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Nat Commun. 2016 Jan 21;7:10353. doi: 10.1038/ncomms10353.

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

Author information

1
Université Paris-Descartes, Sorbonne Paris Cité, Assistance Publique-Hôpitaux de Paris, Laboratoire de Biologie et Génétique Moléculaire, Hôpital Cochin, Paris 75014, France.
2
INSERM, UMR_1163, Institut Imagine, Laboratoire de Génétique Ophtalmologique (LGO), Université Paris Descartes, Sorbonne Paris Cité, Paris 75015, France.
3
INSERM, U1016, Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France.
4
Sorbonne Universités, UPMC Univ Paris 06, INSERM, Université Paris-Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris 75006, France.
5
Centre for Amyloidosis and Acute Phase Proteins, National Amyloidosis Centre, University College London, London NW3 2PF, UK.
6
Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, Via Taramelli 3b, Pavia 27100, Italy.
7
Université de Marseille, AP-HM, Hôpital de la Conception, Marseille 13005, France.
8
Université de Poitiers, CHU Poitiers, Department of Nephrology and Kidney Transplantation, Centre National de Référence Amylose AL et autres maladies par dépôts d'immunoglobulines monoclonales, Poitiers 86021, France.
9
Institut de Recherche en Cancérologie de Montpellier (IRCM), Montpellier 34298, France.
10
INSERM, U1194, Montpellier 34298, France.
11
Université de Montpellier, Montpellier 34090, France.
12
Institut régional du Cancer de Montpellier, Montpellier 34298, France.
13
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55901, USA.
14
Departments of Laboratory Medicine and Pathology, Memorial Sloan-Kettering Cancer Centre, New York, NY 10065, USA.
15
Université de Poitiers, CHU Poitiers, Service d'Anatomie et Cytologie Pathologiques, Centre National de Référence Amylose AL et autres maladies par dépôts d'immunoglobulines monoclonales, Poitiers 86021, France.
16
Lipidomic core, ICANalytics, Institute of Cardiometabolism and Nutrition, ICAN, Pitié-Salpôtrière Hospital, F-75013 Paris, France.
17
Sorbonne Universités, UPMC Univ Paris 06, Institute of Cardiometabolism and Nutrition (ICAN), UMR_S 1166, Hôpital de la Pitié, Paris 75013, France.
18
Ecole Pratique des Hautes Etudes, PSL Research University, Laboratoire de Pharmacologie cellulaire et Moléculaire, Paris 75006, France.
19
Institute of Structural and Molecular Biology, University College London and Birkbeck College, University of London, London WC1E 6BT, UK.
20
Department of Physics, University of Genoa, Via Dodecaneso 33, Genoa 16146, Italy.
21
Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London WC1E 6JF, UK.
22
Department of Medical Biosciences, Umeå University, Umeå SE-901 87, Sweden.
23
Hôpital Tenon, AP-HP, Service de Médecine Interne, Centre de référence des amyloses d'origine inflammatoire et de la fièvre méditerranéenne familiale, Paris 75020, France.

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.

PMID:
26790392
PMCID:
PMC4735822
DOI:
10.1038/ncomms10353
[Indexed for MEDLINE]
Free PMC Article

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