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

Abstract

Complete T4-binding globulin deficiency (TBG-CD) 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.

Thyroxine-Binding Globulin Variant(TBG-Kumamoto): Identification of a Point Mutation and Genotype Analysis of Its Family.

“…Further investigations will be needed to examine this possibility. Both the TBG-Kumamoto reported herein and the complete TBG deficiency in Japanese families shown by Yamamori et al [9] had the mutation near the carboxy-terminus on exon 4. From the results of these studies, it is suggested that the amino acid residues near the carboxy-terminus may be responsible for the intracellular processing of the TBG molecule.…”

“…Blood samples from her children were not analyzed, since we could not obtain any collaboration with them because of their young age. It was concluded that TBG-Kumamoto was a different familial type of TBG deficiency from those reported previously [5][6][7][8][9][10][11][12].…”

“…More recently, gene analyses have been performed on families with partial or complete TBG deficiency [5][6][7][8][9][10][11][12]. To our knowledge, there are three different types of complete TBG deficiency in which gene analyses have been undertaken.…”

“…The first report was by Mori et al who showed that a single nucleotide substitution (CTA to CCA) in codon 227 was located in exon 2 and that the replacement of leucine by proline was related to the complete TBG deficiency (TBG-CD) in three of eight caucasian families of French Canadian origin [8]. The second report was prepared by Yamamori et al and showed that a single nucleotide deletion in the first base of codon 352 located in exon 4 was associated with TBG-CD in six Japanese families for a frameshift which led to the premature termination of translation [9]. Li terminal position in the polymerase chain reaction.…”

Sequence of a Variant Thyroxine-Binding Globulin(TBG) in a Family with Partial TBG Deficiency in Japanese(TBG-PDJ).

“…Thus, the prevalence of TBG-PD having the same mutation should be studied. For complete TBG deficiency, we found only one kind of mutation of the TBG gene, a single nucleotide deletion in exon 4 of the TBG gene, in 18 unrelated Japanese families living in various areas [12]. It is noted that the same mutation was reported in a family with TBG-PD by Shirotani et al in an abstract form [20].…”