Subjects

Abstract

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

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

  2. 2.

    et al. Arterioscler. Thromb. Vasc. Biol. 20, 1089–1093 (2000).

  3. 3.

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

  4. 4.

    & Proc. Natl. Acad. Sci. USA 96, 11041–11048 (1999).

  5. 5.

    , , , & J. Biol. Chem. 277, 11265–11275 (2002).

  6. 6.

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

Download references

Acknowledgements

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.

Author information

Affiliations

  1. INSERM U383, Hôpital Necker-Enfants Malades, AP-HP, Université Paris V, 149-161 rue de Sèvres, 75743 Paris Cedex 15, France.

    • Marianne Abifadel
    • , Mathilde Varret
    • , Jean-Pierre Rabès
    • , Delphine Allard
    • , Martine Devillers
    • , Danièle Erlich
    • , Aurélie Derré
    • , Ludovic Villéger
    • , Claudine Junien
    •  & Catherine Boileau
  2. Faculté de Pharmacie, Université Saint-Joseph, BP.11-5076 Beirut, Lebanon.

    • Marianne Abifadel
  3. Laboratoire de Biochimie, d'Hormonologie et de Génétique Moléculaire, CHU Ambroise Paré, AP-HP, Université Versailles-Saint-Quentin-en-Yvelines, 9 avenue Charles de Gaulle, 92104 Boulogne Cedex, France.

    • Jean-Pierre Rabès
    • , Claudine Junien
    •  & Catherine Boileau
  4. Service d'Endocrinologie, CHU Hôtel Dieu, 44093 Nantes, France.

    • Khadija Ouguerram
    •  & Michel Krempf
  5. Génoscope, Centre National de Séquençage, 2 rue G. Crémieux, CP 5706, Evry, France.

    • Corinne Cruaud
    •  & Jean Weissenbach
  6. Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, 110 Pine Ave. West, Montreal, QC H2W 1R7, Canada.

    • Suzanne Benjannet
    • , Louise Wickham
    • , Annick Prat
    •  & Nabil G Seidah
  7. Point Médical, Rond Point de la Nation, 21000 Dijon, France.

    • Michel Farnier
  8. Laboratoire des Lipides, Hôpital Pitié Salpétrière, 83 boulevard de l'Hôpital, 75013 Paris, France.

    • Isabel Beucler
  9. Service d'Endocrinologie-Métabolisme, Hôpital Pitié Salpétrière, 83 boulevard de l'Hôpital, 75013 Paris, France.

    • Eric Bruckert
  10. INSERM U505, Institut des Cordeliers, 15 rue de l'Ecole de Médecine, 75006 Paris, France.

    • Jean Chambaz
  11. Service de Médecine Interne, Hôpital Henri Mondor, 51 avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France.

    • Bernard Chanu
  12. Service de Médecine Interne, Hôpital Huriez, Place de Verdun, 59019 Lille, France.

    • Jean-Michel Lecerf
    •  & Gerald Luc
  13. Service d'Endocrinologie et des Maladies de la Nutrition, Hôpital de l'Antiquaille, rue de l'Antiquaille, 69005 Lyon, France.

    • Philippe Moulin

Authors

  1. Search for Marianne Abifadel in:

  2. Search for Mathilde Varret in:

  3. Search for Jean-Pierre Rabès in:

  4. Search for Delphine Allard in:

  5. Search for Khadija Ouguerram in:

  6. Search for Martine Devillers in:

  7. Search for Corinne Cruaud in:

  8. Search for Suzanne Benjannet in:

  9. Search for Louise Wickham in:

  10. Search for Danièle Erlich in:

  11. Search for Aurélie Derré in:

  12. Search for Ludovic Villéger in:

  13. Search for Michel Farnier in:

  14. Search for Isabel Beucler in:

  15. Search for Eric Bruckert in:

  16. Search for Jean Chambaz in:

  17. Search for Bernard Chanu in:

  18. Search for Jean-Michel Lecerf in:

  19. Search for Gerald Luc in:

  20. Search for Philippe Moulin in:

  21. Search for Jean Weissenbach in:

  22. Search for Annick Prat in:

  23. Search for Michel Krempf in:

  24. Search for Claudine Junien in:

  25. Search for Nabil G Seidah in:

  26. Search for Catherine Boileau in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Catherine Boileau.

Supplementary information

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng1161

Further reading