THYROXINE-BINDING GLOBULIN - ORGANIZATION OF THE GENE AND VARIANTS

Thyroxine-binding globulin (TBG), the principal thyroid hormone transp ort protein in human serum, is synthesized by the liver and secreted i nto the bloodstream as a 54-kD acidic glycoprotein made up of a single polypeptide chain of 395 amino acids and four heterosaccharide units. The carbohydrate chains are important for the correct posttranslation al folding, secretion and degradation of the molecule but are not requ ired for hormone binding. TBG, encoded by a single gene copy located o n Xq22, consists of five exons spanning 5.5 kbp. An upstream sequence of 218 nucleotides containing a hepatocyte nuclear factor 1 binding mo tif imparts to the gene a strong liver-specific transcriptional activi ty. Inherited TBG defects produce three phenotypes based on the level of TBG in serum of affected hemizygotes: complete TBG deficiency (TBG- CD), partial TBG deficiency (TBG-PD) and TBG excess (TBG-E). The molec ular basis of the TBG defect has been identified in 12 of 16 known TBG variants. TBG-CD is caused by either premature termination of transla tion or an amino acid substitution resulting in failure of secretion. Point mutations resulting in single amino acid substitutions are respo nsible for the alteration of the properties and/or concentration of TB G-PD variants. Gene duplication and triplication has been recently ide ntified in subjects with TBG-E.