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Mutations in PCSK9 cause autosomal dominant hypercholesterolemia


Autosomal dominant hypercholesterolemia (ADH; OMIM144400), a risk factor for coronary heart disease, is characterized by an increase in low-density lipoprotein cholesterol levels that is associated with mutations in the genes LDLR (encoding low-density lipoprotein receptor) or APOB (encoding apolipoprotein B). We mapped a third locus associated with ADH, HCHOLA3 at 1p32, and now report two mutations in the gene PCSK9 (encoding proprotein convertase subtilisin/kexin type 9) that cause ADH. PCSK9 encodes NARC-1 (neural apoptosis regulated convertase), a newly identified human subtilase that is highly expressed in the liver and contributes to cholesterol homeostasis.

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Figure 1: Pedigree of family HC92 and genetic analysis with markers spanning the 1p34.1–p32 region.
Figure 2: Genetic analysis and mutation detection in families HC92 and HC60.


  1. Varret, M. et al. Am. J. Hum. Genet. 64, 1378–1387 (1999).

    Article  CAS  Google Scholar 

  2. Hunt, S.C. et al. Arterioscler. Thromb. Vasc. Biol. 20, 1089–1093 (2000).

    Article  CAS  Google Scholar 

  3. Seidah, N.G. et al. Proc. Natl. Acad. Sci. USA 100, 928–933 (2003).

    Article  CAS  Google Scholar 

  4. Brown, M.S. & Goldstein, J.L. Proc. Natl. Acad. Sci. USA 96, 11041–11048 (1999).

    Article  CAS  Google Scholar 

  5. Elagoz, A., Benjannet, S., Mammarbassi, A., Wickham, L. & Seidah N.G. J. Biol. Chem. 277, 11265–11275 (2002).

    Article  CAS  Google Scholar 

  6. Ruoslahti, E. Annu. Rev. Cell. Dev. Biol. 12, 697–715 (1996).

    Article  CAS  Google Scholar 

Download references


We are indebted to the family members for their cooperation and to C. Mugnier for expert assistance in computing the statistics. This work was supported by grants from Progrès-Institut National de la Santé et de la Recherche Médicale, Pfizer, Fondation de France, Comité Français de Coordination des Recherches sur l'Athérosclérose et le Cholestérol and Canadian Research grants (to N.G.S.). M.A. was supported by grants from Société Française d'Athérosclérose, Comité Français de Coordination des Recherches sur l'Athérosclérose et le Cholestérol, Fondation de la Recherche Médicale, Université René Descartes, Conseil de Recherche de l'Université Saint-Joseph. M.V. was supported by a grant from Société Française d'Athérosclérose and Pfizer. L.V. and D.A. were supported by grants from Ministère de l'Education Nationale de la Recherche et de la Technologie.

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Correspondence to Catherine Boileau.

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Abifadel, M., Varret, M., Rabès, JP. et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 34, 154–156 (2003).

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