title: D25V apolipoprotein C-III variant causes dominant hereditary systemic amyloidosis and confers cardiovascular protective lipoprotein profile.
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.
authors.affiliation: Université Paris-Descartes, Sorbonne Paris Cité, Assistance Publique-Hôpitaux de Paris, Laboratoire de Biologie et Génétique Moléculaire, Hôpital Cochin, Paris 75014, France.|INSERM, UMR_1163, Institut Imagine, Laboratoire de Génétique Ophtalmologique (LGO), Université Paris Descartes, Sorbonne Paris Cité, Paris 75015, France.|INSERM, U1016, Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France.|Sorbonne Universités, UPMC Univ Paris 06, INSERM, Université Paris-Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris 75006, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Valleix
authors.affiliation: Centre for Amyloidosis and Acute Phase Proteins, National Amyloidosis Centre, University College London, London NW3 2PF, UK.|Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, Via Taramelli 3b, Pavia 27100, Italy.
authors.forename: Guglielmo
authors.initials: G
authors.lastname: Verona
authors.affiliation: Université de Marseille, AP-HM, Hôpital de la Conception, Marseille 13005, France.
authors.forename: Noémie
authors.initials: N
authors.lastname: Jourde-Chiche
authors.affiliation: INSERM, UMR_1163, Institut Imagine, Laboratoire de Génétique Ophtalmologique (LGO), Université Paris Descartes, Sorbonne Paris Cité, Paris 75015, France.|INSERM, U1016, Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France.|Sorbonne Universités, UPMC Univ Paris 06, INSERM, Université Paris-Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris 75006, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Nédelec
authors.affiliation: Centre for Amyloidosis and Acute Phase Proteins, National Amyloidosis Centre, University College London, London NW3 2PF, UK.|Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, Via Taramelli 3b, Pavia 27100, Italy.
authors.forename: P Patrizia
authors.initials: PP
authors.lastname: Mangione
authors.affiliation: Université de Poitiers, CHU Poitiers, Department of Nephrology and Kidney Transplantation, Centre National de Référence Amylose AL et autres maladies par dépôts d'immunoglobulines monoclonales, Poitiers 86021, France.
authors.forename: Frank
authors.initials: F
authors.lastname: Bridoux
authors.affiliation: Institut de Recherche en Cancérologie de Montpellier (IRCM), Montpellier 34298, France.|INSERM, U1194, Montpellier 34298, France.|Université de Montpellier, Montpellier 34090, France.|Institut régional du Cancer de Montpellier, Montpellier 34298, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Mangé
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55901, USA.|Departments of Laboratory Medicine and Pathology, Memorial Sloan-Kettering Cancer Centre, New York, NY 10065, USA.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Dogan
authors.affiliation: 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, Poitiers 86021, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Goujon
authors.affiliation: Lipidomic core, ICANalytics, Institute of Cardiometabolism and Nutrition, ICAN, Pitié-Salpôtrière Hospital, F-75013 Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Lhomme
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Institute of Cardiometabolism and Nutrition (ICAN), UMR_S 1166, Hôpital de la Pitié, Paris 75013, France.
authors.forename: Carolane
authors.initials: C
authors.lastname: Dauteuille
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, Université Paris-Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris 75006, France.|Sorbonne Universités, UPMC Univ Paris 06, Institute of Cardiometabolism and Nutrition (ICAN), UMR_S 1166, Hôpital de la Pitié, Paris 75013, France.|Ecole Pratique des Hautes Etudes, PSL Research University, Laboratoire de Pharmacologie cellulaire et Moléculaire, Paris 75006, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Chabert
authors.affiliation: Centre for Amyloidosis and Acute Phase Proteins, National Amyloidosis Centre, University College London, London NW3 2PF, UK.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Porcari
authors.affiliation: Institute of Structural and Molecular Biology, University College London and Birkbeck College, University of London, London WC1E 6BT, UK.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Waudby
authors.affiliation: Department of Physics, University of Genoa, Via Dodecaneso 33, Genoa 16146, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Relini
authors.affiliation: Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London WC1E 6JF, UK.
authors.forename: Philippa J
authors.initials: PJ
authors.lastname: Talmud
authors.affiliation: Department of Medical Biosciences, Umeå University, Umeå SE-901 87, Sweden.
authors.forename: Oleg
authors.initials: O
authors.lastname: Kovrov
authors.affiliation: Department of Medical Biosciences, Umeå University, Umeå SE-901 87, Sweden.
authors.forename: Gunilla
authors.initials: G
authors.lastname: Olivecrona
authors.affiliation: Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, Via Taramelli 3b, Pavia 27100, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Stoppini
authors.affiliation: Institute of Structural and Molecular Biology, University College London and Birkbeck College, University of London, London WC1E 6BT, UK.
authors.forename: John
authors.initials: J
authors.lastname: Christodoulou
authors.affiliation: Centre for Amyloidosis and Acute Phase Proteins, National Amyloidosis Centre, University College London, London NW3 2PF, UK.
authors.forename: Philip N
authors.initials: PN
authors.lastname: Hawkins
authors.affiliation: Hôpital Tenon, AP-HP, Service de Médecine Interne, Centre de référence des amyloses d'origine inflammatoire et de la fièvre méditerranéenne familiale, Paris 75020, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Grateau
authors.affiliation: Université Paris-Descartes, Sorbonne Paris Cité, Assistance Publique-Hôpitaux de Paris, Laboratoire de Biologie et Génétique Moléculaire, Hôpital Cochin, Paris 75014, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Delpech
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Institute of Cardiometabolism and Nutrition (ICAN), UMR_S 1166, Hôpital de la Pitié, Paris 75013, France.
authors.forename: Anatol
authors.initials: A
authors.lastname: Kontush
authors.affiliation: Centre for Amyloidosis and Acute Phase Proteins, National Amyloidosis Centre, University College London, London NW3 2PF, UK.
authors.forename: Julian D
authors.initials: JD
authors.lastname: Gillmore
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, Université Paris-Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris 75006, France.
authors.forename: Athina D
authors.initials: AD
authors.lastname: Kalopissis
authors.affiliation: Centre for Amyloidosis and Acute Phase Proteins, National Amyloidosis Centre, University College London, London NW3 2PF, UK.|Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, Via Taramelli 3b, Pavia 27100, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Bellotti
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000686:Amyloidosis / Q000235:genetics* / Q000378:metabolism*; D053305:Apolipoprotein C-III / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D002318:Cardiovascular Diseases / Q000517:prevention & control*; D005260:Female; D005602:France; D006801:Humans; D006951:Hyperlipoproteinemias / Q000235:genetics / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree
chemical_list: D053305:Apolipoprotein C-III; D008075:Lipoproteins, HDL; D008079:Lipoproteins, VLDL