D25V apolipoprotein C-III variant causes dominant hereditary systemic amyloidosis and confers cardiovascular protective lipoprotein profile Journal Article
| Authors: | 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.; Christodoulou, J.; Hawkins, P. N.; Grateau, G.; Delpech, M.; Kontush, A.; Gillmore, J. D.; Kalopissis, A. D.; Bellotti, V. |
| Article Title: | D25V apolipoprotein C-III variant causes dominant hereditary systemic amyloidosis and confers cardiovascular protective lipoprotein profile |
| 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. |
| Keywords: | immunohistochemistry; adult; controlled study; human tissue; middle aged; unclassified drug; histopathology; hypertension; mass spectrometry; proteome; esophagitis; lipid; protein; creatinine; creatinine blood level; kidney failure; in vivo study; in vitro study; enzyme activity; proteomics; pruritus; disease severity; chronic kidney disease; cardiovascular disease; family history; triacylglycerol; triacylglycerol blood level; staphylococcus infection; protein secondary structure; protein structure; gastroesophageal reflux; protein variant; kidney biopsy; proteinuria; heart protection; heart amyloidosis; hypertriglyceridemia; proton nuclear magnetic resonance; raynaud phenomenon; kidney transplantation; laser microdissection; transmission electron microscopy; amyloid; nitrogen nuclear magnetic resonance; atomic force microscopy; high density lipoprotein; hydrodynamics; immunogold staining; kidney amyloidosis; end stage renal disease; sjoegren syndrome; very low density lipoprotein; human; male; article; salivary gland biopsy; apolipoprotein c3; d25v protein; high density lipoprotein 2; high density lipoprotein 3; bronchus biopsy; lipoprotein blood level |
| Journal Title: | Nature Communications |
| Volume: | 7 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2016-01-21 |
| Start Page: | 10353 |
| Language: | English |
| PROVIDER: | scopus |
| PMCID: | PMC4735822 |
| PUBMED: | 26790392 |
| DOI: | 10.1038/ncomms10353 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 March 2016 -- Source: Scopus |
