Molecular basis for the properties of the thyroxine-binding globulin-slow variant in American blacks

Thyroxine-binding globulin-slow (TBG-S), a variant found in 4-12% of Black and Pacific Island populations, is inherited as an X-chromosome linked trait. This variant is detected on isoelectric focusing by the characteristic cathodal shift of all its isoforms, suggesting that the difference resides in the core protein. In addition, TBG-S is slightly more thermolabile, which explains why subjects expressing TBG-S have on the average lower serum TBG, and thus reduced T4, concentrations. We now report the molecular basis for this TBG variant, deduced from sequencing the TBG-S gene of an American Black man. Sequencing of the four coding regions and all intron/exon junctions revealed a single nucleotide substitution in the codon for amino acid 171 of the mature protein. The resulting change of the codon GAC to AAC results in replacement of the normal aspartic acid by asparagine. Since the negative charge provided by the aspartic acid is lost when replaced by the neutral asparagine, this substitution seems responsible for the cathodal shift on isoelectric focusing and slower electrophoretic mobility of TBG-S. An identical nucleotide substitution was identified in an unrelated American Black man expressing TBG-S. Whether the TBG-S phenotype observed in populations from the Pacific Islands is caused by the same mutation remains to be determined.