Thyroxine binding in a TTR Met 119 kindred.

Abstract

Recently, a transthyretin variant, TTR Met 119, in which methionine substitutes for threonine 119, a component of the protein's iodothyronine binding site, was identified in individuals with transient euthyroid hyperthyroxinemia. Healthy carriers of Met 119 have normal serum thyroid hormone concentrations, but two studies of Met 119 carriers have differed as to whether T4 binding to TTR is increased. An additional kindred has been identified by hybrid isoelectric focusing in an ongoing screening program for TTR variants in the Portuguese population with TTR Met 30 associated familial amyloidotic polyneuropathy. Cyanogen bromide peptide mapping and DNA restriction length polymorphism analyses showed that the propositus was a compound heterozygote for two TTR variants: Asn 90 and Met 119. Family analysis revealed that he inherited the TTR Met 119 variant from the mother and the TTR Asn 90 variant from the father. Neither the compound heterozygote nor his parents had symptoms of familial amyloidotic polyneuropathy. Serum dialysis with stepwise saturation of iodothyronine binding sites confirmed that TTR binding of T4 is increased in TTR Met 119. The increased binding is due to a higher TTR concentration rather than an increased association constant for T4. Because of the small proportion of serum T4 bound by TTR, increased T4 binding by TTR did not affect the ratio of free to bound T4 or T4 concentrations. In contrast, plasma retinol binding protein, almost all of which is bound by TTR, was elevated. The Asn 90 mutation does not affect either the concentration or the hormone binding characteristics of the protein. Possible long-term effects of these mutations and the combined heterozygotic state remain to be determined.

Transthyretin: a review from a structural perspective

“…With Thr119Met transthyretin, the thyroxine affinity was approximately doubled (K a = 3.40 ± 0.76 ¥ 10 7 l/mol; P< 0.001) with no change in immunoreactive transthyretin variant in the undiluted serum. This doubling in affinity explained the observed thyroxine levels of about 120 nmol/l in individuals with this mutation, which is identical to the value found by both Alves et al [50] and Harrison et al [51] in individuals with the Thr119Met transthyretin variant. Identical experiments carried out with Glu54Gly transthyretin showed that the thyroxine affinity of this variant was the same as for normal transthyretin.…”

“…However, in a later, slightly higher resolution X-ray study, Hamilton et al [49] showed that residue 6 was not involved in thyroxine binding. In 1993, a group of researchers lead by Pedro Costa and Maria Saraiva identified individuals who had the transthyretin variant Thr119Met, which was associated with transient euthyroid hyperthyroxinemia [50]. In addition, they found an individual who was heterozygous for the double mutation Thr119Met and His90Asn.…”

Small Transthyretin (TTR) Ligands as Possible Therapeutic Agents in TTR Amyloidoses

“…In opposition, TTR T119M is a non-pathogenic variant. This is a particularly interesting variant since it has been described in heterozygotic carriers and also in compound heterozygotic carriers of both TTR V30M and TTR T119M [25]. Curiously in the last case the TTR T119M variant seems to have a protective role over the effect of TTR V30M since these compound heterozygotes present a more benign form of the disease [26,27,28].…”

Natural polyphenols inhibit different steps of the process of transthyretin (TTR) amyloid fibril formation

“…TTR L55P, a variant with a substitution of a proline for leucine, is highly amyloidogenic and is associated with the most aggressive form of the disease [3]. Likewise, TTR Y78F is a very aggregate-prone mutant, namely under physiological conditions [4], while TTR T119M, with a substitution of methionine for threonine, is a non-amyloidogenic and non-pathogenic TTR variant with protective properties [5].…”