Founder Effect in Different European Countries for the Recurrent P392L SQSTM1 Mutation in Paget's Disease of Bone

P.Y.J. Chung, G. Beyens, N. Guanabens, S. Boonen, S. Papapoulos, Hermanus Bernardus Johannes Karperien, M. Eekhoff, L. van Wesenbeek, [Unknown] ... [et al.]

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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 × 10−14, providing strong evidence for a founder effect of the P392L SQSTM1 mutation in Belgian, Dutch, and Spanish patients with PDB.
Original languageEnglish
Pages (from-to)42-
Number of pages34
JournalCalcified tissue international
Volume83
Issue number1
DOIs
Publication statusPublished - 2008

Fingerprint

Founder Effect
Osteitis Deformans
Mutation
Haplotypes
Population
Exons
Metabolic Bone Diseases
3' Untranslated Regions
Mutation Rate
Single Nucleotide Polymorphism
Software
Chromosomes
Alleles

Keywords

  • METIS-253646
  • IR-83265

Cite this

Chung, P.Y.J. ; Beyens, G. ; Guanabens, N. ; Boonen, S. ; Papapoulos, S. ; Karperien, Hermanus Bernardus Johannes ; Eekhoff, M. ; van Wesenbeek, L. ; ... [et al.], [Unknown]. / Founder Effect in Different European Countries for the Recurrent P392L SQSTM1 Mutation in Paget's Disease of Bone. In: Calcified tissue international. 2008 ; Vol. 83, No. 1. pp. 42-.
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title = "Founder Effect in Different European Countries for the Recurrent P392L SQSTM1 Mutation in Paget's Disease of Bone",
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 × 10−14, providing strong evidence for a founder effect of the P392L SQSTM1 mutation in Belgian, Dutch, and Spanish patients with PDB.",
keywords = "METIS-253646, IR-83265",
author = "P.Y.J. Chung and G. Beyens and N. Guanabens and S. Boonen and S. Papapoulos and Karperien, {Hermanus Bernardus Johannes} and M. Eekhoff and {van Wesenbeek}, L. and {... [et al.]}, [Unknown]",
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Chung, PYJ, Beyens, G, Guanabens, N, Boonen, S, Papapoulos, S, Karperien, HBJ, Eekhoff, M, van Wesenbeek, L & ... [et al.], U 2008, 'Founder Effect in Different European Countries for the Recurrent P392L SQSTM1 Mutation in Paget's Disease of Bone' Calcified tissue international, vol. 83, no. 1, pp. 42-. https://doi.org/10.1007/s00223-008-9137-2

Founder Effect in Different European Countries for the Recurrent P392L SQSTM1 Mutation in Paget's Disease of Bone. / Chung, P.Y.J.; Beyens, G.; Guanabens, N.; Boonen, S.; Papapoulos, S.; Karperien, Hermanus Bernardus Johannes; Eekhoff, M.; van Wesenbeek, L.; ... [et al.], [Unknown].

In: Calcified tissue international, Vol. 83, No. 1, 2008, p. 42-.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Founder Effect in Different European Countries for the Recurrent P392L SQSTM1 Mutation in Paget's Disease of Bone

AU - Chung, P.Y.J.

AU - Beyens, G.

AU - Guanabens, N.

AU - Boonen, S.

AU - Papapoulos, S.

AU - Karperien, Hermanus Bernardus Johannes

AU - Eekhoff, M.

AU - van Wesenbeek, L.

AU - ... [et al.], [Unknown]

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 - METIS-253646

KW - IR-83265

U2 - 10.1007/s00223-008-9137-2

DO - 10.1007/s00223-008-9137-2

M3 - Article

VL - 83

SP - 42-

JO - Calcified tissue international

JF - Calcified tissue international

SN - 0171-967X

IS - 1

ER -