THYROXINE-BINDING IN A TTR MET-119 KINDRED

Recently, a transthyretin variant, TTR Met 119, in which methionine su bstitutes for threonine 119, a component of the protein's iodothyronin e binding site, was identified in individuals with transient euthyroid hyperthyroxinemia. Healthy carriers of Met 119 have normal serum thyr oid hormone concentrations, but two studies of Met 119 carriers have d iffered as to whether T4 binding to TTR is increased An additional kin dred has been identified by hybrid isoelectric focusing in an ongoing screening program for TTR variants in the Portuguese population with T TR Met 30 associated familial amyloidotic polyneuropathy. Cyanogen bro mide peptide mapping and DNA restriction length polymorphism analyses showed that the propositus was a compound heterozygote for two TTR var iants: 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 fro m the father. Neither the compound heterozygote nor his parents had sy mptoms of familial amyloidotic polyneuropathy. Serum dialysis with ste pwise saturation of iodothyronine binding sites confirmed that TTR bin ding of T4 is increased in TTR Met 119. The increased binding is due t o a higher TTR concentration rather than an increased association cons tant 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 mutatio n does not affect either the concentration or the hormone binding char acteristics of the protein. Possible long-term effects of these mutati ons and the combined heterozygotic state remain to be determined.