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

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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.

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Acknowledgement

This work was supported by grants from the Paget Foundation (2004 John G. Haddad, Jr., Research Award for research on PDB), Fonds voor Wetenschappelijk Onderzoek (FWO, G.0117.06), and a network of excellence grant (Eurobonet) from the European Union (FP6), all to W. V. H. S. B. is a senior clinical investigator of the Fund of Scientific Research (FWO-Vlaanderen).

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Authors and Affiliations

  1. Department of Medical Genetics, University & University Hospital of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium

    Pui Yan Jenny Chung, Greet Beyens, Liesbeth Van Wesenbeeck, Karen Jennes & Wim Van Hul

  2. Department of Rheumatology, Hospital Clinic, University of Barcelona, C/. Villarroel 170, 08036, Barcelona, Spain

    Núria Guañabens

  3. Department of Experimental Medicine, Bone Research Unit, Universitair Ziekenhuis & Katholieke Universiteit Leuven, Herestraat 49, 3000, Leuven, Belgium

    Steven Boonen

  4. Endocrinology and Metabolic Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands

    Socrates Papapoulos, Marcel Karperien & Marelise Eekhoff

  5. Biomedical Research Institute, University of Hasselt, Agoralaan Gebouw A, 3590, Diepenbeek, Belgium

    Piet Geusens

  6. Internal Medicine/Rheumatology, University Hospital, Maastricht, The Netherlands

    Piet Geusens

  7. University ENT Department, Algemeen Ziekenhuis St. Augustinus, University of Antwerp, Oosterveldlaan 24, 2610, Wilrijk, Belgium

    Erwin Offeciers

  8. Department of Immunology and Rheumatology, University Hospital of Antwerp, Wilrijkstraat 10, 2650, Edegem, Belgium

    Jan Van Offel

  9. Department of Rheumatology, Universitair Ziekenhuis & Katholieke Universiteit Leuven, Herestraat 49, 3000, Leuven, Belgium

    Rene Westhovens

  10. Unit of Osteoporosis and Metabolic Bone Diseases, University Hospital of Ghent, De Pintelaan 185, 9000, Ghent, Belgium

    Hans Zmierczak

  11. Department of Rheumatology, Saint-Luc University Hospital, Université Catholique de Louvain, Avenue Hippocrate 10, 1200, Brussels, Belgium

    Jean-Pierre Devogelaer

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  1. Pui Yan Jenny Chung
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Correspondence to Wim Van Hul.

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Chung, P.Y.J., Beyens, G., Guañabens, N. et al. Founder Effect in Different European Countries for the Recurrent P392L SQSTM1 Mutation in Paget’s Disease of Bone. Calcif Tissue Int 83, 34–42 (2008). https://doi.org/10.1007/s00223-008-9137-2

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