Pathological, biochemical, and biophysical characteristics of the transthyretin variant Y114H (p.Y134H) explain its very mild clinical phenotype.

Transthyretin (TTR) is a homotetrameric protein that must misfold in order to form amyloid fibrils. Misfolding includes rate limiting tetramer dissociation, followed by fast tertiary structural changes of the monomer that enable aggregation. Hereditary ATTR amyloidosis is an autosomal dominant genetic disorder with systemic deposition of amyloid fibrils induced by TTR gene mutation. We identified a rare Y114H (p.Y134H) TTR variant in a Japanese patient presenting with late-onset, very mild clinical course. The patient had an extremely low serum variant TTR concentration (18% of total TTR), whereas the composition of variant TTR was 55% in amyloid fibrils in tenosynovial tissues obtained at carpal tunnel release surgery. The amyloid fibril deposits in the ATTR Y114H patient had an altered structure compared with that in wild-type ATTR patients, as determined by luminescent conjugated poly/oligo-thiophene fluorescence spectroscopy. Biophysical studies using recombinant protein showed that Y114H TTR was markedly destabilized both thermodynamically and kinetically and was highly amyloidogenic in vitro. These data suggest that extremely low serum variant Y114H TTR concentration, probably due to endoplasmic reticulum-associated degradation of unstable variant TTR protein, protected this patient from severe amyloidosis, as self-assembly of the amyloidogenic intermediate is a concentration-dependent process.