Inherited Heat-Stable Variant Thyroxine-Binding Globulin (TBG-Chicago)∗

The five known types of inherited variant T4-binding globulin (TBG) have in common increased sensitivity to heat denaturation compared to the common type TBG (TBG-C). In the course of studies to screen for and characterize variant TBGs in population groups, we detected a unique TBG with marked resistance to heat denaturation. The propositus was a 22-year-old black man without personal or family history of thyroid disease. His native TBG (nTBG) in serum had a t1/2 of denaturation at 56 C of 90 min compared to a mean value of 6.8 +/- 1.1 (+/- SD) min for TBG-C. This variant TBG, termed TBG-Chicago, was also resistant to acid denaturation, but was indistinguishable from TBG-C in terms of immunoreactivity, microheterogeneity on isoelectric focusing, and affinity for T4. It had a single T4-binding site and a normal concentration in serum associated with iodothyronine levels within the normal range. The mode of inheritance of TBG-Chicago appears to be X-chromosome linked. The mother of the propositus was heterozygous; her serum contained approximately 40% TBG-Chicago and 60% of another variant TBG common in blacks, TBG-S. The father had TBG-C, a trait that was not transmitted to his son. The exact nature of this variant TBG is not known. It most likely represents a mutation in the polypeptide chain of the molecule with formation of stronger intramolecular bonds.