title: Complete deficiency of thyroxine-binding globulin (TBG-CD Buffalo) caused by a new nonsense mutation in the thyroxine-binding globulin gene.
abstract: 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 this 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 serum and two obligatory heterozygote females with borderline low values. Sequencing of the exons encoding the mature protein, adjacent introns and the promoter region, revealed differences in two nucleotides compared to the common type TBG, both located in exon 3: TGG (Trp) TAG (Stop) at codon 280 and TTG (Leu) TTT (Phe) at codon 283. The former mutation was not previously described and the latter is a polymorphic variant. Genotyping revealed that the two affected males had the mutant and polymorphic allele and their obligatory heterozygous mothers have each a common type and a mutant allele associated with the polymorphic variant. The mutant TBG Trp280Stop causes premature termination of translation that results in the production of a truncated protein 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.
authors.affiliation: Department of Medicine, The University of Chicago, Illinois 60637, USA.
authors.forename: G A
authors.initials: GA
authors.lastname: Carvalho
authors.forename: R E
authors.initials: RE
authors.lastname: Weiss
authors.forename: A O
authors.initials: AO
authors.lastname: Vladutiu
authors.forename: S
authors.initials: S
authors.lastname: Refetoff
mesh_terms: D000328:Adult; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation / Q000502:physiology*; D010375:Pedigree; D013975:Thyroxine-Binding Proteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism
chemical_list: D013975:Thyroxine-Binding Proteins; C111966:thyroxine-binding globulin-Buffalo; D004247:DNA