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

    Valleix, S. and Verona, G. and Jourde-Chiche, N. and Nédelec, B. and Mangione, P.P. and Bridoux, F. and Mangé, A. and Dogan, A. and Goujon, J.-M. and Lhomme, M. and Dauteuille, C. and Chabert, M. and Porcari, R. and Waudby, Christopher and Relini, A. and Talmud, P.J. and Kovrov, O. and Olivecrona, G. and Stoppini, M. and Christodoulou, John and Hawkins, P.N. and Grateau, G. and Delpech, M. and Kontush, A. and Gillmore, J.D. and Kalopissis, A.D. and Bellotti, V. (2016) D25V apolipoprotein C-III variant causes dominant hereditary systemic amyloidosis and confers cardiovascular protective lipoprotein profile. Nature Communications 7 , p. 10353. ISSN 2041-1723.

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    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.

    Metadata

    Item Type: Article
    School: Birkbeck Schools and Departments > School of Science > Biological Sciences
    Depositing User: Administrator
    Date Deposited: 01 Mar 2016 14:49
    Last Modified: 23 Mar 2018 08:49
    URI: http://eprints.bbk.ac.uk/id/eprint/14544

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