A novel apolipoprotein A-1 variant, Arg173Pro, associated with cardiac andcutaneous amyloidosis

An American kindred was found to have hereditary amyloidosis with cutaneous and cardiac involvement. Characterization of fibrils isolated from skin id entified the amyloid protein as the N-terminal 90 to 100 residues of apolip oprotein A-1. Sequence of the apolipoprotein A-1 gene was normal except for a G/C transversion at position 1638 which predicts an Arg to Pro substitut ion at residue 173, This mutation, unlike previously described amyloidogeni c mutations is not in the N-terminal fragment which is incorporated into th e fibril. The mutation is at the same residue as in apolipoprotein A-1 Mila no (Arg173Cys) which does not result in amyloid formation. Decreased plasma HDL cholesterol levels in carriers of the Arg173Pro mutation suggest an in creased rate of catabolism as has been shown for the amyloidogenic Gly26Arg mutation. This suggests that altered metabolism caused by the mutation may be a significant factor in apolipoprotein A-1 fibrillogenesis. (C) 1999 Ac ademic Press.