Support for the multigenic hypothesis of amyloidosis: The binding stoichiometry of retinol-binding protein, vitamin A, and thyroid hormone influencestransthyretin amyloidogenicity in vitro

The amyloidoses are a large group of protein misfolding diseases. Genetic a nd biochemical evidence support the hypothesis that amyloid formation from wild-type or 1 of 80 sequence variants of transthyretin causes the human am yloid diseases senile systemic amyloidosis or familial amyloid polyneuropat hy, respectively. The late onset and variable penetrance of these diseases has led to their designation as multigenic-implying that the expression lev els and alleles of multiple gene products influence the course of pathology . Here we show that the binding stoichiometry of three interacting molecule s, retinol-binding protein, vitamin A, and L-thyroxine, notably influenced transthyretin amyloidogenicity in vitro. At least 70 genes control retinol- binding protein, vitamin A, and L-thyroxine levels in plasma and have the p otential to modulate the course of senile systemic amyloidosis or familial amyloid polyneuropathy.