Advertisement

Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Ancestral origins of the prion protein gene D178N mutation in the Basque Country

  • 151 Accesses

  • 6 Citations

Abstract

Fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD) are familial prion diseases with autosomal dominant inheritance of the D178N mutation. FFI has been reported in at least 27 pedigrees around the world. Twelve apparently unrelated FFI and fCJD pedigrees with the characteristic D178N mutation have been reported in the Prion Diseases Registry of the Basque Country since 1993. The high incidence of familial prion diseases in this region may reflect a unique ancestral origin of the chromosome carrying this mutation. In order to investigate this putative founder effect, we developed “happy typing”, a new approach to the happy mapping method, which consists of the physical isolation of large haploid genomic DNA fragments and their analysis by the Polymerase Chain Reaction in order to perform haplotypic analysis instead of pedigree analysis. Six novel microsatellite markers, located in a 150-kb genomic segment flanking the PRNP gene were characterized for typing haploid DNA fragments of 285 kb in size. A common haplotype was found in patients from the Basque region, strongly suggesting a founder effect. We propose that “happy typing” constitutes an efficient method for determining disease-associated haplotypes, since the analysis of a single affected individual per pedigree should provide sufficient evidence.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2

References

  1. Alonso S, Castro A, Fernández I, Gomez de Cedron M, Garcia-Orad A, Meyer E, Martinez De Pancorbo M (1995) Population study of 3 STR loci in de Basque country (northern Spain). Int J Leg Med 107:239–245

  2. Brown DR (2002) Molecular advances in understanding inherited prion diseases. Mol Neurobiol 25:287–301

  3. Brown P, Cervenakova L, Goldfarb LG, McCombie WR, Rubenstein R, Will RG, Pocchiari M, Martinez-Lage JF, Scalici C, Masullo C, et al (1994) Iatrogenic Creutzfeldt-Jakob disease: an example of the interplay between ancient genes and modern medicine. Neurology 44:291–293

  4. Collins A, Lanjou C, Morton NE (1999) Genetic epidemiology of single-nucleotide polymorphisms. Proc Natl Acad Sci USA 96:15173–15177

  5. Dagvadorj A, Petersen RB, Lee HS, Cervenakova L, Shatunov A, Budka H, Brown P, Gambetti P, Goldfarb LG (2002) Spontaneous mutation in the prion protein gene causing transmissible spongiform encephalopathies. Ann Neurol 52:355–359

  6. De Pancorbo MM, Lopez-Martinez M, Martinez-Bouzas C, Castro A, Fernandez-Fernandez I, Mayolo GA de, Mayolo AA de, Mayolo PA de, Rowold DJ, Herrera RJ (2001) The Basques according to polymorphic Alu insertions. Hum Genet 109:224–233

  7. Dear HP, Cook PR (1993) Happy mapping: linkage mapping using a physical analogue of meiosis. Nucleic Acids Res 21:13–20

  8. Dear HP, Bankier AY, Piper MB (1998) A high-resolution happy map of human chromosome 14. Genomics 48:232–241

  9. DeArmond SJ, Johnson RT, Prusiner SB (1995) Etiology and pathogenesis of prion diseases. Am J Pathol 146:785–811

  10. De Knijff P (2000) Messages through bottlenecks: on the combined use of slow and fast evolving polymorphic markers on the human Y chromosome. Am J Hum Genet 67:1055–1061

  11. DNA Commission of the International Society for Forensic Haemogenetics (1992) 1992 report concerning recommendations of the DNA Commission of the International Society for Forensic Haemogenetics relating to the use of PCR-based polymorphisms. Int J Leg Med 105:63–64

  12. Dolukhanov PM (2000) “Prehistoric revolutions” and languages in Europe. In: Künnap A (ed) The roots of peoples and languages of northern Eurasia II and III. University of Tartu, Tartu, pp 71–78

  13. Excoffier L (2001) Analysis of population subdivision. In: Balding DJ, Boshop M, Cannings C (eds) Handbook of statistical genetics. Wiley, New York, pp 271–307

  14. Goldfarb LG, Petersen RB, Tabaton M, Brown P, LeBlanc AC, Montagna P, Cortelli P, Julien J, Vital C, Pendelbury WW, et al (1992) Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease phenotype determined by a DNA polymorphism. Science 258:806–807

  15. Haltia M (2000) Human prion diseases. Ann Med 32:493–500

  16. Hammer MF, Zegura SL (2002) The human Y chromosome haplogroup tree: nomenclature and phylogeography of its major divisions. Annu Rev Anthropol 31:303–321

  17. Harder A, Jendroska K, Kreuz F, Wirth T, Schafranka C, Karnatz N, Theallier-Janko A, Dreier J, Lohan K, Emmerich D, et al (1999) Novel twelve-generation kindred of fatal familial insomnia from Germany representing the entire spectrum of disease expression. Am J Hum Genet 87:311–316

  18. Hill AF, Desbruslais M, Joiner S, Sidle KC, Gowland I, Collinge J, Doey LJ, Lantos P (1997) The same prion strain causes vCJD and BSE. Nature 389:448–450

  19. Horwich AL, Weissman JS (1997) Deadly conformations—protein misfolding in prion disease. Cell 89:499–510

  20. Housley RA, Gamble CS, Street M, Pettitt P (1997) Radiocarbon evidence for the late glacial human recolonisation of northern Europe. Proc Prehist Soc 63:25–54

  21. Hsiao K, Prusiner SB (1990) Inherited human prion diseases. Neurology 40:1820–1827

  22. Johnson RT, Gibbs CJ (1998) Creutzfeldt-Jakob disease and related transmissible spongiform encephalopathies. N Engl J Med 339:1994–2004

  23. Lee HS, Sambuughin N, Cervenakova L, Chapman J, Pocchiari M, Litvak S, Qi HY, Budka H, Ser T del, Furukawa H, et al (1999) Ancestral origins and worldwide distribution of the PRNP 200 K mutation causing familial Creutzfeldt-Jakob disease. Am J Hum Genet 64:1063–1070

  24. Medori R, Montagna P, Tritschler HJ, LeBlanc A, Cortelli P, Tinuper P, Lugaresi E, Gambetti P (1992b) Fatal familial insomnia: a second kindred with mutation of prion protein gene at codon 178. Neurology 42:669–670

  25. Medori R, Tritschler HJ, LeBlanc A, Villare F, Manetto V, Chen HY, Xue R, Leal S, Montagna P, Cortelli P, et al (1992a) Fatal familial insomnia, a prion disease with a mutation at codon 178 of the prion protein gene. N Engl J Med 326:444–449

  26. Montagna P, Gambetti P, Cortelli P, Lugaresi E (2003) Familial and sporadic fatal insomnia. Lancet Neurol 2:167–176

  27. Moreno MJ, Romero J (2002) Sporadic Creutzfeldt-Jakob disease: phenotypic variability. Neurología 17:366–377

  28. Ott J (2000) Predicting the range of linkage disequilibrium. Proc Natl Acad Sci USA 97:2–3

  29. Parchi P, Gambetti P (1995) Human prion diseases. Curr Opin Neurol 8:286–293

  30. Petit J, Boisseau P, Arveiler B (1994) Glucanex: a cost-effective yeast lytic enzyme. Trends Genet 10:4–5

  31. Preuss S, Peischl T, Melchinger E, Geldermann H (2004) Numerous polymorphic microsatellites in the human prion gene complex (including PRNP, PRND and PRNT). Gene 329:197–203

  32. Prusiner SB (1997) Prion diseases and the BSE crisis. Science 278:245–251

  33. Schlötterer C, Harr B (2001) Microsatellite instability. Encyclopedia of life sciences. Nature Publishing Group, London

  34. Urquhart A, Kimpton CP, Downes TJ, Gill P (1994) Variation in short tandem repeat sequences-a survey of twelve microsatellite loci for use as forensic identification markers. Int J Leg Med 107:13–20

  35. Will RG, Ironside JW, Zeidler M, Cousens SN, Estibeiro K, Alperovitch A, Poser S, Pocchiari M, Hofman A, Smith PG (1996) A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 347:921–9257

  36. Will RG, Alperovitch A, Poser S, Pocchiari M, Hofman A, Mitrova E, Silva R de, D’Alessandro M, Delasnerie-Laupretre N, Zerr I, Duijn C van (1998) Descriptive epidemiology of Creutzfeldt-Jakob disease in six European countries, 1993–1995. EU Collaborative Study Group for CJD. Ann Neurol 43:763–767

  37. Windl O, Dempster M, Estibeiro JP, Lathe R, Silva R de, Esmonde T, Will R, Springbett A, Campbell TA, Sidle KC, Palmer MS, Collinge J (1996) Genetic basis of Creutzfeldt-Jakob disease in the United Kingdom: a systematic analysis of predisposing mutations and allelic variation in the PRNP gene. Hum Genet 98:259–264

  38. Zarranz JJ, Digon A, Atares B, Arteagoitia JM, Carrera N, Fernandez-Manchola I, Fernandez-Martinez M, Fernandez-Maiztegui C, Forcadas I, Galdos L, Ibanez A, Lezcano E, Marti-Masso JF, Mendibe MM, Urtasun M, Uterga JM, Saracibar N, Velasco F, Gonzalez De Galdeano L (2004) Familial prion diseases in the Basque country (Spain). Neuroepidemiology 24:103–109

Download references

Acknowledgements

We thank Prof. M. Aigle (IBGC; UMR 5095) for judicious suggestions during the time course of this work, M. Alonso for discussions, and J. Garaizar, A.B. Vivanco, J. Alvarez for technical support. Some of the samples used in this study were supplied by the sample bank of the CJD Unit of the Hospital Clínic of Barcelona, Spain (MCyT EET 2001–2216). This work was supported by grants from the Basque Government (BFI02.1) and the French Embassy in Spain (I/19786/1321) to A.B. R.-M. and by funding from CICYT (EET-2002/05165) and the “Fond commun de coopération Aquitaine-Euskadi” from the “Conseil Régional d’Aquitaine”.

Author information

Correspondence to Marian M. de Pancorbo.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Rodríguez-Martínez, A.B., Barreau, C., Coupry, I. et al. Ancestral origins of the prion protein gene D178N mutation in the Basque Country. Hum Genet 117, 61–69 (2005). https://doi.org/10.1007/s00439-005-1277-0

Download citation

Keywords

  • Prion Disease
  • Founder Effect
  • Basque Country
  • D178N Mutation
  • PRNP Gene