The New Apolipoprotein A-I Variant Leu174 → Ser Causes Hereditary Cardiac Amyloidosis, and the Amyloid Fibrils Are Constituted by the 93-Residue N-Terminal Polypeptide

摘要: We identified a novel missense mutation in the apolipoprotein A-I gene, T2069C Leu 174 → Ser, patient affected by familial systemic nonneuropathic amyloidosis. The amyloid deposits mostly heart of proband, who underwent transplantation for end-stage congestive failure. Amyloid fibrils myocardial and periumbilical fat samples immunoreacted exclusively with anti-ApoA-I antibodies. extracted from were constituted, according to amino acid sequencing mass spectrometry analysis, an amino-terminal polypeptide ending at Val 93 (apoA-I); no other significant fragments detected. segregates disease; it was demonstrated proband uncle excluded three healthy siblings. plasma levels high-density lipoprotein apoA-I significantly lower than unaffected individuals. This represents first case amyloidosis which is outside fragment deposited as fibrils. Visualization three-dimensional structure lipid-free apoA-I, composed four identical chains, indicates that position one chain located near adjacent suggests replacement permissive proteolytic split C-terminal .