COMPLETE DEFICIENCY OF THYROXINE-BINDING GLOBULIN (TBG-CD BUFFALO) CAUSED BY A NEW NONSENSE MUTATION IN THE THYROXINE-BINDING GLOBULIN GENE

Complete deficiency of thyroxine-binding globulin (TBG-CD) is defined as undetectable TBG in the serum of affected hemizygous subjects. Four distinct mutations have been identified in the TBG gene that cause th is phenotype: TBG-CDJ (Japan), TBG-CD6, TBG-CD5, and TBG-CD Yonago. We report a new mutation producing TBG-CD phenotype. Five family members were studied, including two affected males with undetectable TBG in s erum and two obligatory heterozygote females with borderline low value s. Sequencing of the exons encoding the mature protein, adjacent intro ns and the promoter region, revealed differences in two nucleotides co mpared to the common type TBG, both located in exon 3: TGG (Trp) --> T AG (Stop) at codon 280 and TTG (Leu) --> TTT (Phe) at codon 283. The f ormer mutation was not previously described and the latter is a polymo rphic variant. Genotyping revealed that the two affected males had the mutant and polymorphic allele and their obligatory heterozygous mothe rs have each a common type and a mutant allele associated with the pol ymorphic variant. The mutant TBG Trp280Stop causes premature terminati on of translation that results in the production of a truncated protei n that lacks 116 carboxyl terminal amino acids. The latter is believed to be responsible for the TBG-CD either because the aberrant protein is not secreted or because of reduced abundance of its mRNA.