COMPLETE THYROXINE-BINDING GLOBULIN (TBG) DEFICIENCY PRODUCED BY A MUTATION IN ACCEPTOR SPLICE-SITE CAUSING FRAMESHIFT AND EARLY TERMINATION OF TRANSLATION (TBG-KANKAKEE)

Fourteen T-4-binding globulin (TBG) variants have been identified at t he gene level. They are all located in the coding region of the gene a nd 6 produce complete deficiency of TBG (TBG-CD). We now describe the first mutation in a noncoding region producing TBG-CD. The proband was treated for over 20 yr with L-T-4 because of fatigue associated with a low concentration of serum total T-4. Fifteen family members were st udied showing low total T-4 inherited as an X chromosome-linked trait, and affected males had undetectable TBG in serum. Sequencing of the e ntire coding region and promoter of the TEG gene revealed no abnormali ty. However, an A to G transition was found in the acceptor splice jun ction of intron II that produced a new HaeIII restriction site cosegre gating with the TBG-CD phenotype. Sequencing exon 1 to exon 3 of TBG c omplementary DNA reverse transcribed from messenger RNA of skin fibrob lasts from an affected male, confirmed a shift in the ag acceptor spli ce site. This results in the insertion of a G in exon 2 and causes a f rameshift and a premature stop at codon 195. This early termination of translation predicts a truncated TBG lacking 201 amino acids.