Molecular Genetics and Genomics

, Volume 283, Issue 6, pp 565–574 | Cite as

Haplotype analyses, mechanism and evolution of common double mutants in the human LDL receptor gene

  • M. T. TejedorEmail author
  • A. Cenarro
  • D. Tejedor
  • M. Stef
  • R. Mateo-Gallego
  • I. de Castro
  • A. L. García-Otin
  • L. V. Monteagudo
  • F. Civeira
  • M. Pocovi
Original Paper


Familial hypercholesterolemia (FH), an autosomal dominant inherited disorder resulting in increased levels of circulating plasma low-density lipoprotein (LDL), tendon xanthomas and premature coronary artery disease (CAD), is caused by defects in the LDL receptor gene (LDLR). Three widespread LDLR alterations not causing FH (c.1061-8T>C, c.2177C>T and c.829G>A) and one mutation (c.12G>A) with narrow geographical distribution and thought to cause disease were investigated. In an attempt to improve knowledge on their origin, spread and possible selective effects, estimations of the ages of these variants (t generations) and haplotype analysis were performed by genotyping 86 healthy individuals and 98 FH patients in Spain for five LDLR SNPs: c.81T>C, c.1413G>A, c.1725C>T, c.1959T>C, and c.2232G>A; most patients carried two of these LDLR variants simultaneously. It was found that both the c.1061-8T>C (t = 54) and c.2177C>T alterations (t = 62) arose at about the same time (54 and 62 generations ago, respectively) in the CGCTG haplotype, while the c.12G>A mutation (t = 70) appeared in a CGCCG haplotype carrying an earlier c.829G>A alteration (t = 83). The estimated ages of selectively neutral alterations could explain their distribution by migrations. The origin of the c.12G>A mutation could be in the Iberian Peninsula; despite its estimated age, a low selective pressure could explain its conservation in Spain from where it could have spread to China and Mexico, since the sixteenth century through the Spanish/Portuguese colonial expeditions.


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



The authors thank Dr. D. Savva (University of Reading, UK) for his help with the English manuscript. This study was funded by Grants from the Spanish Ministry of Health FIS PI06/0365 and RTIC C06/01(RECAVA: Cooperative Cardiovascular Disease Research Network). The authors also thank CIBERER (Biomedical Network Research Centre on Rare Diseases).Ethical standards: The authors declare that the experiments carried out in this study comply with the current Spanish laws.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Supplementary material

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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • M. T. Tejedor
    • 1
    Email author
  • A. Cenarro
    • 2
  • D. Tejedor
    • 3
  • M. Stef
    • 3
  • R. Mateo-Gallego
    • 2
  • I. de Castro
    • 4
  • A. L. García-Otin
    • 2
  • L. V. Monteagudo
    • 1
  • F. Civeira
    • 2
  • M. Pocovi
    • 4
  1. 1.Departamento de Anatomía, Embriología y GenéticaUniversidad de ZaragozaZaragozaSpain
  2. 2.Instituto Aragonés de Ciencias de la Salud (I+CS)Hospital Universitario Miguel ServetZaragozaSpain
  3. 3.Progenika Biopharma S.A. Parque Tecnológico de BizkaiaDerioSpain
  4. 4.Departamento de Bioquímica, Biología Molecular y Celular e I+CSUniversidad de ZaragozaZaragozaSpain

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