| Abstract: |
The first case of hereditary fibrinogen Aa-chain amyloidosis was recognized >20 years ago, but disease mechanisms still remain unknown. Here we report detailed clinical and proteomics studies of a French kindred with a novel amyloidogenic fibrinogen Aa-chain frameshift variant, Phe521Leufs, causing a severe familial form of renal amyloidosis. Next, we focused our investigations to elucidate the molecular basis that render this Aa-chain variant amyloidogenic. We show that a 49-mer peptide derived from the C-Terminal part of the Phe521Leufs chain is deposited as fibrils in the patient's kidneys, establishing that only a small portion of Phe521Leufs directly contributes to amyloid formation in vivo. In silico analysis indicated that this 49-mer Aa-chain peptide contained a motif (VLITL), with a high intrinsic propensity for b-Aggregation at residues 44 to 48 of human renal fibrils. To experimentally verify the amyloid propensity of VLITL, we generated synthetic Phe521Leufs-derived peptides and compared their capacity for fibril formation in vitro with that of their VLITL-deleted counterparts.Weshow that VLITL forms typical amyloid fibrils in vitro and is a major signal for cross-b-sheet self-Association of the 49-mer Phe521Leufs peptide identified in vivo, whereas its absence abrogates fibril formation. This study provides compelling evidence that VLITL confers amyloidogenic properties to Aa-chain frameshift variants, yielding a previously unknown molecular basis for the pathogenesis of Aa-chain amyloidosis. © 2017 by The American Society of Hematology. |
