Journal Article

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

Jourde-Chiche, Noémie, Lhomme, Marie, Porcari, Riccardo, Delpech, Marc, Kalopissis, Athina D., Relini, Annalisa, Grateau, Gilles, Christodoulou, John, Verona, Guglielmo, Bridoux, Frank, Bellotti, Vittorio, Mangé, Alain, Nédelec, Brigitte, Dogan, Ahmet, Hawkins, Philip N., Kontush, Anatol, Waudby, Christopher A., Stoppini, Monica, Goujon, Jean-Michel, Kovrov, Oleg, Olivecrona, Gunilla, Chabert, Michèle, Mangione, P. Patrizia, Talmud, Philippa J., Dauteuille, Carolane, Valleix, Sophie, Gillmore, Julian D.

2016

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 140/131 / 631/443/319/1642 / 631/443/592 / 631/45/287/1191 / 692/308 / 82/16 / 82/29 / 82/51 / 82/80 / Adult / Aged / Aged, 80 and over / Amyloidosis - genetics / Amyloidosis - metabolism / Apolipoprotein C-III - chemistry / Apolipoprotein C-III - genetics / Apolipoprotein C-III - metabolism / Base Sequence / Cardiovascular Diseases - prevention & control / Female / France / Humanities and Social Sciences / Humans / Hyperlipoproteinemias - genetics / Hyperlipoproteinemias - metabolism / Life Sciences / Lipoproteins, HDL - metabolism / Lipoproteins, VLDL - metabolism / Male / Middle Aged / Molecular Sequence Data / multidisciplinary / Mutation, Missense / Pedigree / Science / Science (multidisciplinary)