THYROXINE INTERACTIONS WITH TRANSTHYRETIN - A COMPARISON OF 10 DIFFERENT NATURALLY-OCCURRING HUMAN TRANSTHYRETIN VARIANTS

Transthyretin (TTR) is a tetrameric protein that transports 15-20% of circulating T4. Alterations in TTR structure can manifest clinically a s familial amyloidotic polyneuropathy or euthyroid hyperthyroxinemia. We have measured the relative affinity for T4 of several variant TTR m olecules in human plasma. We have compared control plasma to plasma fr om a patient heterozygous for a [Thr109]TTR mutation associated with a 3-fold increased affinity for T4 and to plasma from patients with fam ilial amyloidotic polyneuropathy with different point mutations in TTR . Relative affinity was measured in an assay in which [I-125]T4 bound by TTR was isolated by immunoprecipitation with an antibody specific f or TTR. [Thr109]TTR displayed the highest affinity for T4, whereas hom ozygous [Met30]TTR did not bind appreciable amounts of [I-125]T4. The rank order of affinity of the various TTR mutations for T4 was: Thr109 heterozygous > wild type = Ala60 heterozygous = Ile122 heterozygous > His58 heterozygous almost-equal-to Tyr77 heterozygous almost-equal-to Ser84 heterozygous almost-equal-to Ile122 homozygous almost-equal-to Met30 heterozygous > > Met30 homozygous TTR. Thus, different point mut ations in TTR increase, decrease, or do not affect TTR's affinity for T4. The ability of TTR to form amyloid fibrils does not appear to be r elated to its affinity for T4. Further study is required to define the molecular basis of alterations in T4 binding induced by point mutatio ns located along the TTR tetramer.