Two novel variants in the thyroxine-binding globulin (TBG) gene behind the diagnosis of TBG deficiency.
OBJECTIVE
Search for germline mutations in the thyroxine-binding globulin (TBG) gene of two unrelated Portuguese females of Caucasian origin in whom the diagnosis of TBG deficiency was suspected because of suppressed TSH despite marginally low total thyroxine and tri-iodothyronine.


METHODS
Screening for germline mutations was conducted by non-radioactive PCR-SSCP analysis. The variants documented by this approach were characterized by sequencing. Moreover, in order to define whether they were mutations or polymorphisms we looked for the same variants analysing 100 alleles at random. To achieve this goal we used, alternatively, restriction analysis and the minisequencing method with an automated capillary electrophoresis system and fluorescent-labelled dideoxynucleotides.


CONCLUSIONS
Two novel variants, one in each patient, were identified. One, involved codon 23 (TCA-->TAA) and the other, codon 223 (CAA-->TAA). Analysis of 50 DNA samples, randomly chosen, revealed that all were homozygous for the wild variant at codon 23. One of them was heterozygous for the variant CAA-->TAA at codon 223. This sample was found to correspond to a Caucasian female in whom serum TBG proved to be not detected. Since both variants identified result in stop codons likely to induce truncated TBG proteins, they are probably responsible for the TBG phenotype observed in the individuals studied.
Domingues
Rita
R
Centro de Investigacao de Patobiologia Molecular and Servico de Endocrinologia do Instituto Portugues de Oncologia de Lisboa, Lisbon, Portugal.
Bugalho
Maria João
MJ
Garrão
António
A
Boavida
José Manuel
JM
Sobrinho
Luís
L
D001483:Base Sequence / Q000235:genetics; D003062:Codon / Q000235:genetics; D004247:DNA / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D008659:Metabolic Diseases / Q000175:diagnosis / Q000235:genetics; D008875:Middle Aged; D017354:Point Mutation / Q000235:genetics; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D013975:Thyroxine-Binding Proteins / Q000172:deficiency* / Q000235:genetics*
D003062:Codon; D013975:Thyroxine-Binding Proteins; D004247:DNA