Amyloid fibril composition and transthyretin gene structure in senile systemic amyloidosis

Abstract

Background: In many different forms of amyloidosis, transthyretin (TTR) comprises the major amyloid fibril protein. In the familial forms, various TTR mutations are linked to disease. This study was designed to characterize the components of the TTR-derived amyloid fibril protein in senile systemic amyloidosis and to determine whether any mutation in the TTR gene was present.

Experimental design: Heart tissues from two patients with advanced senile systemic amyloidosis were studied. Amyloid fibrils were extracted and the amyloid fibril protein purified. The relationship between full-length and fragmented TTR and the amino acid sequence of the TTR were determined. The TTR gene was studied by single-strand conformation polymorphism analysis or direct sequencing.

Results: In both cases, the amyloid deposits contained full-length TTR and a complex mixture of TTR fragments. The fragments, most of which had their N-termini at positions 46-52, predominated. No amino acid substitution was identified. The N-terminal fragment (1-45) was not identified in either patient. In each case, the four exons of the TTR gene were of normal sequence.

Conclusions: In familial amyloidosis resulting from deposition of TTR Met 30 (Swedish-type familial amyloidosis), full-length TTR molecules (some mutant) usually predominate, and TTR fragments lacking three of the eight beta-strands (nonmutant) form a major part of the fibril in senile systemic amyloidosis. This may indicate a difference in the fibrillogenesis between these two forms of TTR-derived amyloidosis. We propose that the name senile systemic amyloidosis be used only for normal-sequence TTR amyloidosis occurring in advanced age.