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

Kirsten M. Timms, Susanne Wagner, Mark E. Samuels, Kristian Forbey, Howard Goldfine, Srikanth Jammalapati, Mark H. Skolnick, Paul N. Hopkins, Steve C. Hunt, Donna M. Shattuck

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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.

Original languageEnglish
Pages (from-to)349-353
Number of pages5
JournalHuman Genetics
Issue number4
Publication statusPublished - 1 Mar 2004



  • Autosomal-dominant hypercholesterolemia
  • Chromosome 1p32
  • PCSK9

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Timms, K. M., Wagner, S., Samuels, M. E., Forbey, K., Goldfine, H., Jammalapati, S., Skolnick, M. H., Hopkins, P. N., Hunt, S. C., & Shattuck, D. M. (2004). A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree. Human Genetics, 114(4), 349-353. https://doi.org/10.1007/s00439-003-1071-9