Alternative titles; symbols
HGNC Approved Gene Symbol: SERPINA7
Cytogenetic location: Xq22.3 Genomic coordinates (GRCh38) : X:106,032,435-106,038,727 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq22.3 | [Thyroxine-binding globulin QTL] | 300932 | X-linked | 3 |
Thyroxine-binding globulin (TBG) is the major thyroid hormone transport protein in serum (summary by Mori et al., 1995).
Flink et al. (1986) used antibodies against TBG to screen a human liver expression library and identified a 1.46-kb clone that encodes nearly the complete amino acid sequence, beginning at amino acid 17, of the mature protein. To complete the protein sequence, this cDNA clone was used to identify a genomic clone coding for TBG in a human X-chromosome library. Unexpectedly, the nucleotide sequence of TBG was found to be closely homologous to those encoding the plasma serine antiproteases alpha-1-antichymotrypsin (107280) and alpha-1-antitrypsin (107400). There was little overall homology, however, between TBG and transthyretin (176300), the other major thyroxine-binding protein of human plasma.
Kambe et al. (1988) found 2 TBG mRNA species and suggested that these may be produced by alternative processing and polyadenylation at 2 different sites.
Jirasakuldech et al. (2000) reported a characteristic serpin cleavage product of TBG in sepsis sera. At 49 to 50 kD, the TBG remnant is 4 to 5 kD smaller than the intact protein and is the same molecular mass as a TBG cleavage product produced by incubation with polymorphonuclear elastase (130130). Incubation with polymorphonuclear leukocytes also produces the 49- to 50-kD remnant, and this proteolysis is stimulated by zymosan activation. Polymorphonuclear cell cleavage of TBG increases the ratio of free/bound T4. In vitro cleavage of TBG by elastase also increases free/bound T4. The authors concluded that their findings are consistent with the hypothesis that serine proteases present at inflammatory sites cleave TBG, releasing its hormonal ligands.
Hill et al. (1982) showed that a human recombinant DNA sequence corresponding to TGB was X-specific by hybridization to DNA from a human-mouse somatic cell hybrid containing X as the only human chromosome. The cloned sequence was located on Xq distal to Xq13 by study of a somatic cell hybrid with a partial human X chromosome.
Using DNA blot hybridization, Flink et al. (1986) detected a single-copy TBG gene located on the long arm of the X chromosome.
By use of a cDNA clone for analysis of somatic cell hybrids and for in situ hybridization, Trent et al. (1987) assigned the TBG locus to Xq21-q22. Their evidence indicated the presence of a single gene, located on the X chromosome.
The TBG locus was one of those mapped on Xq by the method of telomere-associated chromosome fragmentation (TACF). The method involves the nontargeted introduction of cloned telomeres into mammalian cells. Farr et al. (1992) used TACF to generate a panel of somatic cell hybrids with nested terminal deletions of the long arm of the human X chromosome, extending from Xq26 to the centromere. Recovery of the end clones by plasmid rescue produced a telomeric marker for each cell line, and partial sequencing allowed the generation of sequence tagged sites (STSs). Farr et al. (1992) determined the following order of markers on the basis of the deletion panel: cen--AR--PGK1P1--RPS4X--(XIST/DXS441/PGK1)-- DXS26--CHM----GLA--(TBG/DXS456/COL4A5)--(LAMP2/DXS424)--HPRT. Since both GLA and COL4A5 are in Xq22, it seems likely that TBG is likewise in Xq22.
By fluorescence in situ hybridization, Mori et al. (1995) localized the TBG gene to Xq22.2.
Two qualitative TBG variants occur in particular populations: TBG-A (314200.0002), found in 40% of Australian aborigines, has reduced affinity for thyroxine and triiodothyroxine and increased susceptibility to inactivation by heat or acid; it is, however, indistinguishable immunologically and in isoelectric focusing from the normal (Dick and Watson, 1981; Murata et al., 1985). TBG-S (314200.0004), found in blacks, Eskimos, Melanesians, Polynesians and Indonesians, but not in Caucasians, shows a cathodal (slow) shift (5-10%) on isoelectric focusing (Daiger et al., 1981; Kamboh and Kirwood, 1984; Grimaldi et al., 1983). The frequency of the slow allele in American blacks, 0.11, means that this is a potentially useful marker for X-chromosome mapping. TBG-A and TBG-S appear to have a change in the structure of the TBG molecule.
Murata et al. (1986) stated that 5 types of inherited TBG variants have been described. All are X-linked. Three that are thought to be quantitative variants are widely distributed. The TBG indeed seems to be completely absent in the first form; in the second and third form, TBG appears to be physically, antigenically, and functionally normal. Alteration in the rate of TBG synthesis appears to be responsible since rates of degradation are normal.
Murata et al. (1986) described a 'new' rare form of X-linked TBG defect (TBG-Gary) in a family with TBG deficiency (see 300932): the abnormal TBG had no demonstrable thyroxine-binding activity and high serum levels of denatured TBG. Apparently the mutant protein was abnormally vulnerable to degradation followed by removal. Mori et al. (1989) demonstrated that TBG-Gary carries a T to A transversion in the TBG gene, resulting in an ile96-to-asn substitution (314200.0008).
Takamatsu and Refetoff (1986) described a sixth type of inherited variant TBG, TBG-Chicago (314200.0010), which differed from all 5 of the previously reported variants in being markedly resistant to heat denaturation. The others have a variable degree of increased sensitivity to denaturation by heat and by acid, including. One of these is frequent in Australian aborigines and another is frequent in blacks and Pacific islanders; the others, including the heat-stable TBG-Chicago, are rare variants. Inheritance of TBG-Chicago appeared to be X-linked.
Takamatsu et al. (1987) measured denatured TBG in sera from 32 unrelated families with inherited TBG deficiency. High levels were found in serum samples from 2 of 16 families with partial TBG deficiency. Further studies showed that these 2 families had variant TBGs with alteration in both stability and isoelectric focusing patterns, thus indicating the presence of structural gene mutations. The mutations in these 2 families--TBG-Quebec (314200.0005) and TBG-Montreal (314200.0006)--were distinguishable.
Sarne et al. (1989) added another TBG abnormality to the 4 rare ones already described--Gary, Quebec, Montreal, and Chicago. The new variant, TBG-San Diego, showed decreased affinity for thyroxine and triiodothyronine.
Luckenbach et al. (1990) found no charge variants of TBG in a sample of 840 unrelated persons living in southwestern Germany. Results from a family with quantitative TBG deficiency supported X-linked inheritance.
Janssen et al. (1992) reviewed the molecular basis of 9 inherited TBG defects of which 8 were associated with partial or complete TBG deficiency. Nucleotide substitutions were found in cases of partial TBG deficiency, whereas substitutions or deletions were found in the complete deficiency variants. Hershkovitz et al. (1995) found an unusually high prevalence of TBG deficiency among Bedouin newborns in the Negev area of southern Israel. Preliminary studies in 4 of the TBG-deficient newborns indicated that at least 2 distinct mutations may coexist among the Bedouin: one associated with complete deficiency of TBG and the other associated with partial deficiency.
Reutrakul et al. (2001) found 3 novel mutations in 3 different families producing complete TBG deficiency. The proposita of a family from Harwichport was a female with XO Turner syndrome (Refetoff and Selenkow, 1968) who expressed only the mutant TBG allele. Her TBG sequence had a 19-nucleotide deletion in the distal portion of exon 4 (314200.0016), causing a frameshift and a premature stop at codon 384 of the mature protein. The propositi of 2 other families with complete TBG deficiency were 7-month-old and 3-week-old male infants who were identified because of low serum T4 levels detected during neonatal screening. Sequencing of the TBG gene of the former revealed a single-nucleotide deletion, a G at position 2690 in exon 3 (314200.0017). This led to an alteration of the amino acid sequence starting at codon 283 and a premature stop at codon 301. The latter propositus had a deletion of the first nucleotide of exon 4, a G at position 3358 (314200.0018). This led to a frameshift and a premature stop at codon 374. As in the case of complete TBG deficiency J (314200.0009), which has also a nucleotide deletion but downstream (position 3421) and a stop at codon 374, these 2 TBG mutants undoubtedly have a defect in intracellular transport and therefore fail to be secreted. This explains the lack of TBG in the hemizygous affected subjects.
Reutrakul et al. (2002) reported 2 families, designated K and H, with X-linked complete TBG deficiency without mutations in the coding or promoter regions of the TBG gene. The propositi of both families presented with euthyroid hypothyroxinemia and were found to have undetectable TBG in serum. Affected females had approximately half the normal serum TBG concentration except for 1 woman from family H who also had undetectable TBG. All 4 of her children (2 boys and 2 girls) were affected. Affected members of family K had no mutations in any of the 5 exons or in the minimal promoter region of the TBG gene. However, a G-to-A transition, 5-bp downstream from exon 3 (314200.0019), was associated with the phenotype of TBG deficiency (TBG-Jackson) and was not present in 100 normal alleles. In contrast to individuals without this mutation, no TBG mRNA could be detected in fibroblasts of the propositus, expressing solely TBG-Jackson. In vitro transcription of genomic DNA containing the mutant intron in an exon-trapping system showed that this mutation, reducing the consensus value on the 5-prime donor splice site, affected the normal splicing process. The authors concluded that the transcript of TBG-Jackson lacks exon 3 and is unstable. The deduced amino acid sequence has a frameshift and an early stop codon at position 325. No mutation was identified in the TBG gene in family H, and the cause of TBG deficiency in this family was undetermined.
In 3 Polish sibs with complete TBG deficiency, Lacka et al. (2007) identified hemizygosity for a 1-bp deletion in the TBG gene (314200.0020).
TBG Excess
Although the molecular bases of TBG deficiency had been confirmed on the basis of many mutations, the molecular basis of TBG excess was not determined until Mori et al. (1995) demonstrated gene amplification (314200.0011) as the basis in 2 Japanese families. In 1 family, the serum TBG levels were 3-fold the normal value and in the second family they were 2-fold. The TBG molecule had normal properties in terms of heat stability and isoelectric focusing pattern. The sequence of the coding region and the promoter activity of the TBG gene were also indistinguishable between hemizygotes and normal subjects. In 3 additional Japanese families, 1 with familial and 2 with sporadic TBG excess, Mori et al. (1999) found results compatible with 3 copies of the TBG gene on the affected X chromosome. The mothers of the sporadic cases had the same TBG gene dosage as normal females, suggesting that de novo gene duplication arose in gametes. Amplification of the TBG gene was not recognized in these 3 families by in situ hybridization of prometaphase chromosomes.
X-linked TBG polymorphism occurs also in baboons, according to Lockwood et al. (1984), who could not find such in several other primate species, however.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
Thorson et al. (1966) presented evidence for 2 thyroid-binding globulins, thus creating the possibility of appreciable genetic heterogeneity in both high and low TBG.
In a French Canadian male with complete TBG deficiency (300932), Mori et al. (1990) found a CTA-to-CCA change at codon 227, leading to substitution of proline for leucine. In addition, a TTG (leu)-to-TTT (phe) change at codon 283 was found. The leu-to-phe substitution is a TBG polymorphism present in about 16% of French Canadian males (see 314200.0003). It has no effect on the serum concentration or properties of the common type of TBG (TBG-C). Janssen et al. (1992) referred to this variant as CD5 for 'complete deficiency 5.'
Takeda et al. (1989) showed that the sequence of the gene for TBG-A present in Australian aborigines differs at 2 positions from that of the normal TBG allele: ACA (threonine) for GCA (alanine) at codon 191 and TTT (phenylalanine) for TTG (leucine) at codon 283. They concluded that the abnormal properties of TBG-A are due to substitution of alanine for threonine at residue 191. The biochemical properties of TBG(phe283) in 1 patient who had only this change were indistinguishable from those of normal TBG(leu283); see 314200.0003. The ala191-to-thr variant has been designated TBG-A or TBG-Aborigine.
This polymorphism, TBG-P, is found in several populations including French Canadians (Mori et al., 1990) and Australian aborigines (Takeda et al., 1989). Bertenshaw et al. (1991) found this polymorphism in the proband with TBG-Quebec; see 314200.0005. This polymorphism is a TTG/TTT variation at codon 283. Janssen et al. (1992) pointed out that 3 of the 7 examples of partial or complete TBG deficiency characterized at the molecular level carried the phe283 form of the polymorphism. These are TBG-Aborigine (314200.0002), complete TBG deficiency 5 (CD5; 314200.0001), and TBG-Quebec (314200.0005). In addition to the mutation unique to each variant, they all share the substitution of leucine-283 with phenylalanine. The latter substitution has also been found alone in a TBG with normal properties. Since the phe283 variant does not have a high allele frequency, its association with other mutations may not be fortuitous.
The electrophoretically slow variant of TBG (TBG-S) is found in 4 to 12% of black and Pacific Island populations. It is detected on isoelectric focusing by the characteristic cathodal shift of all its isoforms, suggesting that the difference resides in the core protein. In addition, TBG-S is slightly more thermolabile, which explains why persons expressing this variant have, on the average, lower serum TBG, and thus reduced T4, concentrations. By sequencing the 4 coding regions and all intron/exon junctions of the TBG gene in 2 American black men with the TBG-S variant, Waltz et al. (1990) showed that the variant is due to a change in codon 171 from GAC to AAC, resulting in replacement of the usual aspartic acid by asparagine. Since the negative charge provided by the aspartic acid residue is lost when replaced by the neutral asparagine, this substitution is responsible for the cathodal shift and slower electrophoretic mobility of TBG-S. Whether the TBG-S phenotype observed in Pacific Island populations is caused by the same mutation has not yet been determined.
Takamatsu et al. (1987) described a family which came to medical attention through the province of Quebec's screening program for neonatal hypothyroidism, which, at that time, was based on the measurement of total serum thyroxine. Affected family members were found to have partial TBG deficiency (300932). The variant, called TBG-Quebec, has cathodal shift on isoelectric focusing, reduced affinity for thyroxine, and markedly reduced stability. The latter property of the variant molecule was probably responsible for the partial TBG deficiency. By sequencing the entire coding region and the exon-intron junctions of TBG-Quebec, Bertenshaw et al. (1991) found 2 nucleotide substitutions: one, located in exon 3, changed the normal codon 283 of TTG (leucine) to that of TTT (phenylalanine); the other, in exon 4, resulted in the replacement of histidine-331 (CAT) by tyrosine (TAT). The substitution in codon 283 is a polymorphism (314200.0003); thus, it appeared that the replacement of histidine-331 by tyrosine was responsible for the observed altered properties of TBG-Quebec. Whether substitution of both amino acids was necessary for expression of the variant phenotype had not yet been determined.
In a family from Montreal with an affected male with partial TBG deficiency (300932), Janssen et al. (1991) showed that a change of codon 113 from GCC to CCC resulted in replacement of alanine by proline. The variant is designated TBG-Montreal.
In 3 generations of a family of English origin, Li et al. (1991) found 5 males hemizygous for a unique mutation in the TBG gene as well as 2 heterozygous carriers. The hemizygous males showed complete TBG deficiency (300932). The mutation was deletion of a single nucleotide in codon 165 converting GTT (valine) to GTG (also valine) and causing a val166-to-trp and gly167-to-val change through frameshift and a premature leu168-to-ter. Presumably, a truncated nonfunctional gene product of 167 amino acids resulted in place of the normal 395 residues. This variant was referred to as CD6 for 'complete deficiency 6' by Janssen et al. (1992).
Mori et al. (1990) demonstrated that TBG-Gary carries an ATC-to-AAC transversion at codon 96, which results in the replacement of the normal isoleucine by asparagine. This creates a new potential site for N-linked glycosylation (asn-cys-ser). The addition of a carbohydrate chain would cause an increase in negative charge of all TBG isoforms producing the anodal shift of all bands as observed by IEF of TBG-Gary.
In 6 Japanese families with complete TBG deficiency (300932), Yamamori et al. (1991) found a frameshift caused by deletion of a single nucleotide in codon 352. Change of CTT to TT in codon 352 resulted in a frameshift and a premature stop codon at position 374. This resulted in the synthesis of a molecule with 22 different amino acids followed by the deletion of another 22 amino acids at its carboxyl terminus. See 314200.0012. Okamoto et al. (1996) encountered a female manifesting complete deficiency of TBG although she was only heterozygous for a mutation that causes complete deficiency in males. The X-chromosome inactivation status was evaluated in family members using the PGK gene located at Xq13. Three TBG-CDJ (Japanese complete deficiency) heterozygotes and 1 unaffected female, all confirmed to be PGK heterozygotes for a polymorphic BstXI site, were analyzed. Only the heterozygous female with complete deficiency was shown to have undergone selective inactivation of the X chromosome carrying the normal (or common) TBG allele. Moreover, the X chromosome with the common form of TBG was suggested to be inactivated selectively from the linkage of PGK and TBG alleles recognized in 8 of 9 family members. In these studies, the BstXI site was examined after digestion with the methylation-sensitive enzyme HpaII.
Janssen et al. (1995) demonstrated that the heat-resistant variant TBG-Chicago has a substitution of the normal tyrosine-309 with phenylalanine. When expressed in Xenopus oocytes, the mutant TBG was secreted into the culture medium in a normal manner and could not be distinguished by gel electrophoresis. TBG-Chicago showed no significant difference in T(4) binding affinity from normal. On the other hand, the half-life values of denaturation of normal TBG and TBG-Chicago were 7 and 132 minutes, respectively.
In a Japanese family with TBG excess (300932), Mori et al. (1995) found evidence that the TBG gene was present in duplicate in hemizygous males; in a second family, they presented evidence that the gene was present in triplicate in males with inherited TBG excess. Thus, gene amplification was the apparent basis.
Inagaki et al. (1996) determined the prevalence of 2 previously detected TBG gene mutations. These were a single nucleotide deletion in codon 352 (CTT to TT) (314200.0009) and a substitution in codon 363 changing CCT (pro) to CTT (leu) (Miura et al., 1993) in Japanese males with complete and partial TBG deficiency, respectively. They investigated the prevalence of both mutations among 50 unrelated Japanese subjects with complete or partial TBG deficiency from various areas of the Japanese Archipelago. All 30 males manifesting complete TBG deficiency and all 4 females manifesting partial TBG deficiency were hemizygous or heterozygous for the nucleotide deletion in codon 352, respectively. All 16 males with partial TBG deficiency (300932) were hemizygous for the P363L mutation. They concluded that these 2 TBG mutations may account for most or all Japanese cases of TBG deficiency.
Carvalho et al. (1998) reported a family with complete deficiency of thyroxine-binding globulin (300932). Five members of the family were studied; 2 males had undetectable TBG and 2 obligate heterozygous females had borderline low values of TBG. Sequencing revealed a 2680G-A transition in the TBG gene, resulting in a trp280-to-ter substitution (TBG-Buffalo), and the leu283-to-phe polymorphism (314200.0003). The 2 affected males had the mutant and the polymorphic allele, and their obligate heterozygous mothers had each a wildtype and a mutant allele associated with the polymorphic variant.
Carvalho et al. (1998) reported a proband who was treated for over 20 years with L-T4 due to fatigue associated with a low concentration of serum total T4. Fifteen family members were studied showing low total T4 inherited through an X-linked mode, and affected males had undetectable TBG in serum (300932). Sequencing of the entire coding and promoter regions of the TBG gene revealed no abnormality. However, an A-to-G transition was found at -2 of the 3-prime splice site of intron 2 that produced a new HaeIII restriction site and cosegregated with the TBG complete deficiency phenotype. By sequencing exons 1 to 3 of TBG cDNA reverse transcribed from mRNA of skin fibroblasts from an affected male, the authors confirmed the A-to-G transition at -2 that changed the conserved AG of the 3-prime splice site to GG. This change resulted in the insertion of a G in exon 2 that caused a frameshift and a premature stop at codon 195, resulting in a truncated TBG protein lacking 201 amino acids. Carvalho et al. (1998) referred to the resulting TBG-CD variant as 'TBG-CD Kankakee.'
A high prevalence of complete TBG deficiency (300932) has been reported among the Bedouin population in the Negev (southern Israel). Miura et al. (2000) reported a novel single mutation causing complete TBG deficiency due to a deletion of the last base of codon 38 (exon 1), which led to a frameshift resulting in a premature stop at codon 51 and a presumed truncated peptide of 50 residues. This variant of TBG (TBG-CD-Negev) was found among all of the patients studied. The authors concluded that a single mutation may account for TBG deficiency among the Bedouins in the Negev.
In the patient with complete TBG deficiency (300932) and Turner syndrome described by Refetoff and Selenkow (1968), Reutrakul et al. (2001) found a 19-nucleotide deletion in exon 4 of the TBG gene, from position 3515 to 3524. Reutrakul et al. (2001) stated that this was the largest deletion described to that time. The mutation caused a frameshift, leading to the substitution of 2 amino acids and a premature stop (TGA) at codon 384, a deletion of 12 amino acids. Structural analysis showed that this modification results in removal of beta-strand s5B from the core of the TBG molecule, implicating a severe folding defect. The authors referred to this family, which originated from Harwichport, as TBG-CDH.
In the propositus of a family (TBG-CD7) with TBG deficiency (300932), a 7-month-old male identified because of low serum T4 levels through neonatal screening, Reutrakul et al. (2001) found a 1-bp deletion in the TBG gene. The deletion of a G at position 2690 in exon 3 caused a leu283-to-phe alteration and a frameshift downstream, leading to a premature stop at codon 301. The child demonstrated complete TBG deficiency, and his mother, partial deficiency.
In a family (TBG-CD8) with complete TBG deficiency (300932), Reutrakul et al. (2001) found a 1-bp deletion in the TBG gene: deletion of a G at position 3358, which is the first nucleotide of exon 4. This deletion led to a frameshift and premature stop at codon 374.
In affected members of their family K with complete TBG deficiency (300932), Reutrakul et al. (2002) identified a G-to-A transition 5-bp downstream from exon 3 in the TBG gene that was associated with TBG deficiency (TBG-Jackson). The mutation was not present in 100 normal alleles. In contrast to individuals without this mutation, no TBG mRNA could be detected in fibroblasts of the propositus, expressing solely TBG-Jackson. In vitro transcription of genomic DNA containing the mutant intron in an exon-trapping system showed that this mutation, reducing the consensus value on the 5-prime donor splice site, affected the normal splicing process. The authors concluded that the transcript of TBG-Jackson lacks exon 3 and is unstable. The deduced amino acid sequence has a frameshift and an early stop codon at position 325.
In 3 Polish sibs with complete TBG deficiency (300932), Lacka et al. (2007) identified hemizygosity for a 1-bp deletion (c.1711delG) in exon 2 of the TBG gene predicted to result in a frameshift and premature termination at codon 206. The mutation was identified by direct sequencing of the TBG gene, and the mother was heterozygous for the mutation. The 3 sibs had undetectable serum thyroxine-binding globulin.
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