1. D25V apolipoprotein C-III variant causes dominant hereditary systemic amyloidosis and confers cardiovascular protective lipoprotein profile
- Author
-
Valleix, S., Guglielmo Verona, Jourde-Chiche, N., Nédelec, B., Mangione, P. P., Bridoux, F., Mangé, A., Dogan, A., Goujon, J. -M, Lhomme, M., Dauteuille, C., Chabert, M., Porcari, R., Waudby, C. A., Relini, A., Talmud, P. J., Kovrov, O., Olivecrona, G., Stoppini, M., Christodoulou, J., Hawkins, P. N., Grateau, G., Delpech, M., Kontush, A., Gillmore, J. D., Kalopissis, A. D., Bellotti, V., Laboratoire de Biochimie et Génétique Moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Bocconi University, Bocconi University [Milan, Italy], Vascular research center of Marseille (VRCM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie de l'Endothelium, Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Università degli Studi di Pavia = University of Pavia (UNIPV), Service de Néphrologie CHU Poitiers, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Mayo Clinic, Service d’Anapathomopathologie, Centre hospitalier universitaire de Poitiers (CHU Poitiers), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Sorbonne Université (SU), University College of London [London] (UCL), University of London [London], Università degli studi di Genova = University of Genoa (UniGe), Centre For Cardiovascular Genetics, Royal Free and UCL Medical School, Umeå University, Dept Mol Med, Genetic Metabolic Disorders Research Unit, Kids Research Institute-Westmead Hospital [Sydney], Discipline of Paediatrics & Child Health, The University of Sydney, Discipline of Genetic Medicine, Sydney Medical School-The University of Sydney, Western Sydney Genetics Program, Westmead Hospital [Sydney], CHU Tenon [AP-HP], CHU Saint-Antoine [AP-HP], UCL, Ctr Amyloidosis & Acute Phase Prot, University College of London [London] (UCL)-University ofLondon, l’Association Franc ̧aise contre l’Amylose, the Institut Nationalde la Sante ́et de la Recherche Me ́dicale (INSERM) and the French National ReferenceCenter for AL amyloidosis, the UK NHS Research and Development funds, theUniversity College London Amyloidosis Research Fund and grants from the UK MedicalResearch Council (MR/K000187/1), the Rosetrees Trust/Royal Free Charity PhDprogramme (M427), the British Heart Foundation (PG08/008), the Wellcome TrustInvestigator Award (097806/Z/11/Z), the Cariplo Foundation Projects (2014–0700 and2013-0964), the Telethon Grant GG14127, the INBB (National Institute of Biostructuresand Biosystems), the Italian Ministry of Health and the Italian Ministry of University andResearch (Projects FIRB RBFR109EOS), Laboratoire commun de biologie et génétique moléculaires [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], DIGNAT-GEORGE, Françoise, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ), Vascular research center of Marseille ( VRCM ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital de la Conception [CHU - APHM] ( LA CONCEPTION ), Université Montpellier 1 ( UM1 ), Centre hospitalier universitaire de Poitiers ( CHU Poitiers ), CHU Pitié-Salpêtrière [APHP], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition ( ICAN ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP], University of Genoa ( UNIGE ), University of Pavia, Children's Hospital at Westmead-Kids Research Institute, The University of Sydney [Sydney], Sydney Medical School-The University of Sydney [Sydney], Children's Hospital at Westmead, University College of London [London] ( UCL ) -University ofLondon, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Genoa (UNIGE), and Westmead Hospital [Sydney]-Kids Research Institute
- Subjects
Adult ,Male ,Hyperlipoproteinemias ,Science ,[SDV]Life Sciences [q-bio] ,Molecular Sequence Data ,Mutation, Missense ,Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) ,Lipoproteins, VLDL ,bcs ,Article ,LIPASE ACTIVITY ,OF-FUNCTION MUTATIONS ,Humans ,Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) ,Aged ,Aged, 80 and over ,Apolipoprotein C-III ,CELLULAR CHOLESTEROL EFFLUX ,[ SDV ] Life Sciences [q-bio] ,Base Sequence ,Amyloidosis ,Middle Aged ,LIPID-BINDING ,ANTIOXIDATIVE ACTIVITY ,Pedigree ,[SDV] Life Sciences [q-bio] ,HDL PARTICLES ,A-I ,ELEVATED OXIDATIVE STRESS ,Cardiovascular Diseases ,Female ,lipids (amino acids, peptides, and proteins) ,France ,Lipoproteins, HDL ,DENSE LDL ,TRIGLYCERIDE-RICH LIPOPROTEINS - 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., Decrease in Apolipoprotein C-III (ApoC-III) yields a cardioprotective lipoprotein profile. Here, Valleix et al. reveal a novel ApoC-III variant conferring low plasma ApoC-III concentration and cardioprotection despite renal insufficiency, and, unexpectedly, causing dominant hereditary systemic amyloidosis due to its fibrillogenic nature.
- Published
- 2016
- Full Text
- View/download PDF