Two Novel Mutations in the Serpina7 Gene Are Associated with Complete Deficiency of Thyroxine-Binding Globulin

Abstract

Background: Thyroxine-binding globulin (TBG) is the main transport protein for T₄ in blood. Until now, 22 mutations leading to complete TBG deficiency (TBG-CD) have been reported. Objective: We report two mutations associated with TBG-CD found in patients from Andrews, S.C., USA (TBG-CD-Andrews), and Berlin, Germany (TBG-CD-Berlin). Methods: Automated chemiluminescence immunoassays were used for the determination of TSH, free and total T₄ and T₃ (fT₄, TT₄, TT₃) and TBG. Direct DNA sequencing was used to identify the TBG mutations in the propositi. Results: TBG-CD-Andrews was found in a 1-month-old boy who was euthyroid with normal TSH and fT₄, but reduced TT₄, indicating TBG deficiency. TBG was not detectable, confirming TBG-CD. No mutation in the coding region and the promoter of the TBG gene was found, but a single nucleotide substitution in intron 1 disrupts the donor splice site of exon 0 (IVS1+2T>C). Another mutation was found in an 11-year-old boy. He was also euthyroid with normal fT₄ and TSH. However, TT₄ and TT₃ were low, suggesting TBG-CD. Sequencing revealed a 79-nucleotide deletion, ranging from intron 3 into exon 3. Conclusion: We report two novel mutations of the TBG gene associated with TBG-CD. Whereas most TBG-CDs are caused by small deletions, in TBG-CD-Andrews the disruption of a donor splice site was detected, whilst in TBG-CD-Berlin the largest deletion in the Serpina7 gene to date was found.