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D25V apolipoprotein C-III variant causes dominant hereditary systemic amyloidosis and confers cardiovascular protective lipoprotein profile

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  • Sophie Valleix

    (Université Paris-Descartes, Sorbonne Paris Cité, Assistance Publique-Hôpitaux de Paris, Laboratoire de Biologie et Génétique Moléculaire, Hôpital Cochin
    INSERM, UMR_1163, Institut Imagine, Laboratoire de Génétique Ophtalmologique (LGO), Université Paris Descartes, Sorbonne Paris Cité
    INSERM, U1016, Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité
    Sorbonne Universités, UPMC Univ Paris 06, INSERM, Université Paris-Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers)

  • Guglielmo Verona

    (Centre for Amyloidosis and Acute Phase Proteins, National Amyloidosis Centre, University College London
    Institute of Biochemistry, University of Pavia)

  • Noémie Jourde-Chiche

    (Université de Marseille, AP-HM, Hôpital de la Conception)

  • Brigitte Nédelec

    (INSERM, UMR_1163, Institut Imagine, Laboratoire de Génétique Ophtalmologique (LGO), Université Paris Descartes, Sorbonne Paris Cité
    INSERM, U1016, Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité
    Sorbonne Universités, UPMC Univ Paris 06, INSERM, Université Paris-Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers)

  • P. Patrizia Mangione

    (Centre for Amyloidosis and Acute Phase Proteins, National Amyloidosis Centre, University College London
    Institute of Biochemistry, University of Pavia)

  • Frank Bridoux

    (Université de Poitiers, CHU Poitiers, Centre National de Référence Amylose AL et autres maladies par dépôts d'immunoglobulines monoclonales)

  • Alain Mangé

    (Institut de Recherche en Cancérologie de Montpellier (IRCM)
    INSERM, U1194
    Université de Montpellier
    Institut régional du Cancer de Montpellier)

  • Ahmet Dogan

    (Mayo Clinic
    Memorial Sloan-Kettering Cancer Centre)

  • Jean-Michel Goujon

    (Université de Poitiers, CHU Poitiers, Service d’Anatomie et Cytologie Pathologiques, Centre National de Référence Amylose AL et autres maladies par dépôts d'immunoglobulines monoclonales)

  • Marie Lhomme

    (Lipidomic core, ICANalytics, Institute of Cardiometabolism and Nutrition, ICAN, Pitié-Salpôtrière Hospital)

  • Carolane Dauteuille

    (Sorbonne Universités, UPMC Univ Paris 06, Institute of Cardiometabolism and Nutrition (ICAN), UMR_S 1166, Hôpital de la Pitié)

  • Michèle Chabert

    (Sorbonne Universités, UPMC Univ Paris 06, INSERM, Université Paris-Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers
    Sorbonne Universités, UPMC Univ Paris 06, Institute of Cardiometabolism and Nutrition (ICAN), UMR_S 1166, Hôpital de la Pitié
    Ecole Pratique des Hautes Etudes, PSL Research University, Laboratoire de Pharmacologie cellulaire et Moléculaire)

  • Riccardo Porcari

    (Centre for Amyloidosis and Acute Phase Proteins, National Amyloidosis Centre, University College London)

  • Christopher A. Waudby

    (Institute of Structural and Molecular Biology, University College London and Birkbeck College, University of London)

  • Annalisa Relini

    (University of Genoa)

  • Philippa J. Talmud

    (Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London)

  • Oleg Kovrov

    (Umeå University)

  • Gunilla Olivecrona

    (Umeå University)

  • Monica Stoppini

    (Institute of Biochemistry, University of Pavia)

  • John Christodoulou

    (Institute of Structural and Molecular Biology, University College London and Birkbeck College, University of London)

  • Philip N. Hawkins

    (Centre for Amyloidosis and Acute Phase Proteins, National Amyloidosis Centre, University College London)

  • Gilles Grateau

    (Hôpital Tenon, AP-HP, Service de Médecine Interne, Centre de référence des amyloses d'origine inflammatoire et de la fièvre méditerranéenne familiale)

  • Marc Delpech

    (Université Paris-Descartes, Sorbonne Paris Cité, Assistance Publique-Hôpitaux de Paris, Laboratoire de Biologie et Génétique Moléculaire, Hôpital Cochin)

  • Anatol Kontush

    (Sorbonne Universités, UPMC Univ Paris 06, Institute of Cardiometabolism and Nutrition (ICAN), UMR_S 1166, Hôpital de la Pitié)

  • Julian D. Gillmore

    (Centre for Amyloidosis and Acute Phase Proteins, National Amyloidosis Centre, University College London)

  • Athina D. Kalopissis

    (Sorbonne Universités, UPMC Univ Paris 06, INSERM, Université Paris-Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers)

  • Vittorio Bellotti

    (Centre for Amyloidosis and Acute Phase Proteins, National Amyloidosis Centre, University College London
    Institute of Biochemistry, University of Pavia)

Abstract

Apolipoprotein C-III deficiency provides cardiovascular protection, but apolipoprotein C-III is not known to be associated with human amyloidosis. Here we report a form of amyloidosis characterized by renal insufficiency caused by a new apolipoprotein C-III variant, D25V. Despite their uremic state, the D25V-carriers exhibit low triglyceride (TG) and apolipoprotein C-III levels, and low very-low-density lipoprotein (VLDL)/high high-density lipoprotein (HDL) profile. Amyloid fibrils comprise the D25V-variant only, showing that wild-type apolipoprotein C-III does not contribute to amyloid deposition in vivo. The mutation profoundly impacts helical structure stability of D25V-variant, which is remarkably fibrillogenic under physiological conditions in vitro producing typical amyloid fibrils in its lipid-free form. D25V apolipoprotein C-III is a new human amyloidogenic protein and the first conferring cardioprotection even in the unfavourable context of renal failure, extending the evidence for an important cardiovascular protective role of apolipoprotein C-III deficiency. Thus, fibrate therapy, which reduces hepatic APOC3 transcription, may delay amyloid deposition in affected patients.

Suggested Citation

  • Sophie Valleix & Guglielmo Verona & Noémie Jourde-Chiche & Brigitte Nédelec & P. Patrizia Mangione & Frank Bridoux & Alain Mangé & Ahmet Dogan & Jean-Michel Goujon & Marie Lhomme & Carolane Dauteuille, 2016. "D25V apolipoprotein C-III variant causes dominant hereditary systemic amyloidosis and confers cardiovascular protective lipoprotein profile," Nature Communications, Nature, vol. 7(1), pages 1-14, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10353
    DOI: 10.1038/ncomms10353
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