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.
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Abifadel M, Varret M, Rabes J-P, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derré A, Villéger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf J-M, Luc G, Moulin P, Weissenbach J, Prat A, Krempt M, Junien C, Seidah NG, Boileau C (2003) Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 34:154–156
Grantham R (1974) Amino acid difference formula to help explain protein evolution. Science 185:862–864
Haddad L, Day INM, Hunt S, Williams RR, Humphries SE, Hopkins PN (1999) Evidence for a third genetic locus causing autosomal-dominant hypercholesterolemia: a non-LDLR, non-APOB kindred. J Lipid Res 40:1-10
Hunt SC, Hopkins PN, Bulka K, McDermott MT, Thorne TL, Wardell BB, Bowen BR, Ballinger DG, Skolnick MH, Samuels ME (2000) Genetic localization to chromosome 1p32 of the third locus for familial hypercholesterolemia in a Utah kindred. Artherioscler Thromb Vasc Biol 20:1089–1093
International Human Genome Sequencing Consortium (2001) Initial sequencing and analysis of the human genome. Nature 409:860–921
Maxwell KN, Soccio RE, Duncan EM, Sehayek E, Breslow JL (2003) Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice. J Lipid Res 44:2109–2119
Miller MP, Kumar S (2001) Understanding human disease mutations through the use of interspecific genetic variation. Hum Mol Genet 10:2319–2328
Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S, Basak A, Prat A, Chrétien M (2003) The secretary proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci USA 100:928–933
Siezen RJ, Leunissen JAM (1997) Subtilases: the superfamily of subtilisin-like serine proteases. Protein Sci 6:501–523
Tavtigian SV, Simard J, Rommens J, Couch F, Shattuck-Eidens D, Neuhausen S, Merajver S, Thorlacius S, Offit K, Stoppa-Lyonnet D, Belanger C, Bell R, Berry S, Bogden R, Chen Q, Davis T, Dumont M, Frye C, Hattier T, Jammulapati S, Janecki T, Jiang P, Kehrer R, Leblanc JF, Goldgar D, et al. (1996) The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat Genet 12:333–337
Thomas A, Gutin A, Abkevich V, Bansal A (2000) Multilocus linkage analysis by blocked Gibbs sampling. Stat Comput 10:259–269
Varret M, Rabes J-P, Saint-Jore B, Cenarro A, Marinoni JC, Civeira F, Devillers M, Krempf M, Coulon M, Thiart R, Kotze MJ, Schmidt H, Buzzi JC, Kostner GM, Bertolini S, Pocovi M, Rosa A, Farnier M, Martinez M, Junien C, Boileau C (1999) A third major locus for autosomal dominant hypercholesterolemia maps to 1p34.1-p32. Am J Hum Genet 64:1378–1387
Acknowledgements
This study was funded in part by Myriad Genetics, and National Institutes of Health grants HL47561 and HL21088. We would like to thank Lily L. Wu and Yuanpei Xin for expert technical assistance, and Georges Frech, Kirill Ostanin, and Steve Stone for helpful discussions.
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Timms, K.M., Wagner, S., Samuels, M.E. et al. A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree. Hum Genet 114, 349–353 (2004). https://doi.org/10.1007/s00439-003-1071-9
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DOI: https://doi.org/10.1007/s00439-003-1071-9