Naturwissenschaften

, 98:943 | Cite as

New contributions to the study of common double mutants in the human LDL receptor gene

  • M. Teresa Tejedor
  • Ana Cenarro
  • Diego Tejedor
  • Marianne Stef
  • Lourdes Palacios
  • Isabel de Castro
  • Ángel L. García-Otín
  • Luis V. Monteagudo
  • Fernando Civeira
  • Miguel Pocovi
Original Article

Abstract

Variations in the gene encoding the low-density lipoprotein receptor (LDLR) can cause familial hypercholesterolemia (FH), one of the most common inherited metabolic disorders in humans. The functional effects of the p.Gln92Glu and p.Asn564His alterations are predicted as benign, but the c.313 + 1G>C and p.Lys799_Phe801del changes are believed to cause disease. Although p.Gln92Glu and c.313 + 1G>C have been observed only in Spain, p.Asn564His and p.Lys799_Phe801del are widespread in Western Europe. In order to estimate the ages (t generations) of these four variants of the gene, to determine their possible origin and to consider the influence of age and selective pressure on their spread, we analyzed 86 healthy individuals and 126 FH patients in Spain. Most of the FH patients investigated carried two of these four LDLR variants simultaneously, while only one patient carried three of them simultaneously. Haplotype analyses were based on five LDLR SNPs: c.81T>C, c.1413G>A, c.1725C>T, c.1959T>C and c.2232G>A. The results suggest that p.Gln92Glu and c.313 + 1G>C arose at about the same time (99 and 103 generations ago, respectively) in the CACTG haplotype and that p.Asn564His and p.Lys799_Phe801del appeared in the CGCCG haplotype and might be slightly more recent variations (92 and 95 generations ago, respectively). Low selective pressures could explain the maintenance of these variants in spite of their ages. The origin of p.Gln92Glu and c.313 + 1G>C appears to be in Spain whereas p.Asn564His and p.Lys799_Phe801del could have been introduced in Spain by Celtic migrations in the seventh to fifth centuries BC.

Keywords

Age of mutations inference Familial hypercholesterolemia Linkage disequilibrium Populations history Tag SNPs 

References

  1. Bourbon M, Alves AC, Medeiros AM, Silva S, Soutar AK, On behalf of the investigators of the Portuguese FH study (2008) Familial hypercholesterolaemia in Portugal. Atherosclerosis 196:633–642PubMedCrossRefGoogle Scholar
  2. Carlson CS, Eberle MA, Rieder MJ, Yi Q, Kruglyak L, Nickerson DA (2004) Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. Hum Genet 74:106–120CrossRefGoogle Scholar
  3. Cenarro A, Jensen HK, Casao E, Civeira F, González-Bonillo J, Rodríguez-Rey JC, Gregersen N, Pocoví M (1998) Identification of recurrent and novel mutations in the LDL receptor gene in Spanish patients with familial hypercholesterolemia. Mutations in brief no. 135. Online. Hum Mutat 11:413PubMedCrossRefGoogle Scholar
  4. Chabás A, Gort L, Montfort M, Castelló F, Domínguez MC, Grinberg D, Vilageliu L (1998) Recurrence of the D409H mutation in Spanish Gaucher disease patients: description of a new homozygous patient and haplotype analysis. J Med Genet 35:775–777PubMedCrossRefGoogle Scholar
  5. Chaves FJ, Real JT, Garcia-Garcia AB, Civera M, Armengol ME, Ascaso JF, Carmena R (2001) Genetic diagnosis of familial hypercholesterolaemia in a South European outbreed population: Influence of low-density lipoprotein (LDL) receptor gene mutations on treatment response to simvastatin in total, LDL, and high-density lipoprotein cholesterol. J Clin Endocrinol Metab 86:4926–4932PubMedCrossRefGoogle Scholar
  6. Cunliffe B (1997) The ancient Celts. Penguin, AustraliaGoogle Scholar
  7. Day IN, Whittall RA, O’Dell SD, Haddad L, Bolla MK, Gudnason V, Humphries SE (1997) Spectrum of LDL receptor gene mutations in heterozygous familial hypercholesterolemia. Hum Mutat 10:116–127PubMedCrossRefGoogle Scholar
  8. Defesche J, Kastelein JJ (1998) Molecular epidemiology of familial hypercholesterolemia. Lancet 352:1643–1644PubMedCrossRefGoogle Scholar
  9. Ebhardt M, Schmidt H, Doerk T, Tietge U, Haas R, Manns MP, Schmidtke J, Stuhrmann M (1999) Mutation analysis in 46 German families with familial hypercholesterolemia: identification of 8 new mutations. Mutations in brief no. 226. Online. Hum Mutat 13:257PubMedCrossRefGoogle Scholar
  10. Goldstein JL, Hobbs HH, Brown MS (2001) Familial hypercholesterolemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular basis of inherited disease, 8th edn. McGraw-Hill, New York, pp 2863–2913Google Scholar
  11. Jensen HK, Jensen LG, Hansen PS, Faergeman O, Gregersen N (1996) Two mutations in the same low-density lipoprotein receptor allele act in synergy to reduce receptor function in heterozygous familial hypercholesterolemia. Hum Mutat 9:437–344CrossRefGoogle Scholar
  12. Jordá F, Pellicer M, Acosta P, Almagro M (1986) Historia de España. Gredos, MadridGoogle Scholar
  13. Lombardi P, Sijbrands EJ, van de Huyesen K, Smelt AH, Kastelein JJ, Frants RR, Havekes LM (1995) Mutations in the low density lipoprotein receptor gene of familial hypercholesterolemic patients detected by denaturing gradient gel electrophoresis and direct sequencing. J Lipid Res 36:860–867PubMedGoogle Scholar
  14. Lombardi MP, Redeker EJW, Defesche JC, Kamerling SWA, Trip MD, Mannens MMAM, Havekes LM, Kastelein JJP (2000) Molecular genetic testing for familial hypercholesterolemia: spectrum of LDL receptors gene mutations in the Netherlands. Clin Genet 57:116–124PubMedCrossRefGoogle Scholar
  15. Morral N, Bertranpetit J, Estivill X, Nunes V, Casals T, Giménez J, Reis A, Varon-Mateeva R, Macek M Jr, Kalaydjieva L, Angelicheva D, Dancheva R, Romeo G, Russo MP, Garnerone S, Restagno G, Ferrari M, Magnani C, Claustres M, Desgeorges M, Schwartz M, Schwartz M, Dallapiccola B, Novelli G, Ferec C, de Arce M, Nemetti M, Kere J, Anvret M, Dhal N, Kadeshi L (1994) The origin of the major cystic fibrosis mutation (delta F508) in European populations. Nat Genet 7:169–175PubMedCrossRefGoogle Scholar
  16. Mozas P, Cenarro A, Civeira F, Castillo S, Ros E, Pocovi M (2000) Molecular characterization of familial hypercholesterolemia in Spain: identification of 39 novel and 77 recurrent mutations in LDLR. Hum Mutat 24:187CrossRefGoogle Scholar
  17. Rannala B, Bertorelle G (2001) Using linked markers to infer the age of a mutation. Hum Mutat 18:87–100PubMedCrossRefGoogle Scholar
  18. Rannala B, Reeve JP (2001) High-resolution multipoint linkage-disequilibrium mapping in the context of a human genome sequence. Am J Hum Genet 69:159–178PubMedCrossRefGoogle Scholar
  19. Schwartz SB (ed) (2000) Victors and vanquished: Spanish and Nahua Views of the Conquest of Mexico. Bedford, BostonGoogle Scholar
  20. Souverein OW, Defesche JC, Zwinderman AH, Kastelein JJ, Tanck MW (2007) Influence of LDL-receptor mutation type on age at first cardiovascular event in patients with familial hypercholesterolaemia. Eur Heart J 28:299–304PubMedCrossRefGoogle Scholar
  21. Sun XM, Patel DD, Bhatnagar D, Knight BL, Soutar AK (1995) Characterization of a splice-site mutation in the gene for the LDL receptor associated with an unpredictably severe clinical phenotype in English patients with heterozygous FH. Arterioscler Thromb Vasc Biol 15:219–227PubMedCrossRefGoogle Scholar
  22. Tejedor D, Castillo S, Mozas P, Jiménez E, López M, Tejedor MT, Artieda M, Alonso R, Mata P, Simón L, Martínez A, Pocoví M, On behalf of the Spanish FH group (2005) Reliable low-density DNA array based on allele-specific probes for detection of 118 mutations causing familial hypercholesterolemia. Clin Chem 51:1137–1144PubMedCrossRefGoogle Scholar
  23. Tejedor MT, Cenarro A, Tejedor D, Stef M, Mateo-Gallego R, de Castro I, García-Otin AL, Monteagudo LV, Civeira F, Pocovi M (2010) Haplotype analyses, mechanism and evolution of common double mutants in the human LDL receptor gene. Mol Genet Genomics 283:565–574PubMedCrossRefGoogle Scholar
  24. Tremblay M, Vezina H (2000) New estimates of intergenerational time intervals for the calculation of age and origins of mutation. Am J Hum Genet 66:651–658PubMedCrossRefGoogle Scholar
  25. Vaca G, Vázquez A, Magaña MT, Ramírez ML, Dávalos IP, Martínez E, Marín B, Carrillo G (2011) Mutational analysis of the LDL receptor and APOB genes in Mexican individuals with autosomal dominant hypercholesterolemia. Atherosclerosis. doi:10.1016/j.atherosclerosis.2011.06.006
  26. Zaykin DV, Meng Z, Ehm MG (2006) Contrasting linkage-disequilibrium patterns between cases and controls as a novel association-mapping method. Am J Hum Genet 78:737–746PubMedCrossRefGoogle Scholar
  27. Zeegers MP, van Poppel F, Vlietinck R, Spruijt L, Ostrer H (2004) Founder mutations among the Dutch. Eur J Hum Genet 12:591–600PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • M. Teresa Tejedor
    • 1
  • Ana Cenarro
    • 2
  • Diego Tejedor
    • 3
  • Marianne Stef
    • 3
  • Lourdes Palacios
    • 3
  • Isabel de Castro
    • 4
  • Ángel L. García-Otín
    • 2
  • Luis V. Monteagudo
    • 1
  • Fernando Civeira
    • 2
  • Miguel Pocovi
    • 4
  1. 1.Departamento de Anatomía, Embriología y GenéticaUniversidad de ZaragozaZaragozaSpain
  2. 2.Hospital Universitario Miguel Servet, Instituto Aragonés de Ciencias de la Salud (I+CS)ZaragozaSpain
  3. 3.Progenika Biopharma S.A., Parque Tecnológico de BizkaiaDerioSpain
  4. 4.Departamento de Bioquímica, Biología Molecular y Celular e I+CS, Universidad de ZaragozaZaragozaSpain

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