Hereditary amyloid cardiomyopathy caused by a variant apolipoprotein A1

Autosomal dominant hereditary amyloidosis with a unique cutaneous and cardi ac presentation and death from heart failure by the sixth or seventh decade was found to be associated with a previously unreported point mutation (th ymine to cytosine, nt 1389) in exon 4 of the apolipoprotein A1 (apoA1) gene . The predicted substitution of proline for leucine at amino acid position 90 was confirmed by structural analysis of amyloid protein isolated from ca rdiac deposits of amyloid. The subunit protein is composed exclusively of N H2-terminal fragments of the variant apoA1 with the longest ending at resid ue 94 in the wild-type sequence. Amyloid fibrils derived from four previous ly described apoA1 variants are composed of similar fragments with carboxyl -terminal heterogeneity, but contrary to those variants, which all carry on e extra positive charge, the substitution Leu90Pro does not result in any c harge modification. It is unlikely, therefore, that amyloid fibril formatio n is related to change of charge for a specific residue of the precursor pr otein. This is in agreement with studies on transthyretin amyloidosis in wh ich no unifying factor such as change of charge for amino acid residues has been noted.