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

Abstract

Abstract. Thyroxine-binding globulin (TBG) is the major thyroid hormone transport protein. Several inherited TBG variants resulting in partial or complete TBG deficiencies have been shown to be caused by either one or two nucleotide substitutions, or one nucleotide deletion in the coding regions of the TBG gene. In this report, a Japanese female patient (proband) with hyperthyroid state, whose lower TBG levels did not return to normal under the euthyroid state after treatment was examined. Genomic DNA samples from the proband with thyroxine-binding globulin deficiency (termed TBG-Kumamoto) and her family were subjected to the polymerase chain reaction, and the generated DNA fragments were sequenced. A single nucleotide substitution in the codon for the amino acid 363 of native TBG molecule (CCT to CTT) was found, resulting in the replacement of proline by leucine. It was revealed that the proband was a heterozygote and her father was a hemizygote. The mutation was confirmed by the allele-specific amplification of genomic DNAs from the proband and her father using oligonucleotide primers of normal or mutant residues at the 3' position in the polymerase chain reaction. These results indicate that the abnormality of TBG-Kumamoto is the consequence of this mutation. Genetically, this point mutation observed in TBG-Kumamoto might be classified as a new type of TBG deficiency.

A Novel Mutation Causing Complete Thyroid Binding Globulin Deficiency (Tbg-Cd Mia) In A Male With Coexisting Graves Disease

“…Of the 45 distinct mutations identified in the TBG gene (12) 4 have been found in patients with Graves’ disease: TBG-Kumamoto (13), TBG-Japan (16), TBG-A64D (15), and TBG-Mia (this report). In regions of sufficient iodine consumption, the lifetime prevalence of Graves’ disease is 1:200 (21) while familial TBG-deficiency occurs in 1:3000 newborns (2); thus the expected lifetime prevalence of these two conditions occurring in the same individual is 1:600,000.…”

First report of inherited thyroxine-binding globulin deficiency in Iran caused by a known de novo mutation in SERPINA7

“…In TBG-CD serum concentration for TBG is usually below 5 mg/L, while in TBG-PD it overlaps the normal concentration in heterozygote females. To date, about 45 mutations have been described to cause TGB deficiency, mostly in coding regions [5] , [6] , [8] , [9] , [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] , [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] ( Table 2 ) (recently reviewed by Pappa et al [31] ). There does not appear to be a “hot spot”; missense and nonsense mutations are scattered in coding regions and splice sites.…”

Thyroxine-Binding Globulin: Organization of the Gene and Variants

“…Murata et al [63] and Takeda et al [50]: (7) Mori et al [28] and Janssen et al [ 10]: (8) Mori et al [28]: (9) Takamatsu and Refctoff [64] and Janssen et al [65]: (10) Takamatsu et ai. [58] and Bertenshaw et al [66]: (11) Yamamori et al [53] and Miura et al [67]; (12) Shirotani et al [68] and Miura et al [69]. [Reproduced from 70. chapt 36], Fig.…”