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

Sophie Valleix 1 Guglielmo Verona 2 Noemie Jourde-Chiche 3, 4, 5 Brigitte Nédelec 6 P Patrizia Mangione 7 Frank Bridoux 8 Alain Mangé 9 Ahmet Dogan 10 Jean-Michel Goujon 11 Marie Lhomme 12 Carolane Dauteuille 13 Michèle Chabert 14 Riccardo Porcari 15 Christopher A Waudby 16 Annalisa Relini 17 Philippa J Talmud 18 Oleg Kovrov 19 Gunilla Olivecrona 19 Monica Stoppini 20 John Christodoulou 21, 22, 23, 24 Philip N Hawkins 15 Gilles Grateau 25 Marc Delpech 26 Anatol Kontush 13 Julian D Gillmore 15 Athina D Kalopissis 14 Vittorio Bellotti 27, 20
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.
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Sophie Valleix, Guglielmo Verona, Noemie Jourde-Chiche, Brigitte Nédelec, P Patrizia Mangione, et al.. D25V apolipoprotein C-III variant causes dominant hereditary systemic amyloidosis and confers cardiovascular protective lipoprotein profile. Nature Communications, Nature Publishing Group, 2016, pp.10353. ⟨10.1038/ncomms10353⟩. ⟨hal-01467259⟩

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