Apolipoprotein Al and transthyretin as components of amyloid fibrils in a kindred with apoAl Leu178His amyloidosis

We found a new C-terminal amyloidogenic variant of apolipoprotein Al (apoAI ), Leu178His in a French kindred, associated with cardiac and larynx amyloi dosis and skin lesions with onset during the fourth decade. This single-poi nt mutation in exon 4 of the apoAI gene was detected by DNA sequencing of p olymerase chain reaction amplified material and restriction fragment length polymorphism analysis in two siblings. blood, larynx, and skin biopsies we re available from one sibling. Anti-apoAI immunoblotting of isoelectric foc using of plasma showed a +1 alteration In the charge of the protein, Extrac tion of fibrils from the skin biopsy revealed both full-length and N-termin al fragments of apoAI and transthyretin (TTR). ApoAI and TFR co-localized i n amyloid deposits as demonstrated by immunohistochemistry. The present rep ort, together with the first recently described C-terminal amyloidogenic va riant of apoAI, Arg173Pro, shows that amyloidogenicity of apoAI is not a fe ature exclusive to N-terminal variants. The most striking characteristic of amyloid fibrils in Leu178His is that wild-type TTR is co-localized with ap oAI in the fibrils, We have previously determined that a fraction of plasma TFR circulates in plasma bound to high-density lipoprotein and that this i nteraction occurs through binding to apoAI, Therefore we hypothesize that n onmutated TTR might influence deposition of apoAI as amyloid.