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Please use this identifier to cite or link to this item: http://hdl.handle.net/1942/8469

Title: Founder effect in different European countries for the recurrent P392L SQSTM1 mutation in Paget's disease of bone
Authors: Chung, PYJ
Beyens, G
Guanabens, N
Boonen, S
Papapoulos, S
Karperien, M
Eekhoff, M
Van Wesenbeeck, L
Jennes, K
Offeciers, E
Van Offel, J
Westhovens, R
Zmierczak, H
Devogelaer, JP
Van Hul, W
Issue Date: 2008
Publisher: SPRINGER
Abstract: Paget's Disease of Bone ( PDB) is one of the most frequent metabolic bone diseases, affecting 1 - 5% of Western populations older than 55 years. Mutations in the sequestosome1 (SQSTM1) gene cause PDB in about one-third of familial PDB cases and in 2.4 - 9.3% of nonfamilial PDB cases, with the 1215C -> T (P392L) mutation being the most frequent one. We investigated whether a founder effect of the P392L SQSTM1 mutation was present in Belgian (n = 233), Dutch ( n = 82), and Spanish ( n = 64) patients without a PDB family history. First, direct sequencing analysis of exon 8 in these three populations showed that the P392L mutation occurred in 17 Belgian patients ( 7.3%), three Dutch patients without a family history ( 3.7%), and two Dutch patients with a family history. In the Spanish population, 15.6% of patients (n = 10) had the P392L mutation, including one homozygous mutant. This is by far the highest mutation frequency of all populations investigated so far. Next, we examined the genetic background of 33 mutated chromosomes by analyzing haplotypes. We genotyped four single-nucleotide polymorphisms ( SNPs) in exon 6 and the 3'-untranslated region of SQSTM1 (rs4935C/T, rs4797G/A, rs10277T/C, and rs1065154G/T) and used software programs WHAP and PHASE to reconstruct haplotypes. Finally, allele-specific primers allowed us to assign the mutation to one of the two haplotypes from each individual. Sequencing results revealed that all 33 P392L mutations were on the CGTG ( H2) haplotype. The chance to obtain this result due to 33 independent mutation events is 3.97 x 10(-14), providing strong evidence for a founder effect of the P392L SQSTM1 mutation in Belgian, Dutch, and Spanish patients with PDB.
Notes: Univ & Univ Hosp Antwerp, Dept Med Genet, B-2610 Antwerp, Belgium. Univ Barcelona, Hosp Clin, Dept Rheumatol, Barcelona 08036, Spain. Univ Ziekenhuis, Dept Expt Med, Bone Res Unit, B-3000 Leuven, Belgium. Katholieke Univ Leuven, B-3000 Leuven, Belgium. Leiden Univ, Med Ctr, NL-2333 ZA Leiden, Netherlands. Univ Hasselt, Biomed Res Inst, B-3590 Diepenbeek, Belgium. Univ Hosp, Int Med Rheumatol, Maastricht, Netherlands. Univ Antwerp, Univ ENT Dept, B-2610 Antwerp, Belgium. Univ Antwerp Hosp, Dept Immunol & Rheumatol, B-2650 Edegem, Belgium. Univ Ziekenhuis, Dept Rheumatol, B-3000 Leuven, Belgium. Univ Hosp Ghent, Unit Osteoporosis & Metab Bone Dis, B-9000 Ghent, Belgium. Univ Catholique Louvain, St Luc Univ Hosp, Dept Rheumatol, B-1200 Brussels, Belgium.
URI: http://hdl.handle.net/1942/8469
DOI: 10.1007/s00223-008-9137-2
ISI #: 000258613500091
ISSN: 0171-967X
Category: A1
Type: Journal Contribution
Validation: ecoom, 2009
Appears in Collections: Research publications

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