Complete thyroxine-binding globulin (TBG) deficiency caused by a single nucleotide deletion in the TBG gene

Thyroxine-binding globulin (TBG) is the major thyroid hormone transport protein. Several inherited TBG variants resulting in partial and complete TBG deficiency have been shown to be caused by one or two nucleotide replacements in the coding regions of the TBG gene. Each manifests as a different change in the physical properties and/or biological function of the mature TBG protein. We now report sequencing of the entire coding region and exon-intron junctions of a TBG allele of a subject with inherited complete TBG deficiency, previously classified as TBG-CD6. A single nucleotide deletion was found in the codon for amino acid 165 of the normal TBG molecule. The shift in the reading frame due to this nucleotide deletion results in downstream encoding of two different amino acids followed by an early stop codon. This results in a mature protein of only 167 residues, as compared with the normal 395. Nine members of the TBG-CD6 family were tested for the presence of this mutation by allele-specific amplification. Seven of them were found to be carriers of the defect, with five hemizygous subjects manifesting complete TBG deficiency. The mutant allele correlated with the results of TBG analysis in serum. This defect was not present in affected subjects of any of seven unrelated families with complete TBG deficiency tested.