• Open Access

Molecular Spectrum of Autosomal Dominant Hypercholesterolemia in France

Authors

  • Marie Marduel,

    1. Institut National de la Santé et de la Recherche Médicale, U781, 75015, Paris, France
    2. Université Paris Descartes, 75006, Paris, France
    Search for more papers by this author
  • Alain Carrié,

    1. Service de Biochimie Endocrinienne et Oncologique, GH Pitié- Salpêtrière (AP-HP), 75005, Paris, France
    Search for more papers by this author
  • Agnes Sassolas,

    1. UF Dyslipidémies-Cardiobiologie, CBPE, Hospices Civils de Lyon (GHE), Bron, France
    Search for more papers by this author
  • Martine Devillers,

    1. Institut National de la Santé et de la Recherche Médicale, U781, 75015, Paris, France
    Search for more papers by this author
  • Valérie Carreau,

    1. Service d'Endocrinologie-Métabolisme, GH Pitié-Salpétrière, 75005, Paris, France
    Search for more papers by this author
  • Mathilde Di Filippo,

    1. UF Dyslipidémies-Cardiobiologie, CBPE, Hospices Civils de Lyon (GHE), Bron, France
    Search for more papers by this author
  • Danièle Erlich,

    1. Institut National de la Santé et de la Recherche Médicale, U781, 75015, Paris, France
    2. Laboratoire de Biochimie et de Biologie Moléculaire, CHU Saint-Louis (AP-HP & Université Paris Denis Diderot), 75019, Paris, France
    Search for more papers by this author
  • Marianne Abifadel,

    1. Institut National de la Santé et de la Recherche Médicale, U781, 75015, Paris, France
    2. Faculté de Pharmacie, Université Saint-Joseph, Beirut, Lebanon
    Search for more papers by this author
  • Alice Marques-Pinheiro,

    1. Institut National de la Santé et de la Recherche Médicale, U781, 75015, Paris, France
    2. Université Paris Descartes, 75006, Paris, France
    Search for more papers by this author
  • Arnold Munnich,

    1. Institut National de la Santé et de la Recherche Médicale, U781, 75015, Paris, France
    2. Université Paris Descartes, 75006, Paris, France
    Search for more papers by this author
  • Claudine Junien,

    1. Institut National de la Santé et de la Recherche Médicale, U781, 75015, Paris, France
    2. Université Paris Descartes, 75006, Paris, France
    Search for more papers by this author
  • Catherine Boileau,

    1. Institut National de la Santé et de la Recherche Médicale, U781, 75015, Paris, France
    2. AP-HP, Hôpital Ambroise Paré, Service de Biochimie et Génétique Moléculaire, Boulogne, 92104, France
    3. Université Versailles Saint-Quentin-en-Yvelines, UFR de Médecine Paris Ile-de-France Ouest, Guyancourt, 78280, France
    Search for more papers by this author
  • Mathilde Varret,

    1. Institut National de la Santé et de la Recherche Médicale, U781, 75015, Paris, France
    2. Université Paris Descartes, 75006, Paris, France
    Search for more papers by this author
  • Jean-Pierre Rabès

    Corresponding author
    1. Institut National de la Santé et de la Recherche Médicale, U781, 75015, Paris, France
    2. AP-HP, Hôpital Ambroise Paré, Service de Biochimie et Génétique Moléculaire, Boulogne, 92104, France
    3. Université Versailles Saint-Quentin-en-Yvelines, UFR de Médecine Paris Ile-de-France Ouest, Guyancourt, 78280, France
    • Dr Jean-Pierre RABÈS, Laboratoire de Biochimie et de Génétique Moléculaire, CHU Ambroise Paré, 9 avenue Charles de Gaulle 92104 Boulogne Cedex, Fax: +33 1 49 09 58 63
    Search for more papers by this author

  • Communicated by Jurgen Horst

  • The French ADH Research Network: Dr. Michel Farnier (Dijon), Pr. Gérald Luc, Pr. Jean-Michel Lecerf (Lille), Pr. Eric Bruckert, Dr. Dominique Bonnefont-Rousselot, Dr. Philippe Giral, Dr. Athina Kalopissis, Pr. Jean-Philippe Girardet, Pr. Michel Polak (Paris), Dr. Bernard Chanu (Bondy), Pr. Philippe Moulin, Dr. Laurence Perrot (Lyon), Pr. Michel Krempf, Dr. Yassine Zaïr (Nantes), Pr. Jacques Bonnet (Bordeaux), Pr. Jean Ferrières, Dr Dorota Ferrières, Dr Vanina Bongard, Dr. Maxime Cournot (Toulouse), Pr Yves Reznick (Caen), Pr. Jean-Louis Schlienger (Strasbourg), Pr. Alexandre Fredenrich (Nice), Pr. Vincent Durlach (Reims).

Abstract

Autosomal Dominant Hypercholesterolemia (ADH), characterized by isolated elevation of plasmatic LDL cholesterol and premature cardiovascular complications, is associated with mutations in 3 major genes: LDLR (LDL receptor), APOB (apolipoprotein B) and PCSK9 (proprotein convertase subtilisin-kexin type 9). Through the French ADH Research Network, we collected molecular data from 1358 French probands from eleven different regions in France. Mutations in the LDLR gene were identified in 1003 subjects representing 391 unique events with 46.0% missense, 14.6% frameshift, 13.6% splice, and 11.3% nonsense mutations, 9.7% major rearrangements, 3.8% small in frame deletions/insertions, and 1.0% UTR mutations. Interestingly, 175 are novel mutational events and represent 45% of the unique events we identified, highlighting a specificity of the LDLR mutation spectrum in France. Furthermore, mutations in the APOB gene were identified in 89 probands and in the PCSK9 gene in 10 probands. Comparison of available clinical and biochemical data showed a gradient of severity for ADH-causing mutations: FH=PCSK9>FDB>‘Others’ genes. The respective contribution of each known gene to ADH in this French cohort is: LDLR 73.9%, APOB 6.6%, PCSK9 0.7%. Finally, in 19.0% of the probands, no mutation was found, thus underscoring the existence of ADH mutations located in still unknown genes. © 2010 Wiley-Liss, Inc.

Ancillary