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Nucleotide Deletion Resulting in Frameshift as a Possible Cause of Complete Thyroxine-Binding Globulin Deficiency in Six Japanese Families

First Department of Internal Medicine, Nagoya University School of Medicine Aichi, Japan
The Department of Endocrinology and Metabolism, Research Institute of Environmental Medicine, Nagoya University Aichi, Japan
The Fourth Department of Internal Medicine, Aichi Medical University Aichi, Japan

Address all correspondence and requests for reprints to: Yuichi Mori, M.D., First Department of Internal Medicine, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466 Japan.

Complete T₄-binding globulin deficiency (TBGCD) is inherited in an X-linked fashion. A nucleotide substitution has been shown to cause this hereditary condition in Caucasians of French Canadian origin. Heterogeneity in molecular mechanisms for TBG-CD has also been reported.

Genomic DNA from a Japanese male exhibiting TBG-CD was subjected to polymerase chain reaction, and the generated DNA fragments were sequenced. A single nucleotide deletion was found in the first base of the codon for amino acid 352 of the common-type TBG molecule. This mutation causes a frameshift in translation and premature termination. Compared with common-type TBG, the mutated polypeptide results in 1) 22 different amino acids on its carboxy-terminus, 2) a 22-amino acid truncation, and 3) the absence of a potential N-linked glycosylation site. These alterations may lead to profound changes in the secondary and tertiary structures of the molecule.

To ascertain the presence of this nucleotide deletion in the genomic DNA of affected subjects, a mutated primer was designed which together with the nucleotide deletion produced a new endonuclease restriction site in the polymerase chain reaction fragment. Results revealed the presence of the mutation in genomic DNA of the subject, and his mother was shown to have both mutant and normal alleles. The same mutation was also detected in five other unrelated families carrying TBG-CD. This mutation may be frequent in Japanese subjects with TBG-CD.

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