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Clinical ApoA‐IV amyloid is associated with fibrillogenic signal sequence
Author(s) -
Canetti Diana,
Nocerino Paola,
Rendell Nigel B,
Botcher Nicola,
Gilbertson Janet A,
Blanco Angel,
Rowczenio Dorota,
Morelli Alessandra,
Mangione P Patrizia,
Corazza Alessandra,
Verona Guglielmo,
Giorgetti Sofia,
Marchese Loredana,
Westermark Per,
Hawkins Philip N,
Gillmore Julian D,
Bellotti Vittorio,
Taylor Graham W
Publication year - 2021
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5770
Subject(s) - sequence (biology) , chemistry , amyloid β , amyloid (mycology) , signal peptide , peptide sequence , biochemistry , medicine , disease , gene , inorganic chemistry
Apolipoprotein A‐IV amyloidosis is an uncommon form of the disease normally resulting in renal and cardiac dysfunction. ApoA‐IV amyloidosis was identified in 16 patients attending the National Amyloidosis Centre and in eight clinical samples received for histology review. Unexpectedly, proteomics identified the presence of ApoA‐IV signal sequence residues (p.18‐43 to p.20‐43) in 16/24 trypsin‐digested amyloid deposits but in only 1/266 non‐ApoA‐IV amyloid samples examined. These additional signal residues were also detected in the cardiac sample from the Swedish patient in which ApoA‐IV amyloid was first described, and in plasma from a single cardiac ApoA‐IV amyloidosis patient. The most common signal‐containing peptide observed in ApoA‐IV amyloid, p.20‐43, and to a far lesser extent the N‐terminal peptide, p.21‐43, were fibrillogenic in vitro at physiological pH, generating Congo red‐positive fibrils. The addition of a single signal‐derived alanine residue to the N‐terminus has resulted in markedly increased fibrillogenesis. If this effect translates to the mature circulating protein in vivo , then the presence of signal may result in preferential deposition as amyloid, perhaps acting as seed for the main circulating native form of the protein; it may also influence other ApoA‐IV‐associated pathologies. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.