A NEW FAMILY WITH HYPERTHYROXINEMIA CAUSED BY TRANSTHYRETIN VAL(109) MISDIAGNOSED AS THYROTOXICOSIS AND RESISTANCE TO THYROID-HORMONE - A CLINICAL RESEARCH-CENTER STUDY

Serum transthyretin (TTR) is a protein of liver origin that under norm al conditions transports approximately 20% T-4. Missense mutations of the TTR gene produce familial amyloidotic polyneuropathy and rarely, e uthyroid hyperthyroxinemia (EHT). Of the 3 TTR variants so far identif ied with increased affinity for T-4, Ser(6), Thr(109), and Met(119), o nly TTR-Thr(109) has high enough affinity for T-4 to produce consisten t hyperthyroxinemia in the heterozygous individuals. Because the mutat ion GCC-->ACC in codon 109 results in the loss of one Bso FI site in e xon 4 of the TTR gene, the use of this enzyme was suggested to screen for TR-Thr(109) in subjects with EHT. We investigated a family with do minantly inherited EHT, in which two of eight affected members receive d ablative thyroid treatment for presumed thyrotoxicosis, and one was misdiagnosed as having resistance to thyroid hormone. All affected ind ividuals had serum reverse T-3 concentrations above normal and average T-4 50% above the mean of unaffected relatives. Total T-3 and TSH lev els were within the normal range. Although loss of the Bso Fl site in one allele of the two TTR suggested the presence of Thr(109), gene seq uencing revealed a different mutation in the same codon (GCC-->GTC) pr oducing TTR-Val(109). T-4-binding to TTR-Val(109) was compared to that of the normal TTR-Ala(109) and the formerly identified variant TTR-Th r(109). Association constants were 1.3, 9.5, and 13.6 x 10(7) M(-1) fo r TTR-Ala(109), Val(109), and Thr(109), respectively. Thus, for equall y expressed mutant and normal allele and 20% of serum T-4 bound to TTR , the calculated mean serum T,concentration of heterozygotes for TTR-V al(109) should be 50% above the normal mean; the observed value being 55%. These results are in agreement with the observations based on the crystallographic structure of TTR-Thr(109) indicating that the extra atoms in Val as in Thr, which are absent in the (A)la of the wild type TTR, widen the ligand binding site.