GENE SCREENING IN JAPANESE FAMILIES WITH COMPLETE DEFICIENCY OF THYROXINE-BINDING GLOBULIN DEMONSTRATES THAT A NUCLEOTIDE DELETION AT CODON-352 MAY BE A RACE-SPECIFIC MUTATION

OBJECTIVE Thyroxine-binding globulin (TBG) is a serum protein that tra nsports 75% of circulating thyroxine. Eleven naturally occurring mutat ions in the human TBG gene have been identified, ten of which alter th e properties of the molecule. Three of these mutations produce complet e deficiency of TBG (TBG-CD) and four are associated with a second mut ation in codon 283 (TBG-poly) which is polymorphic in some ethnic grou ps but, when present alone, does not alter the properties of the TBG m olecule. In this communication we investigate whether two unrelated Ja panese families with TBG-CD harboured the TBG-CDJ mutation in codon 35 2 associated with TBG-CD in families residing in more distant location s of the Japanese Islands. In addition we examined the possible associ ation with TBG-poly and its incidence in the Japanese population. DESI GN Mutant alleles were identified by amplification of genomic DNAs by the polymerase chain reaction, using allele-specific oligonucleotide p rimers. PATIENTS Eight family members and 25 normal subjects. MEASUREM ENTS Serum free thyroxine and TBG concentration were measured by a con ventional radioimmunoassay and a more sensitive enzyme immunoassay. Ge nomic DNAs were extracted from white blood cells and specific mutation s at codons 352 and 283 were identified by allele specific amplificati on. RESULTS Three males and three females, whose serum TBG levels were decreased, had mutations at codon 352 as hemizygous and heterozygous, respectively. This mutation was not present in the DNA of any of the related or unrelated subjects with normal TBG concentration. The prese nce of TBG-poly was demonstrated in only one heterozygous family membe r and in six out of 30 alleles (20%) in normal unrelated subjects. The frequency of this TBG polymorphism in the Japanese is similar to that of 16% reported in French Canadians. CONCLUSIONS We conclude that TBG -CDJ might be a prevalent cause of complete deficiency of thyroxine bi nding globulin in the Japanese and that TBG-poly probably appeared bef ore the divergence of human races.