A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree

Hum Genet. 2004 Mar;114(4):349-53. doi: 10.1007/s00439-003-1071-9. Epub 2004 Jan 15.


Familial hypercholesterolemia results from mutations in the low-density lipoprotein (LDL) receptor or apolipoprotein B genes. We have previously reported the identification of a Utah autosomal-dominant hypercholesterolemia pedigree (kindred 1173) that did not show linkage to either of these loci (Hunt et al. 2000). Expansion of the pedigree and increased marker density within the region of interest have resulted in a multipoint LOD score of 9.6 and enabled us to decrease the size of the linked region to approximately 7.5 Mbp. In addition, we were able to identify additional families sharing the same microsatellite haplotype. While all haplotype carriers in kindred 1173 (K1173) are affected, the haplotype carriers within the newly identified families are unaffected, suggesting that the causal mutation in K1173 had occurred after divergence of these pedigrees from a common ancestor. Mutation screening of genes in the region identified a single nucleotide variant (G-->T) present on the K1173 haplotype that was not present on the same haplotype in the other kindreds. This variant results in a D374Y missense change in the gene PCSK9.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Female
  • Genes, Dominant
  • Haplotypes
  • Heterozygote
  • Humans
  • Hyperlipoproteinemia Type II / genetics*
  • Lod Score
  • Male
  • Mutation, Missense
  • Pedigree
  • Phenotype
  • Point Mutation*
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases / genetics*
  • Utah


  • PCSK9 protein, human
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases