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

Abstract

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.

Amyloid fibril polymorphism: a challenge for molecular imaging and therapy

“…It was recently shown that imaging of TTR in tissue reveals differences in LCP and LCO spectra indicating differences in structure. The differences were attributed to a mutation Y114H comprising a significant proportion of the amyloid protein deposit . Amyloid fibril structures from microcrystals of TTR peptides downstream and upstream of this site suggest that a structural difference due to the Y114H mutation could induce a packing variation and thereby a new polymorph to explain these differences in probe fluorescence.…”

Hereditary ATTR Amyloidosis with Cardiomyopathy Caused by the Novel Variant Transthyretin Y114S (p.Y134S)

“…The TTR Y114C mutation results in rapidly progressive cerebral amyloid angiopa- (16). Patients with the TTR Y114H mutation showed slowly progressive amyloidosis with carpal tunnel syndrome (17). In contrast, the TTR Y114S mutation as described here mainly showed rapidly progressive cardiomyopathy.…”

Efficient Generation of Pathogenic A-to-G Mutations in Human Tripronuclear Embryos via ABE-Mediated Base Editing

“…To comprehensively analyze the characteristics of the ABE system in human embryos, we produced the A-to-G mutation in human cells and embryos using ABE7.10. Five genes, TTR , 15 ALDOB , 16 COL9A2 , 17 KCNJ11 , 18 and RPE65 , 19 which had been reported to have pathogenic A-to-G point mutations, were selected (Figure S1A). We first tested the editing of these genes with the ABE system in HEK293T cells.…”