Familial Euthyroid Thyroxine Excess: Characterization of Abnormal Intermediate Affinity Thyroxine Binding to Albumin*

Barlow, John W.; Csicsmann, J.; White, Elizabeth L.; Funder, John W.; Stockigt, Jan R.

doi:10.1210/jcem-55-2-244

Cited by 54 publications

(13 citation statements)

References 20 publications

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“…Although this condition had been widely reported in the medical literature (1)(2)(3)(4)(5)(6)(7)(8), the molecular basis of FDH was not known until the identification of a single point mutation in the HSA gene of several FDH individuals resulting in the substitution of histidine for arginine at amino acid position 218 (9). This result was confirmed by another study in which the same mutation was identified in FDH individuals from eight unrelated families (10).…”

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confidence: 86%

Mutations in a Specific Human Serum Albumin Thyroxine Binding Site Define the Structural Basis of Familial Dysalbuminemic Hyperthyroxinemia

Petersen

Jameson

et al. 1996

Journal of Biological Chemistry

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The familial dysalbuminemic hyperthyroxinemia (FDH) phenotype results from a natural human serum albumin (HSA) mutant with histidine instead of arginine at amino acid position 218. This mutation results in an enhanced affinity for thyroxine. Site-directed mutagenesis and a yeast protein expression system were used to synthesize wild type HSA and FDH HSA as well as several other HSA mutants. Studies on the binding of thyroxine to these HSA species using equilibrium dialysis and quenching of tryptophan 214 fluorescence suggest that the FDH mutation affects a single thyroxine binding site located in the 2A subdomain of HSA. Sitedirected mutagenesis of HSA and thyroxine analogs were used to obtain information about the mechanism of thyroxine binding to both wild type and FDH HSA. These studies suggest that the guanidino group of arginine at amino acid position 218 in wild type HSA is involved in an unfavorable binding interaction with the amino group of thyroxine, whereas histidine at amino acid position 218 in FDH HSA is involved in a favorable binding interaction with thyroxine. Neither arginine at amino acid position 222 nor tryptophan at amino acid position 214 appears to favorably influence the binding of thyroxine to wild type HSA. Familial dysalbuminemic hyperthyroxinemia (FDH),1 an autosomal dominant condition in which the total thyroxine level in serum is elevated while the free thyroxine level is normal, results from the presence of an abnormal human serum albumin (HSA) with an enhanced affinity for thyroxine (1). Although this condition had been widely reported in the medical literature (1-8), the molecular basis of FDH was not known until the identification of a single point mutation in the HSA gene of several FDH individuals resulting in the substitution of histidine for arginine at amino acid position 218 (9). This result was confirmed by another study in which the same mutation was identified in FDH individuals from eight unrelated families (10). Recently, it was shown that recombinantly produced FDH HSA has an enhanced affinity for thyroxine similar to that seen for natural FDH HSA (11), a result that confirmed that all of the information necessary to generate the FDH phenotype is contained in the FDH mutation.The binding of thyroxine to HSA has been extensively studied (12-23), yet the molecular basis of this interaction remains obscure. Early studies used equilibrium dialysis to measure the binding of radiolabeled thyroxine and radiolabeled thyroxine analogs to HSA. Interpretation of these results was complicated by the observation of several binding components, which were difficult to resolve. For example, some of these studies assigned four equal binding sites for thyroxine with dissociation constants (K d ) of 6.6 M (12-14), whereas other studies resolved the binding data into two sites with The aforementioned results indicated that HSA has multiple thyroxine binding sites, whereas the existence of a specific thyroxine binding site in the 2A subdomain of HSA was suggested by other observations. ...

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confidence: 86%

Mutations in a Specific Human Serum Albumin Thyroxine Binding Site Define the Structural Basis of Familial Dysalbuminemic Hyperthyroxinemia

Petersen

Jameson

et al. 1996

Journal of Biological Chemistry

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“…The K a of the abnormal albumin has been estimated to be approximately 10 7 M" 1 (2,5,22), while that of normal albumin has been variously judged to be 10 5 -10 6 M" 1 (23)(24)(25)(26)(27).…”

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confidence: 99%

Heterogeneity of Thyroxine Binding by Serum Albumins in Normal Subjects and Patients with Familial Dysalbuminemic Hyperthyroxinemia*

Yabu

Amir

Ruiz

et al. 1985

The Journal of Clinical Endocrinology & Metabolism

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The nature and properties of the T4-binding albumins in the sera of normal subjects and patients with the syndrome of familial dysalbuminemic hyperthyroxinemia (FDH) were investigated by means of isoelectric focusing in polyacrylamide gels. Albumins isolated from normal sera and sera of patients with FDH displayed multiple protein bands, with isoelectric points between 4.65 and 5.75, and protein patterns were the same in the two groups. In normal albumin, [125I]T4 was consistently localized in two bands, termed B1 and B2, whose isoelectric points (pIs) were 5.44 +/- 0.03 and 5.31 +/- 0.02 (mean +/- SE), respectively. Occasionally, binding of far smaller proportions of [125I]T4 was seen in two additional bands of lower pI (5.22 +/- 0.03 and 4.97 +/- 0.07), termed B3 and B4, respectively. In FDH albumin, [125I]T4 was also localized in four bands whose PIs were almost identical to those of B1-B4 in normal albumin. In FDH albumin, however, bands corresponding to B1 and B2 bound only a minor fraction of [125I]T4, the great majority being bound by bands corresponding to B3 and B4, especially the latter. Identity of the four T4-binding albumins in normal and FDH albumin was suggested by their virtually identical pIs in both types of albumin, by the emergence or intensification of the B3 band in both after extraction of endogenous T4, and by the finding that an 125I-labeled derivative of T4 used in a commercial one-step assay for serum free T4 was bound by the B4 band in both normal and FDH albumin, though more intensely in the latter. Treatment of FDH albumin with increasing concentrations of dithiothreitol (DTT; 0.1-5.0 mM) caused a progressive loss of [125I]T4 binding by B3 and B4, leaving [125I]T4 bound by B1 or B2, and had little effect on the binding of [125I]T4 by B1 and B2 in normal albumin. These effects of DTT appeared to correlate well with earlier dialysis studies at physiological pH which revealed that the same concentrations of DTT decreased or abolished the high affinity binding of T4 in FDH albumin but had little effect on the residual lower affinity binding of T4 in FDH albumin or that characteristic of normal albumin. These findings suggest that T4 binding patterns evident during isoelectric focusing of albumin at low pH have relevance to binding of T4 by albumins at physiological pH.(ABSTRACT TRUNCATED AT 400 WORDS)

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“…Familial dysalbuminemic hyperthyroxinemia (FDH) is a recently described syndrome characterized by an increase in T 4 binding to albumin (11)(12)(13)(14)(15)(16). The serum albumin, in these subjects has an affinity constant for T 4 intermediate between T 4 -binding globulin (TBG) and T 4 -binding prealbumin (TBPA) and that for albumin in normal serum and binds T 4 much more avidly than T 3 (13)(14)(15).…”

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confidence: 99%

“…The serum albumin, in these subjects has an affinity constant for T 4 intermediate between T 4 -binding globulin (TBG) and T 4 -binding prealbumin (TBPA) and that for albumin in normal serum and binds T 4 much more avidly than T 3 (13)(14)(15). Patients with FDH are clinically euthyroid with increased serum T 4 concentrations and FT 4 index values and normal serum T 3 concentrations.…”

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confidence: 99%

“…Patients with FDH are clinically euthyroid with increased serum T 4 concentrations and FT 4 index values and normal serum T 3 concentrations. The serum FT 4 measured by equilibrium dialysis in phosphate buffer without saline or in other buffers is normal (11)(12)(13)(14)(15)(16). Serum FT 4 measured by RIA when the assays employ 125 I-T 4 but not 125 I-T 4 analogs is also within the normal range (17,18).…”

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confidence: 99%

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Effect of Chloride on Serum Thyroxine Binding in Familial Dysalbuminemic Hyperthyroxinemia*

Rajatanavin

Young

Braverman

1984

The Journal of Clinical Endocrinology & Metabolism

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Chloride ion is known to inhibit the T4-albumin interaction in normal serum. To determine the extent of this effect on T4 binding to albumin in patients with familial dysalbuminemic hyperthyroxinemia (FDH), the serum percent free T4 (FT4) was measured by equilibrium dialysis in 0.1 M phosphate buffer, pH 7.4, and in phosphate buffer with 0.14 M NaCl (phosphate-saline buffer) in patients with FDH, normal subjects, and women in the third trimester of pregnancy, who served as a population with high serum T4-binding globulin concentrations. The FT4 was calculated as the product of the percent FT4 and total T4 concentration. The mean values of serum FT4 were similar among the three groups when equilibrium dialysis was performed in phosphate buffer. When the assay was carried out in phosphate-saline buffer, the mean percent FT4 in each group was higher than that obtained in phosphate buffer, resulting in higher mean serum FT4 concentrations. However, the mean serum FT4 in normal subjects and pregnant women remained similar. The increase in percent FT4 in phosphate-saline buffer was proportionally greater in the patients with FDH, and therefore the mean serum FT4 in these patients was significantly higher than that of normal subjects when phosphate-saline buffer was used (2.67 +/- 0.07 (SE) vs. 1.80 +/- 0.09 ng/dl, P less than 0.001), and all FT4 values were above the normal range. It is concluded that chloride ion inhibits serum T4 binding in patients with FDH more than it does in normal subjects, perhaps due to the fact that albumin plays a much greater role in overall T4 binding in these patients.

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Familial Euthyroid Thyroxine Excess: Characterization of Abnormal Intermediate Affinity Thyroxine Binding to Albumin*

Cited by 54 publications

References 20 publications

Mutations in a Specific Human Serum Albumin Thyroxine Binding Site Define the Structural Basis of Familial Dysalbuminemic Hyperthyroxinemia

Mutations in a Specific Human Serum Albumin Thyroxine Binding Site Define the Structural Basis of Familial Dysalbuminemic Hyperthyroxinemia

Heterogeneity of Thyroxine Binding by Serum Albumins in Normal Subjects and Patients with Familial Dysalbuminemic Hyperthyroxinemia*

Effect of Chloride on Serum Thyroxine Binding in Familial Dysalbuminemic Hyperthyroxinemia*

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