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Mutations in PCSK9 cause autosomal dominant hypercholesterolemia

Nature Genetics volume 34, pages 154–156 (2003)Cite this article

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.

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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.

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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.

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Authors and Affiliations

  1. INSERM U383, Hôpital Necker-Enfants Malades, AP-HP, Université Paris V, 149-161 rue de Sèvres, Paris, 75743 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, Beirut, BP.11-5076, 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, Boulogne, 92104, Cedex, France

    Jean-Pierre Rabès, Claudine Junien & Catherine Boileau

  4. Service d'Endocrinologie, CHU Hôtel Dieu, Nantes, 44093, France

    Khadija Ouguerram & Michel Krempf

  5. Génoscope, Centre National de Séquençage, 2 rue G. Crémieux, Evry, CP 5706, 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, Dijon, 21000, France

    Michel Farnier

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

    Isabel Beucler

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

    Eric Bruckert

  10. INSERM U505, Institut des Cordeliers, 15 rue de l'Ecole de Médecine

    Jean Chambaz

  11. 75006, Paris, France

    Jean Chambaz

  12. Service de Médecine Interne, Hôpital Henri Mondor, 51 avenue du Maréchal de Lattre de Tassigny, Créteil, 94010, France

    Bernard Chanu

  13. Service de Médecine Interne, Hôpital Huriez, Place de Verdun, Lille, 59019, France

    Jean-Michel Lecerf & Gerald Luc

  14. Service d'Endocrinologie et des Maladies de la Nutrition, Hôpital de l'Antiquaille, rue de l'Antiquaille, Lyon, 69005, France

    Philippe Moulin

Authors
  1. Marianne Abifadel
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  2. Mathilde Varret
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  3. Jean-Pierre Rabès
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  9. Louise Wickham
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  10. Danièle Erlich
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  11. Aurélie Derré
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  12. Ludovic Villéger
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  13. Michel Farnier
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  14. Isabel Beucler
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  15. Eric Bruckert
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  16. Jean Chambaz
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  17. Bernard Chanu
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  18. Jean-Michel Lecerf
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  19. Gerald Luc
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  20. Philippe Moulin
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  21. Jean Weissenbach
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  22. Annick Prat
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  23. Michel Krempf
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  24. Claudine Junien
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  25. Nabil G Seidah
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  26. Catherine Boileau
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Corresponding author

Correspondence to Catherine Boileau.

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The authors declare no competing financial interests.

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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). https://doi.org/10.1038/ng1161

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