 50(5): 1650-4, 2004 May.
Article
in En
| MEDLINE
| ID: mdl-15146436
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.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Osteitis Deformans
/
Proteins
/
Carrier Proteins
Type of study:
Diagnostic_studies
/
Etiology_studies
/
Observational_studies
/
Prevalence_studies
/
Risk_factors_studies
Limits:
Humans
Country/Region as subject:
Europa
Language:
En
Journal:
Arthritis Rheum
Year:
2004
Type:
Article
Affiliation country:
Netherlands