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Partial Deficiency of Thyroxine-Binding Globulin-Allentown Is Due to a Mutation in the Signal Peptide

Division of Endocrinology, Department of Medicine (A.F., S.D.K., O.E.J.), University of Essen, 45122 Essen, Germany; Departments of Medicine (Si.R., L.C.M., Sa.R.) and Pediatrics (Sa.R.), and Committees on Genetics and Molecular Medicine (Sa.R.), The University of Chicago, Chicago, Illinois 60637; and Endocrinology & Metabolism, Atlanta Diabetes Associates (C.G.), Atlanta, Georgia 30309

Address all correspondence and requests for reprints to: Onno E. Janssen, M.D., Division of Endocrinology, Department of Medicine, University of Essen, Hufelandstr. 55, 45122 Essen, Germany. E-mail: onno.janssen{at}uni-essen.de.

We present an unusual variant of T₄-binding globulin (TBG) found in a family from Allentown, Pennsylvania (TBG-AT). The heterozygous proposita presented serum total T₄ and TBG levels ranging from low to normal. TBG gene sequencing revealed a C-to-T substitution in codon –2 (CAC to TAC) leading to the substitution of the normal histidine by a tyrosine within the signal peptide. No mutation within the mature peptide was found. Allele-specific PCR confirmed the H(–2)Y mutation in the propositas mother and son. T₄-binding analysis of TBG in serum from the proposita and son showed normal affinity but reduced capacity when compared with the unaffected father. Heat stability and isoelectric focusing of TBG-AT were normal. In vitro expression of a recombinant TBG-AT in Xenopus oocytes revealed a diminished secretory efficiency and confirmed the normal binding affinity and heat stability of the small amount of secreted TBG-AT. This study has defined impaired cotranslational processing as a hitherto unrecognized cause of hereditary TBG deficiency.

This work was supported in part by grants from the National Institutes of Health (DK17050 and RR00050 to Sa.R.) and from the Deutsche Forschungsgemeinschaft (DFG Ja 671/1-3 to O.E.J.). Si.R. was supported by a training grant from the National Institutes of Health (DK07011).

Abbreviations: AT3, Antithrombin III; AT3-D, AT3-Dublin; CBG, corticosterone-binding globulin; ER, endoplasmic reticulum; PI, proteinase inhibitor; PI-Z, common Z mutation causing PI deficiency; SRP, signal recognition particle; TBG, T₄-binding globulin; TBG-AT, TBG-Allentown; TBG-N, normal TBG; TT₃, total T₃; TT₄, total T₄.

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