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.
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.
Authors: Pui Yan Jenny Chung; Greet Beyens; Steven Boonen; Socrates Papapoulos; Piet Geusens; Marcel Karperien; Filip Vanhoenacker; Leon Verbruggen; Erik Fransen; Jan Van Offel; Stefan Goemaere; Hans-Georg Zmierczak; René Westhovens; Jean-Pierre Devogelaer; Wim Van Hul Journal: Hum Genet Date: 2010-09-14 Impact factor: 4.132
Authors: D Rendina; F Gianfrancesco; G De Filippo; D Merlotti; T Esposito; A Aloia; D Benvenuto; C L Vivona; G Annunziata; R Nuti; P Strazzullo; G Mossetti; L Gennari Journal: J Endocrinol Invest Date: 2009-12-22 Impact factor: 4.256
Authors: Anand Merchant; Magda Smielewska; Nimit Patel; Jennifer D Akunowicz; Elizabeth A Saria; John D Delaney; Robin J Leach; Margaret Seton; Marc F Hansen Journal: J Bone Miner Res Date: 2009-03 Impact factor: 6.741
Authors: Alberto Falchetti; Marco Di Stefano; Francesca Marini; Francesca Del Monte; Alessia Gozzini; Laura Masi; Annalisa Tanini; Antonietta Amedei; Annamaria Carossino; Giancarlo Isaia; Maria Luisa Brandi Journal: Arthritis Res Ther Date: 2005-09-15 Impact factor: 5.156