A new family with hyperthyroxinemia caused by transthyretin Val109 misdiagnosed as thyrotoxicosis and resistance to thyroid hormone - A clinical research center study

Samuel Refetoff, Ventzislav S.Z. Marinov, Hakan Tunca, Maria M. Byrne, Thongkum Sunthornthepvarakul, Roy E. Weiss

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


Serum transthyretin (TTR) is a protein of liver origin that under normal conditions transports approximately 20% T4. Missense mutations of the TTR gene produce familial amyloidotic polyneuropathy and rarely, euthyroid hyperthyroxinemia (EHT). Of the 3 TTR variants so far identified with increased affinity for T4, Ser6, Thr109, and Met119, only TTR- Thr109 has high enough affinity for T4 to produce consistent hyperthyroxinemia in the heterozygous individuals. Because the mutation GCC→ACC in codon 109 results in the loss of one Bso FI site in exon 4 of the TTR gene, the use of this enzyme was suggested to screen for TR-Thr109 in subjects with EHT. We investigated a family with dominantly inherited EHT, in which two of eight affected members received ablative thyroid treatment for presumed thyrotoxicosis, and one was misdiagnosed as having resistance to thyroid hormone. All affected individuals had serum reverse T3 concentrations above normal and average T4 50% above the mean of unaffected relatives. Total T3 and TSH levels were within the normal range. Although loss of the Bso FI site in one allele of the two TTR suggested the presence of Thr109 gene sequencing revealed a different mutation in the same codon (GCC→GTC) producing TTR-Val109. T4-binding to TTR-Val109 was compared to that of the normal TTR-Ala109 and the formerly identified variant TTR- Thr109. Association constants were 1.3, 9.5, and 13.6 x 107 M-1 for TTR-Ala109, Va109, and Thr109, respectively. Thus, for equally expressed mutant and normal allele and 20% of serum T4 bound to TTR, the calculated mean serum T4 concentration of heterozygotes for TPR-Va109 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-Thr109 indicating that the extra atoms in Val as in Thr, which are absent in the Ale of the wild type TTR, widen the ligand binding site.

Original languageEnglish (US)
Pages (from-to)3335-3340
Number of pages6
JournalJournal of Clinical Endocrinology and Metabolism
Issue number9
StatePublished - 1996
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical


Dive into the research topics of 'A new family with hyperthyroxinemia caused by transthyretin Val<sup>109</sup> misdiagnosed as thyrotoxicosis and resistance to thyroid hormone - A clinical research center study'. Together they form a unique fingerprint.

Cite this