TY - JOUR
T1 - Founder Effect in Different European Countries for the Recurrent P392L SQSTM1 Mutation in Paget's Disease of Bone
AU - Chung, Pui Yan Jenny
AU - Beyens, Greet
AU - Guañabens, Núria
AU - Boonen, Steven
AU - Papapoulos, Socrates
AU - Karperien, Marcel
AU - Eekhoff, Marliese
AU - van Wesenbeeck, Liesbeth
AU - Jennes, Karen
AU - Geusens, Piet
AU - Offeciers, Erwin
AU - van Offel, Jan
AU - Westhovens, René
AU - Zmierczak, Hans
AU - Devogelaer, Jean-Pierre
AU - van Hul, Wim
PY - 2008
Y1 - 2008
N2 - 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 × 10−14, providing strong evidence for a founder effect of the P392L SQSTM1 mutation in Belgian, Dutch, and Spanish patients with PDB.
AB - 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 × 10−14, providing strong evidence for a founder effect of the P392L SQSTM1 mutation in Belgian, Dutch, and Spanish patients with PDB.
KW - 2024 OA procedure
U2 - 10.1007/s00223-008-9137-2
DO - 10.1007/s00223-008-9137-2
M3 - Article
SN - 0171-967X
VL - 83
SP - 34
EP - 42
JO - Calcified tissue international
JF - Calcified tissue international
IS - 1
ER -