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Complete Thyroxine-Binding Globulin (TBG) Deficiency in Two Families without Mutations in Coding or Promoter Regions of the TBG Genes: In Vitro Demonstration of Exon Skipping

Departments of Medicine (S.Reu., P.E.M., S.Ref.) and Pediatrics (S.Ref.), the J. P. Kennedy Jr. Mental Retardation Research Center (S.Ref.), and the Committee on Genetics (A.D., S.Ref.), The University of Chicago, Chicago, Illinois 60637; University of Mississippi Medical Center (G.W.M.), Jackson, Mississippi 39216; and University Clinic for Internal Medicine III (H.V.), A-1090 Vienna, Austria

Address all correspondence and requests for reprints to: Samuel Refetoff, The University of Chicago, 5841 South Maryland Avenue, Chicago, Illinois 60637. E-mail: . refetoff{at}medicine.bsd.uchicago.edu

Abstract

Inherited thyroxine-binding globulin (TBG) deficiency is caused by mutations in the TBG gene located on the X-chromosome. We now describe two families (K and H) with X-linked complete TBG deficiency without mutations in the coding or promoter regions of the TBG gene. The propositi of both families presented with euthyroid hypothyroxinemia and were found to have undetectable TBG in serum. Affected females had approximately half the normal serum TBG concentration except for one woman who also had undetectable TBG (family H). All four of her children (two boys and two girls) were affected.

Affected members of family K had no mutations in any of the five exons or in the minimal promoter region of the TBG gene. However, a G to A substitution, five base pairs downstream from exon 3, was associated to the phenotype of TBG deficiency (TBG-Jackson) and was not present in 100 normal alleles. In contrast to individuals without this mutation, no TBG mRNA could be detected in fibroblasts of the propositus, expressing solely TBG-Jackson. In vitro transcription of genomic DNA containing the mutant intron in an exon trapping system showed that this mutation, reducing the consensus value on the 5' donor splice site, affects the normal splicing process. The transcript of TBG-Jackson lacks exon 3 and is unstable. The deduced amino acid sequence has a frameshift and an early stop codon at position 325.

Affected subject of family H had no mutations in the TBG gene including all exons, all introns, the minimal promoter, and the 3' untranslated sequence. However, an intragenic A/G polymorphism (125 bp upstream from exon 2) was identified. It allowed us to confirm a cosegregation of the phenotype to the TBG gene and to show that the single female with complete TBG deficiency was homozygous for the polymorphic TBG allele. The cause of TBG deficiency in this family remains unknown.

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