Founder effect in different european countries for the recurrent P392L SQSTM1 mutation in Paget's disease of bone

Pui Yan Jenny Chung, Greet Beyens, Núria Guañabens, Steven Boonen, Socrates Papapoulos, Marcel Karperien, Marelise Eekhoff, Liesbeth Van Wesenbeeck, Karen Jennes, Piet Geusens, Erwin Offeciers, Jan Van Offel, Rene Westhovens, Hans Zmierczak, Jean Pierre Devogelaer, Wim Van Hul

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33 Citations (Scopus)


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)34-42
Number of pages9
JournalCalcified tissue international
Issue number1
Publication statusPublished - Jul 2008


  • Founder effect
  • Haplotype analysis
  • Mutation analysis
  • Paget's Disease of Bone
  • SQSTM1

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