A novel mutation causing complete deficiency of thyroxine binding globulin.

OBJECTIVE

Thyroxine binding globulin (TBG) is a serum protein that transports thyroxine. Three naturally occurring mutations have been reported to produce complete deficiency of TBG (TBG-CD). The first to be reported was TBG-CD5 in caucasian families of French-Canadian origin and consists of substitutions in exons 2 and 3. TBG-CD of English ethnic origin (TBG-CD6) is characterized by a thymine deletion in codon 165 (exon 1). In Japanese families with TBG-CD (TBG-CDJ), a variant has been characterized with a deletion of the first base of the codon for amino acid 352 (exon 4) in the common type TBG. In this communication we report a new type of TBG-CD in a family of Japanese ethnic origin that is characterized by a single nucleotide substitution in place of two nucleotides in exon 1. This is an uncommon mutation which we have been unable to find in other genes.

DESIGN

Exons of the TBG gene amplified by the polymerase chain reaction (PCR) were subcloned and sequenced. To examine for the presence of the same mutation in potentially affected individuals, we performed PCR using primer-directed mutagenesis or allele-specific amplification.

PATIENTS

The index case was of Japanese ethnic origin, and was diagnosed as having TBG deficiency on the basis of undetectable serum TBG. The patient consented to this evaluation and the protocol was in accordance with IRB standards.

MEASUREMENTS

Serum thyroid hormones, thyrotrophin binding inhibitory immunoglobulin and TBG concentrations were measured by conventional radio-immunoassay. Genomic DNA was extracted from white blood cells.

RESULTS

In the index case exons 2, 3 and 4 were normal, but nucleotides 144 (cytosine) and 145 (thymine) in exon 1 were substituted with a single base (adenine) which induced a frame shift in the reading frame, resulting in an early stop codon at codon 51. The patient and his daughters were confirmed as having this mutation using primer-directed mutagenesis or allele-specific amplification.

CONCLUSIONS

We have described a novel mutation in the TBG gene in a Japanese family. This results in a frame shift and premature stop codon, and was associated with undetectable serum TBG in the index case.