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, Steven Hunt, Donna M. Shattuck

Research output: Contribution to journalArticle

226 Citations (Scopus)

Abstract

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
Volume114
Issue number4
DOIs
Publication statusPublished - Mar 2004
Externally publishedYes

Fingerprint

Hyperlipoproteinemia Type II
Pedigree
Haplotypes
Mutation
Genes
LDL Receptors
Apolipoproteins B
Microsatellite Repeats
Nucleotides

Keywords

  • Autosomal-dominant hypercholesterolemia
  • Chromosome 1p32
  • PCSK9

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Timms, K. M., Wagner, S., Samuels, M. E., Forbey, K., Goldfine, H., Jammalapati, S., ... 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

A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree. / Timms, Kirsten M.; Wagner, Susanne; Samuels, Mark E.; Forbey, Kristian; Goldfine, Howard; Jammalapati, Srikanth; Skolnick, Mark H.; Hopkins, Paul N.; Hunt, Steven; Shattuck, Donna M.

In: Human Genetics, Vol. 114, No. 4, 03.2004, p. 349-353.

Research output: Contribution to journalArticle

Timms, KM, Wagner, S, Samuels, ME, Forbey, K, Goldfine, H, Jammalapati, S, Skolnick, MH, Hopkins, PN, Hunt, S & Shattuck, DM 2004, 'A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree', Human Genetics, vol. 114, no. 4, pp. 349-353. https://doi.org/10.1007/s00439-003-1071-9
Timms KM, Wagner S, Samuels ME, Forbey K, Goldfine H, Jammalapati S et al. A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree. Human Genetics. 2004 Mar;114(4):349-353. https://doi.org/10.1007/s00439-003-1071-9
Timms, Kirsten M. ; Wagner, Susanne ; Samuels, Mark E. ; Forbey, Kristian ; Goldfine, Howard ; Jammalapati, Srikanth ; Skolnick, Mark H. ; Hopkins, Paul N. ; Hunt, Steven ; Shattuck, Donna M. / A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree. In: Human Genetics. 2004 ; Vol. 114, No. 4. pp. 349-353.
@article{0ce50a9967464a48b525bcad6f0d4a48,
title = "A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree",
abstract = "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.",
keywords = "Autosomal-dominant hypercholesterolemia, Chromosome 1p32, PCSK9",
author = "Timms, {Kirsten M.} and Susanne Wagner and Samuels, {Mark E.} and Kristian Forbey and Howard Goldfine and Srikanth Jammalapati and Skolnick, {Mark H.} and Hopkins, {Paul N.} and Steven Hunt and Shattuck, {Donna M.}",
year = "2004",
month = "3",
doi = "10.1007/s00439-003-1071-9",
language = "English",
volume = "114",
pages = "349--353",
journal = "Human Genetics",
issn = "0340-6717",
publisher = "Springer Verlag",
number = "4",

}

TY - JOUR

T1 - A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree

AU - Timms, Kirsten M.

AU - Wagner, Susanne

AU - Samuels, Mark E.

AU - Forbey, Kristian

AU - Goldfine, Howard

AU - Jammalapati, Srikanth

AU - Skolnick, Mark H.

AU - Hopkins, Paul N.

AU - Hunt, Steven

AU - Shattuck, Donna M.

PY - 2004/3

Y1 - 2004/3

N2 - 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.

AB - 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.

KW - Autosomal-dominant hypercholesterolemia

KW - Chromosome 1p32

KW - PCSK9

UR - http://www.scopus.com/inward/record.url?scp=12144285659&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=12144285659&partnerID=8YFLogxK

U2 - 10.1007/s00439-003-1071-9

DO - 10.1007/s00439-003-1071-9

M3 - Article

VL - 114

SP - 349

EP - 353

JO - Human Genetics

JF - Human Genetics

SN - 0340-6717

IS - 4

ER -