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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 1 368-372
Copyright © 2000 by The Endocrine Society

Original Studies

Identification of Thyroxine-Binding Globulin-San Diego in a Family from Houston and Its Characterization by in Vitro Expression Using Xenopus Oocytes1

Onno E. Janssen, Sabrina T. Astner, Helmut Grasberger, Sheila K. Gunn and Samuel Refetoff

Department of Medicine, Klinikum Innenstadt, Ludwig Maximilians University (O.E.J., S.T.A., H.G.), D-80336 Munich, Germany; the Department of Pediatric Endocrinology and Metabolism, Baylor College of Medicine (S.K.G.), Houston, Texas 77030; and the Departments of Medicine and Pediatrics and J. P. Kennedy, Jr., Mental Retardation Research Center, University of Chicago (S.R.), Chicago, Illinois 60637

Address all correspondence and requests for reprints to: Dr. Onno E. Janssen, M.D., Molecular Endocrinology, Department of Medicine, Klinikum Innenstadt, Ludwig Maximilians University, Ziemssenstrasse 1, D-80336 Munich, Germany. E-mail: onno.e.janssen{at}lrz.uni-muenchen.de


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
T4-binding globulin (TBG) is a liver glycoprotein that transports iodothyronines in serum. Several TBG variants with reduced T4 binding affinity have been described, all of which are also characterized by reduced serum TBG concentrations and reduced heat stability. Their loss of binding thus appears to be due to a general defect of the molecule. We now report the occurrence of a variant TBG, detected in a family from Houston, TX, with half the normal T4 binding affinity and heat stability but normal serum concentration and isoelectric focussing pattern. The propositus was identified by reduced total T4 and T3 serum levels. All family members were euthyroid, and inheritance followed an X-linked pattern. Sequence analysis of the TBG gene of the propositus and his heterozygous mother revealed two amino acid substitutions: serine 23 with threonine (S23T), and the known polymorphism leucine 283 with phenylalanine (L283F). These substitutions are identical to those of TBG-San Diego (TBG-SD), a variant with similar properties except for a reduced serum concentration. Expression of recombinant TBG-SD/H with the S23T substitution in Xenopus oocytes reproduced the binding defect and heat lability. The amount of TBG-SD/H synthesized and secreted by the oocytes was not different from that of normal TBG. The difference in serum TBG concentrations in affected members of the San Diego and Houston families thus does not appear to be due to an error in the measurement of TBG, but may be related to differences in the rates of degradation.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
T4-BINDING globulin (TBG), a 54-kDa liver glycoprotein, is the principal binding protein for T4 and T3 in blood (1, 2, 3, 4). Except for a recently described exception (5), familial TBG variants follow an X-linked inheritance pattern, compatible with the location of the single copy TBG gene on the long arm of the X-chromosome (6, 7). The TBG complementary DNA (8) and its gene and promoter (9) have been characterized. The mature molecule containing 395 amino acids in a single polypeptide chain (10) and 4 N-linked oligosaccharides (11) is secreted into the bloodstream. Estrogens increase the concentration of TBG in serum by an increased sialic acid content of the carbohydrate moiety, effectively delaying the molecule’s clearance by the hepatic asialo receptors (12, 13, 14).

Based on their serum concentration, familial TBG variants are divided into four major categories: excess (15), normal, partial deficiency, and complete deficiency (1, 4). Attention has been focussed on TBG with altered T4 binding, as they are thought to provide information on the molecular requirements for the high affinity binding site of TBG. However, the six variants characterized to date (Fig. 1Go) did not exhibit an isolated binding defect, but, rather, had properties indicative of a generalized defect of the molecule, characterized by decreased serum concentrations, increased concentrations of the denatured molecule, and reduced heat stability [TBG-SD (16, 17), TBG-G (18, 19), TBG-M (20, 21), TBG-A (22, 23), TBG-Q (20, 24), and TBG-PDJ (25)]. Some are also characterized by shifts on isoelectric focussing (IEF), which can be explained by the loss or gain of charge by the respective amino acid substitutions. The reduced binding affinity and stability of some of these variants [TBG-M (26), TBG-G (27), TBG-PDJ (28), and TBG-Q (our unpublished data)] were verified by in vitro expression.



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  		Figure 1. Characteristics of the TBG variants with T4 binding defects. Schematic representation of the TBG gene and the mature molecule with the locations of the mutations. The properties of the variant TBG molecule are listed in the table below. The T4 binding affinity and serum concentrations of TBG and denatured TBG (dnTBG) (42 ) are expressed as a percentage of that of TBG-N. Heat stability is expressed as the temperature at which 50% denaturation occurred within 7 min (TBG-N, 60 C; see text for references). 0–4, Exons 0–4; SP, signal peptide; ATG, start codon; TAG, stop codon; Y, site of N-linked glycosylation; nd, not determined.

 
We now present the characterization, sequence analysis, and in vitro expression of a TBG variant from a family from Houston, with reduced T4 binding affinity and heat stability, but apparently normal concentration in serum. This TBG had a molecular defect identical to TBG-SD and thus had the same properties, except for differences in serum concentration.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects and characterization of serum samples

Serum samples were obtained from all members of the Houston family. Thyroid function (total T4, total T3, TSH, and TBG) was measured by RIAs used routinely in the clinical diagnostic laboratory. IEF was performed as described previously (1) with reagents from Pharmacia Biotech (Uppsala, Sweden).

Measurement of T4 binding and heat denaturation of TBG

Parameters of T4 binding were measured by a method previously described in detail (29). The affinity constant (Ka) and TBG concentration were determined by the method of Scatchard (30). Heat denaturation was performed as previously described (26).

Sequencing

Genomic DNA isolated from peripheral blood leukocytes served as a template to amplify the coding regions (exons 1–4) and adjacent exon-intron junctions of the TBG gene by PCR under the conditions and with the oligonucleotide primers described previously (31). The PCR products were purified and used for automated sequencing with fluorescent dye terminators (PRISM System 377, PE Applied Biosystems, Foster City, CA) and for subcloning into the pGEM-4Z vector (Promega Corp.). Positive clones were sequenced by the dideoxy termination method using Sequenase (version 2.0, U.S. Biochemical Corp., Cleveland, OH). At least six sequences were obtained for every base of the coding region, including two sense and two antisense sequences. Automated sequencing confirmed heterozygosity of the mother.

Expression of normal and mutant TBG in Xenopus oocytes

A vector for normal TBG (TBG-N) was available (26) and was used to construct a TBG-mSD/H-vector (S23T) by site-directed mutagenesis with the Altered Sites Kit (Promega Corp., Madison, WI) and the oligonucleotide 5'-CTCTACAAGATGACATCCATTAATG-3' (the underlined A indicates the TBG-mSD/H mutation) as recommended by the supplier (Promega Corp.). The coding region of the TBG-mSD/H mutant was verified by sequencing as described above. Synthetic messenger ribonucleic acid (sRNA) was prepared with the Gemini-II in vitro transcription kit and T7 RNA polymerase according to the recommendations of the supplier (Promega Corp.). Expression of the recombinant TBG in microinjected oocytes from Xenopus laevis has also been described in detail previously (32). All animal studies were conducted in accordance with the principles and procedures outlined in the Guidelines for Care and Use of Experimental Animals.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The propositus was found to have a low blood T4 level on neonatal screening. Reduced total T4 and T3 concentrations were confirmed in serum (Fig. 2Go) and remained low on several determinations. The serum TSH concentration was normal at 1.2 mU/L. Although a high resin T3 uptake of 34% (normal, 20–28%) suggested TBG deficiency, direct measurement of the latter by RIA gave normal or slightly elevated results in three determinations [27 mg/L (normal, 20–53), 36 (normal, 12–30), and 17.5 (normal, 13.5–25.5)]. This discrepancy suggested a TBG with altered affinity for the iodothyronines. Growth and development proceeded normally with no hormonal treatment. T4 and T3 levels in serum samples from the father, mother, and a younger brother were within the normal range. All family members had normal TBG and TSH levels (Fig. 2Go), were clinically euthyroid, and showed a normal TBG pattern on IEF (Fig. 3Go).



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  		Figure 2. Pedigree and thyroid function tests of the Houston family. In contrast to his younger brother, the propositus had a reduction in both total T4 (TT4) and total T3 (TT3), but normal TBG and TSH levels. His mother’s TT4 and TT3 values were in the lower range of normal, compatible with her heterozygous state.

 


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  		Figure 3. IEF of serum samples from the Houston family. Serum samples were incubated with [125I]T4 and separated by IEF on precast polyacrylamide gels with an ampholine range from pH 4–6. The propositus’ TBG had a pattern identical to that of TBG-N. As a control, serum from a pregnant woman was used, showing an anodal shift in the relative proportions of the TBG bands.

 
Characterization of serum TBGs

Scatchard analysis of T4 binding (Fig. 4Go) revealed a 2-fold reduction of the Ka of the propositus’ TBG (0.42 x 1010 mol/L-1; normal range, 0.8–1.2 x 1010 mol/L-1). The Ka of the father’s TBG was normal (0.85 x 1010 mol/L-1). The mother was heterozygous, expressing both variant and normal TBG (TBG-N), with Ka values of 0.38 x 1010 and 0.93 x 1010 mol/L-1, respectively. These results are compatible with the known X-linked inheritance of familial TBG defects.



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  		Figure 4. Scatchard analysis of T4 binding to serum TBG. The father expressed TBG-N ({Delta}; Ka = 0.85 x 1010 mol/L-1), the mother was heterozygous (; Ka = 0.38 x 1010 and 0.93 x1010 mol/L-1), and the propositus was hemizygous for the TBG variant ({blacktriangleup}; Ka = 0.42 x 1010 mol/L-1).

 
Heat denaturation at 58 C (Fig. 5Go) revealed a reduced half-life (t1/2) of the variant TBG of the Houston family (11 min), similar to that of TBG-SD (8 min), compared to that of TBG-N (20 min).



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  		Figure 5. Heat denaturation of serum TBGs. The rate of heat denaturation was determined as the residual T4 binding of diluted serum samples after incubation at 58 C for increasing time periods. In comparison to normal TBG ({diamond}, pooled serum; {Delta}, unaffected member of the Houston family; {square}, unaffected member of the San Diego family; t1/2 = 21 min), TBG from the propositus(s) had a reduced t1/2 of 11 min, similar to that of an affected member of the San Diego family ({blacksquare}) of 8 min.

 
Sequencing of the variant TBG from the Houston family

Sequencing the entire coding region (exons 1–4) and adjacent exon-intron junctions of the TBG genes from the hemizygous propositus and his heterozygous mother revealed two nucleotide substitutions: T127 to A, resulting in the substitution of serine 23 with threonine (S23T), and G909 to T, resulting in the substitution of leucine 283 with phenylalanine (L283F). Unexpectedly, these substitutions were identical to those of TBG-SD (17). L283F is a known TBG polymorphism (TBG-P) with no apparent effect on the molecule (1, 4). To confirm that the S23T substitution is the cause of the altered properties of the variant TBG of the Houston family and TBG-SD, a TBG with this substitution was expressed in vitro.

Characterization of TBG-mSD/H expressed in Xenopus oocytes

Oocytes were removed from Xenopus laevis, culled, injected with sRNAs coding for TBG-N and the S23T mutant (designated TBG-mSD/H), and incubated for up to 7 days with daily change of medium. TBG-mSD/H was synthesized and secreted into the medium as efficiently as TBG-N, as shown by Scatchard analysis of T4 binding (Fig. 6Go). Mean ± SD expression from four independent experiments was 4.51 ± 0.52 fmol/oocyte for TBG-N and 4.29 ± 0.37 fmol/oocyte for TBG-mSD/H. Similar expression levels were confirmed by SDS-PAGE of [35S]methionine-labeled samples and a commercial RIA (data not shown). TBG-mSD/H had a 2-fold reduction of binding affinity (0.61 x 1010 mol/L-1) compared to TBG-N (1.2 x 1010 mol/L-1), similar to the reduction of binding affinity of serum TBG from the hemizygous affected members of the Houston and San Diego families. To determine the temperature stability of TBG-mSD/H, heat denaturation was performed at 58 C. The t1/2 was 14 min, about half that of TBG-N (t1/2 = 21 min; Fig. 7Go).



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  		Figure 6. Scatchard analysis of T4 binding of the recombinant TBG-mSD/H. TBG-N ({circ}) and the mutant TBG-mSD/H (•) were expressed in Xenopus oocytes. Scatchard analysis of the secreted proteins revealed a 50% reduction in binding affinity of TBG-mSD/H (0.61 vs. 1.20 x 1010 mol/L-1) but similar expression levels of 4.29 ± 0.37 vs. 4.51 ± 0.52 fmol/oocyte (mean and SD of four independent experiments).

 


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  		Figure 7. Heat stability of recombinant TBG variants. TBG variants synthesized by Xenopus oocytes were heated at 58 ± 0.1 C for increasing time periods, and the residual T4-binding activity was determined. Values are expressed as levels of protein-bound T4 relative to the basal levels. TBG-mSD/H (•) had a shorter t1/2 of denaturation of 14 min compared to that of TBG-N ({circ}) of 22 min.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We have characterized a variant TBG from a Houston family with a T4 binding defect and reduced heat stability, but normal serum concentration and IEF pattern. Unexpectedly, sequence analysis of the gene of this TBG variant revealed two mutations identical to those of the previously described TBG-SD, S23T and L283F. TBG-SD had the same binding defect and heat instability as the TBG found in the Houston family, but also exhibited a slightly reduced concentration in serum (16). The L283F substitution is polymorphic, found in association with 5 of the 15 known TBG variants, with no effect on the molecule’s properties (1, 4, 26). Expression of the S23T mutation in Xenopus oocytes faithfully reproduced the reduced binding and stability of serum TBG found in affected members of the Houston and San Diego families. Recombinant TBG-mSD/H was synthesized and secreted as efficiently as normal TBG, in contrast to other variant TBGs with reduced T4 binding affinity, such as TBG-M, TBG-Q, or TBG-G.

Although T4 binding and heat inactivation studies with serum of the variant TBG found in the Houston family gave, as expected, similar results as those obtained with sera from the San Diego family, the serum TBG concentrations were different. The TBG concentration in the three hemizygous affected subjects of the San Diego family was 38–64% (average, 50%) below the normal mean (corrected for age), and all values were below the lower limit of normal (16). In contrast, all TBG determinations in the affected hemizygotes of the Houston family were above the lower limit of normal for the subjects’ ages and only 10% below the normal mean value. This discrepancy cannot be readily explained. It is not due to age, because one of the affected subjects from the San Diego family with a low serum TBG concentration, 44% below the normal mean, was 3 yr of age. Given that the apparent rate of synthesis of the mutant TBG is unaltered, as determined from in vitro expression, differences in the rates of degradation by the liver among affected members of the two families may be the reason for the differences in the serum TBG concentrations.

Characterization of TBG variants with altered T4 binding was thought to help in understanding its high binding affinity. Due to its microheterogeneity (33), no structure of the molecule is available. However, its homology to the serine proteinase inhibitors (serpins) (34) has allowed modeling of TBG based on the structure of the archetypal serpin {alpha}1-proteinase inhibitor (PI; formerly {alpha}1-antitrypsin). Based on this model, earlier affinity labeling of TBG (35) and the only other ligand-binding serpin, corticosteroid-binding globulin (36), localized the binding site to a ß-barrel domain of the serpins. These theoretical considerations (34, 37) have recently been confirmed by the construction of a T4-binding chimera consisting of the ß-barrel of TBG in the context of the PI molecule (38). Binding studies of T4 analogs suggest that all parts of the TBG molecule participate in its avid binding (39). Taken together with the recent characterization of the structural requirements of the T4-binding site by site-directed mutagenesis (40), T4 would seem to bind deep within the ß-barrel of TBG, similar to T4 binding to transthyretin (41), but with a higher affinity.

Unfortunately, the S23T substitution of TBG-SD/H lies in an area that is not resolved in the crystal structure of PI and several other serpins. This region at the N-terminus of the molecule certainly does not belong to the ß-barrel, but, rather, appears to be a mobile part of the serpins. Furthermore, the conservative substitution of a serine with a threonine, differing only by a methyl group, is difficult to reconcile with a major effect on the properties of TBG. However, as the in vitro expression of the TBG-SD/H mutation leaves no doubt to this end, the mobile N-terminus of the TBG molecule might interfere, when mutated, with ligand binding, e.g. by intercalating into the ß-barrel. Understanding the structural basis of the reduced T4 binding of TBG-SD/H thus requires crystallization of the molecule, attempts at which have now been intensified.


   Acknowledgments
 
We appreciate the cooperation of the Houston family.


   Footnotes
 
1 This work was supported by a grant from the Deutsche Forschungsgemeinschaft (DFG Ja671/1–2; to O.E.J.) and in part by grants (to S.R.) from the NIH (DK-15070) and the USPHS (RR-00055). Back

Received August 16, 1999.

Accepted October 15, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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 J. Clin. Endocrinol. Metab.Home page
A. Fingerhut, S. Reutrakul, S. D. Knuedeler, L. C. Moeller, C. Greenlee, S. Refetoff, and O. E. Janssen
Partial Deficiency of Thyroxine-Binding Globulin-Allentown Is Due to a Mutation in the Signal Peptide
J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2477 - 2483.
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