title: Haplotype analyses, mechanism and evolution of common double mutants in the human LDL receptor gene.
abstract: 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.
authors.affiliation: Departamento de Anatomía, Embriología y Genética, Universidad de Zaragoza, 50013 Zaragoza, Spain. ttejedor@unizar.es
authors.forename: M T
authors.initials: MT
authors.lastname: Tejedor
authors.forename: A
authors.initials: A
authors.lastname: Cenarro
authors.forename: D
authors.initials: D
authors.lastname: Tejedor
authors.forename: M
authors.initials: M
authors.lastname: Stef
authors.forename: R
authors.initials: R
authors.lastname: Mateo-Gallego
authors.forename: I
authors.initials: I
authors.lastname: de Castro
authors.forename: A L
authors.initials: AL
authors.lastname: García-Otin
authors.forename: L V
authors.initials: LV
authors.lastname: Monteagudo
authors.forename: F
authors.initials: F
authors.lastname: Civeira
authors.forename: M
authors.initials: M
authors.lastname: Pocovi
mesh_terms: D003327:Coronary Disease / Q000235:genetics; D019143:Evolution, Molecular; D005191:Family Characteristics; D006239:Haplotypes; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics; D015810:Linkage Disequilibrium; D009140:Musculoskeletal Diseases / Q000235:genetics; D050505:Mutant Proteins / Q000235:genetics; D009154:Mutation / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D011973:Receptors, LDL / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013030:Spain; D013710:Tendons / Q000473:pathology; D014973:Xanthomatosis / Q000235:genetics
chemical_list: D050505:Mutant Proteins; D011973:Receptors, LDL