Inherited defects of thyroxine-binding proteins

Abstract

Thyroid hormones (TH) are bound to three major serum transport proteins, thyroxine-binding globulin (TBG), transthyretin (TTR) and human serum albumin (HSA). TBG has the strongest affinity for TH, whereas HSA is the most abundant protein in plasma. Individuals harboring genetic variations in TH transport proteins present with altered thyroid function tests, but are clinically euthyroid and do not require treatment. Clinical awareness and early recognition of these conditions are important to prevent unnecessary therapy with possible untoward effects. This review summarizes the gene, molecular structure and properties of these TH transport proteins and provides an overview of their inherited abnormalities, clinical presentation, genetic background and pathophysiologic mechanisms.

Keywords: TBG deficiency; familial dysalbuminemic hyperthyroxinemia; human serum albumin; mutations; thyroid hormone transport proteins; thyroxine-binding globulin; transthyretin.

Figure 1

Crystal structures of serum TH-binding proteins. A. Structure of the TBG molecule: intact S-form (left) and cleaved R-form (right). Insertion of the reactive loop (in yellow) occurs following its cleavage by proteases to give an extra strand in the main sheet of the molecule but the T₄-binding site can still retain its active conformation. The S-to-R change in TBG results in a 6 -fold decrease but not a total loss of affinity. B. The homotetrameric structure of TTR composed of four monomers of 127 amino acids. TTR contains eight stands (A-H) and a small α-helix. The contacts between the dimers form two hydrophobic pockets where T₄ binds (T₄ channel). As shown in the magnified insert, each monomer contains one small α-helix and eight β-strands (CBEF and DAGH). C. The structures of HSA in the presence of T₄ as modeled on the structures 1BM0, 1HK1, 1HK3 in the Protein Data Bank (http://www.rcsb.org/pdb/home/home.do). The entire WT HSA molecule (in green) with its four T₄ binding sites [T₄ (1) to T₄(4)].

Figure 2

A. Genomic organization and chromosomal localization of TH-binding proteins. Filled boxes represent exons. Arrows indicate location of initiation codons and termination codons. B. Structure of promoter regions with the location of cis-acting transcriptional regulatory elements. Reproduced with permission.

Figure 3

A Properties of some TBG variants causing partial TBG deficiency (TBG-PD). [Modified from Refetoff et al (51)]. B Serum T₄-bound to TBG and the concentration of TBG and denatured TBG (dnTBG) in hemizygous subjects expressing the different TBG variants. Results, graphed as mean ± SD, were normalized by expressing them as % of those for the common type TBG (TBG-C). For abbreviations used in the nomenclature of the TBG variants, see legend to figure 1. [Adapted from Janssen et al (52)].