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

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

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.

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