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

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, Michèle Chabert, Riccardo Porcari, Christopher A. Waudby, Annalisa Relini, Philippa J. Talmud, Oleg Kovrov, Gunilla Olivecrona, Monica Stoppini, John ChristodoulouPhilip N. Hawkins, Gilles Grateau, Marc Delpech, Anatol Kontush, Julian D. Gillmore, Athina D. Kalopissis, Vittorio Bellotti

Research output: Contribution to journalArticle

34 Scopus citations

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.

Original languageEnglish (US)
Article number10353
JournalNature communications
Volume7
DOIs
StatePublished - Jan 21 2016

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Valleix, S., Verona, G., 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., ... Bellotti, V. (2016). D25V apolipoprotein C-III variant causes dominant hereditary systemic amyloidosis and confers cardiovascular protective lipoprotein profile. Nature communications, 7, [10353]. https://doi.org/10.1038/ncomms10353