Genetics of Thyroid Hormone‐Binding Proteins


Thyroid hormones (TH), T3 and its precursor T4, are transported into circulation mainly by thyroxine‐binding globulin (TBG), transthyretin (TTR) and human serum albumin (HSA). Inherited defects in TH‐binding proteins are not uncommon. Inherited TBG defects are X‐chromosome linked and, based on the serum levels of TBG in hemizygous patients, manifest as complete TBG deficiency, partial TBG deficiency and TBG excess. Mutations in TTR gene produce a protein with either decreased or increased affinity for T4. Mutations of the HSA gene produce mostly increased concentration of serum T4. A variant with increased affinity for T3 has been also identified. Individuals with inherited abnormalities of TH‐binding proteins have altered amount of total serum TH and, although the concentration of free hormones remains unaltered, routine measurement can give erroneous results. Early recognition of these conditions is important to avoid expensive testing and to prevent unnecessary treatments with possible side effects.

Key Concepts

  • Inherited defects of TH‐binding proteins cause alterations of thyroid function tests, which may lead to incorrect diagnosis.
  • Individuals with Inherited defects of TH‐binding proteins are clinically euthyroid and do not require treatment.
  • Novel functions are recognized to TH‐binding proteins. As an example, TBG may regulate the release of TH at sites of inflammation thus influencing the local concentration of TH.
  • TBG deficiency due to mutations in the TBG gene enhancer represents the first demonstration of a hereditary endocrine disorder caused by alterations in a gene expression regulatory element.
  • Lipoproteins, such as LDL, VLDL and HDL, may facilitate efflux of TH from cells.

Keywords: thyroid; thyroid hormone; thyroid hormone transport proteins; thyroxine‐binding globulin; transthyretin; human serum albumin; TBG deficiency; familial dysalbuminaemic hyperthyroxinaemia; mutations

Figure 1. (a) Genomic organisation and chromosomal localisation of TBG, TTR and ALB (HSA) genes. Filled boxes represent exons. Arrows indicate location of initiation codons and termination codons. (b) Structure of promoter regions with the location of transcriptional regulatory elements. Reproduced from Pappa et al. . © Elsevier.


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Ferrara, Alfonso Massimiliano(Sep 2018) Genetics of Thyroid Hormone‐Binding Proteins. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0027314]