The new apolipoprotein A-I variant Leu(174) -> Ser causes hereditary cardiac amyloidosis, and the amyloid fibrils are constituted by the 93-residue N-terminal polypeptide

We identified a novel missense mutation in the apolipoprotein A-I gene, T20 69C Leu(174) --> Ser, in a pa patient affected by familial systemic nonneur opathic amyloidosis, The amyloid deposits mostly affected the heart of the proband, who underwent transplantation for end-stage congestive heart failu re. Amyloid fibrils of myocardial and periumbilical fat samples immunoreact ed exclusively with anti-ApoA-I antibodies, Amyloid fibrils extracted from the heart were constituted, according to amino acid sequencing and mass spe ctrometry analysis, by an amino-terminal polypeptide ending at Val(93) of a polipoprotein A-I (apoA-I); no other significant fragments were detected. T he mutation segregates with the disease; it was demonstrated in the proband and in an affected uncle and excluded in three healthy siblings, The plasm a levels of high-density lipoprotein and apoA-I were significantly lower in the patient than in unaffected individuals. This represents the first case of familial apoA-I amyloidosis in which the mutation is outside the polype ptide fragment deposited as fibrils, Visualization of the mutation in the t hree-dimensional structure of lipid-free apoA-I, composed of four identical polypeptide chains, indicates that position 174 of one chain is located ne ar position 93 of an adjacent chain and suggests that the amino acid replac ement in position 174 is permissive for a proteolytic split at the C-termin al of Val(93).