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Isoelectric Focusing of Variant Thyroxine-Binding Globulin in American Blacks: Increased Heat Lability and Reduced Serum Concentration^*

The Thyroid Study Unit, Departments of Medicine and Pediatrics, The University of Chicago School of Medicine,Chicago, Illinois 60637

Three major bands of T₄-binding globulin (TBG) at pH 4.3-4.5 are seen after isoelectric focusing (IEF) of serum. Daiger et al. detected acathodal shift of all IEF bands in some American blacks, and found that the inheritance of this variant TBG (TBG-S) is X-chromosome linked. However, the properties of the TBG-S molecule and its possible association with changes in thyroid function have not been studied.

Based on IEF analysis of 114 serum samples from adult American blacks, the gene frequency of TBG-S was 12.0%, and the genotype distribution was consistent with X-chromosomal linkage. TBG-S and the common type TBG (TBG-C) cooccurred exclusively in sera from women, whereas sera from men had only TBG-C or TBG-S, confirming the X-linked inheritance of this variant TBG.

At 60 C, TBG-S was denatured with a mean t of 4.7 ± 0.9 (±SD) min compared to 6.8 ±1.1 min for TBG-C (P < 0.001). Heterozygous females with TBG-CS had an intermediate rate of heat denaturation (tA, 5.2 ± 0.7 min). In vitro mixtures of TBG-S and TBG-C also had intermediate t values, indicating that the heat lability of TBG-Sis inherent to the variantTBG molecule. Heat denaturation resulted in loss of T₄-binding activity, which was proportional among corresponding IEF bands for each of the two TBG types. Larger amounts of added T₄ were required to protect against the heat-induced denaturation of TBG-S. No changes in the affinity of TBG-S for T₄ could be demonstrated by analysis of binding kinetics at O C.

Thyroid function tests were carried out in 10 black men with TBG-S and 10 age-matched black men with TBG-C. The mean concentration of total T₄ (TT₄) of 6.8 ± 1.5 µg/di in the group of TBG-S men was lower (P < 0.02) than that in the group of TBG-C men (8.5 ± 1.3 Mg/dl). The finding of lower levels of TT₄ in men with TBG-S was best explained on the basis of a concomitant reduction of serum TBG concentration (1.41 ± 0.30 vs. 1.72 ± 0.23 mg/dl; P < 0.05). This conclusion was confirmed when no significant difference in mean TT₄ concentration was found between the group with TBG-S and another with TBG-C matched by serum TBG concentration. The mean free T₄ concentrations estimated from the TT₄ to TBG ratios or measured by equilibrium dialysis were not significantly different between the two groups. Also, no significant differences were found in the mean serum TSH, total T₃, rT₃, and thyroglobulin levels. Tests of thyroid function were not different between the group of 10 black women with TBG-CS and an equal number of agematched black women with TBG-C (genotype TBGcc).

TBG-S appears to be a variant form of molecular structure inherited as an X-chromosome-linked trait. Its lower concentration in serum may be due to an increased rate of degradation as a consequence of reduced stability of the molecule. However, the possibility of a decreased rate of synthesis or secretion has not been excluded. (J Clin Endocrinol Metab63: 80,1986)

^* Presented in part at the Ninth International Thyroid Congress in Sao Paulo, Brazil, September 1-6, 1985. This work was supported in part by USPHS Grant AM-15070.

Received November 15, 1985.