Replacement of Leu²²⁷by Pro in Thyroxine-Binding Globulin (TBG) Is Associated with Complete TBG Deficiency in Three of Eight Families with This Inherited Defect*

Abstract

The T4-binding globulin (TBG) gene is a single copy located on the X-chromosome. Previous studies have failed to elucidate the molecular defect in individuals with complete TBG deficiency (TBG-CD). Indeed, no major deletions, insertions, or other rearrangements were observed in the TBG gene of six unrelated males with this defect. To clarify the molecular basis of TBG-CD, we have cloned and sequenced the TBG gene of an affected male (CD5) of French Canadian origin. The sequence of the exons encoding the mature protein, adjacent introns, and the promoter region revealed two nucleotide substitutions: CTA(Leu)----CCA(Pro) at codon 227 and TTG(Leu)----TTT(Phe) at codon 283. The Leu----Phe substitution, a relatively conservative replacement, is a TBG polymorphism present in 16% (3 of 19) of French Canadian males. It has no effect on the serum concentration or properties of the common type TBG (TBG-C). The new Leu----Pro substitution, which is predicted to alter the higher order of TBG structure, is probably responsible for the TBG-CD phenotype of the individual studied and two other families with TBG-CD. It possibly impairs TBG biosynthesis or secretion or perhaps alters TBG structure to such a degree that the molecule is not recognized by antibodies against native or denatured TBG and does not bind T4.

The evolutionary and integrative roles of transthyretin in thyroid hormone homeostasis

“…In the absence of clinical evidence of hypo-or hyperthyroidism, they are often uncovered by the fortuitous finding of abnormally high or low concentrations of total T4 in blood (Mori et al 1990). Normal levels of corticotropin-releasing hormone (CRH), and even its increase in response to stress, were observed in null mutants of another hormone-binding protein, namely CRH-binding protein (Karolyi et al 1999).…”

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

“…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.…”

“…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].…”

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

“…Like other TBG variants, the mutation found in TBG-PDJ was a nucleotide substitution at codon 363, replacing proline with leucine. It is of interest to note that the replacement of leucine by proline was reported in one family with complete TBG deficiency (TBG-CD5) [17]. Since proline is an aromatic amino acid which is thought to cause a helix breakage, the mutation Pro to Leu or vice versa may influence the tertiary structure of the TBG molecule.…”