Alternative titles; symbols
HGNC Approved Gene Symbol: TSHB
Cytogenetic location: 1p13.2 Genomic coordinates (GRCh38): 1:115,029,826-115,034,309 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p13.2 | Hypothyroidism, congenital, nongoitrous 4 | 275100 | Autosomal recessive | 3 |
Thyroid-stimulating hormone (TSH) is a noncovalently linked glycoprotein heterodimer and is part of a family of pituitary hormones containing a common alpha subunit (TSHA; see 118850) and a unique beta subunit that confers specificity (summary by Hayashizaki et al., 1985).
Using bovine TSHB cDNA as probe, Hayashizaki et al. (1985) cloned TSHB from human liver and leukocyte genomic DNA libraries. Human TSHB encodes a deduced protein consisting of a 20-amino acid signal sequence, a mature protein of 112 amino acids, and a C-terminal extension of 6 hydrophobic amino acids. Wondisford et al. (1988) also cloned the human TSHB gene.
Wondisford et al. (1988) determined that the TSHB gene contains 3 exons, the first of which is noncoding. The rat TSHB gene also contains one 5-prime noncoding exon, whereas the mouse Tshb gene contains 3.
By study of somatic cell hybrids with a genomic probe, Dracopoli et al. (1985) assigned the beta subunit of thyroid-stimulating hormone to 1p22. Thus, the beta subunits of chorionic gonadotropin and luteinizing hormone are on chromosome 19, but the FSHB (136530) and TSHB genes are located elsewhere. Fukushige et al. (1986) assigned TSHB to human chromosome 1 by Southern blotting after chromosome sorting. By study of somatic cell hybrids, Naylor et al. (1986) confirmed the assignment to 1pter-p21. Dracopoli et al. (1987, 1988) found that TSHB and NGFB, both of which are under strong thyroid hormone control, are very closely linked (theta = 0.00; lod = 42.8); furthermore, using pulsed-field gel electrophoresis (PFGE), they found that the 2 genes are located less than 310 kb apart in man (and 220 kb apart in the mouse). This finding is inconsistent with the assignment of the former to band 1p22 and the latter to band 1p13. Tokino et al. (1990) suggested that TSHB is located in the proximal portion of 1p22. Dracopoli and Meisler (1990) reported that linkage analysis and pulsed field gel electrophoresis demonstrated that TSHB, NGFB (162030), and NRAS (164790) form a very tightly linked gene cluster and must be assigned to the same chromosomal band. Their location proximal to the AMY2B gene in 1p21 and close linkage to the alpha-satellite centromeric repeat D1Z5 provided strong evidence that the correct assignment for these 3 loci is 1p13 and not 1p22.
Using a cDNA clone in mouse-hamster hybrids, Todd et al. (1985) mapped the Tshb gene to mouse chromosome 3, where it is part of a conserved syntenic group homologous to that in proximal 1p of man. The group includes Ngfb also. It is perhaps significant that thyroid hormones stimulate NGF synthesis. It has been suggested that the influence of thyroid hormones on CNS development may be mediated through NGF. The Tsha gene was assigned previously to mouse chromosome 4. Both Tsha and Tshb are unlinked to Lhb (152780), which is on mouse chromosome 7.
One of the most dramatic examples of homology of synteny between man and mouse is provided by human chromosome 1: many genes on chromosome 4 are located on the distal part of 1p, many on mouse chromosome 3 are located in the midportion of chromosome 1, and many genes on mouse chromosome 1 are located on the distal part of 1q. Moseley and Seldin (1989) found that 15 genes located between 1q21 and 1q32 in the human spanned 29.5 cM on distal mouse chromosome 1; 6 genes localized between human 1p22 and 1q21 spanned 15.6 cM on distal mouse chromosome 3. They believed the data indicated that gene order within large chromosome segments have remained stable over long periods of evolution and, since one of these conserved linkage groups spans the centromere, that the position of the centromere may reflect a late event in the evolution of higher eukaryotic organisms. The genes on mouse chromosome 3 that are located on 1p in man include, in addition to TSHB, amylase-2 (104650), CD2 (186990), and ATP1A1 (182310). The genes on mouse chromosome 3 that are carried most distally on 1q of man are GBA (606463) and CACY (114110).
Congenital Nongoitrous Hypothyroidism 4
In patients with congenital thyroid-stimulating hormone deficiency (CHNG4; 275100), Hayashizaki et al. (1989) identified homozygosity for a mutation in the TSHB gene (188540.0001).
Brumm et al. (2002) found that the high prevalence of the homozygous TSHB 313delT mutation (188540.0003) in families with congenital central hypothyroidism (CHNG4) was the result of a common ancestor. Given this finding and the low frequency of the mutation in the general population, Brumm et al. (2002) suggested that the identification and genetic counseling of heterozygous carriers from affected families seemed more advisable than population-wide neonatal T4 screening.
R75G Variant
Shaki et al. (2022) studied 3 Bene Israel Indian Jewish families in which individuals were clinically euthyroid, with FT4 in the normal range, but had low or undetectable TSH levels. All were heterozygous or homozygous for an arg75-to-gly (R75G) substitution in the TSHB gene (c.223A-G, NM_000549.5). The authors noted that this variant had previously been referred to as R55G by Drees et al. (2014). The R75G variant does not impair the function of TSH-beta, but rather results in a structural change that prevents recognition of TSH by some of the monoclonal antibodies used in commercial TSH immune-detection platforms. Analysis of DNA samples from 70 Bene Israel Indian Jews detected 3 heterozygotes for R75G, suggesting an overall allele frequency of approximately 2% and an approximately 4% carrier rate in that population. SNP haplotyping of R75G homozygotes of Pakistani, non-Jewish Indian, South Asian, and Bene Israel Indian Jewish ancestry revealed that the R75G variant resides within a 239.7-kb haplotype block shared by all examined samples. Shaki et al. (2022) concluded that R75G in TSHB represents a founder variant, shared by Bene Israel Indian Jews and the South Asian non-Jewish population.
In a family with 2 sisters with congenital thyroid-stimulating hormone deficiency (275100) born of consanguineous parents, Hayashizaki et al. (1989) found homozygosity for a G-to-A transition in exon 2 of the TSHB gene, resulting in a gly29-to-arg (G29R) substitution. The alteration is in the center of the so-called CAGYC region, which represents an amino acid sequence conserved among all known glycoprotein hormone beta subunits. Microinjection of the mutated beta mRNAs into Xenopus laevis oocytes led to the formation of conformationally altered beta polypeptides that could not associate with alpha subunits. The mutation created a new recognition site for the enzyme MaeI. Heterozygosity in the parents and some other members of the family was demonstrated by Southern blot analysis using MaeI.
In 2 related Greek families segregating congenital nongoitrous hypothyroidism (275100), Dacou-Voutetakis et al. (1990) identified a 94G-T transversion in the TSHB gene, which destroyed the only TaqI site in the TSHB-coding region and gave rise to a novel 8.5-kb TaqI fragment. Restriction analysis showed that the 3 affected children were homozygous for the 8.5-kb allele and that the 4 parents and 2 unaffected children were heterozygous. The 94G-T change caused a glu12-to-ter substitution and gave rise to a truncated peptide that included only the first 11 of the 118 amino acids of the mature TSHB peptide.
Medeiros-Neto et al. (1996) described 2 related Brazilian sibships with congenital nongoitrous hypothyroidism (275100) due to a circulating form of biologically inactive TSH containing a mutation in the TSH-beta subunit. The parents in each case were consanguineous. The affected children had low thyroid hormone levels and radioactive iodine uptake in the thyroid gland associated with measurable serum TSH. TSH secretion stimulated by thyrotropin-releasing hormone (613879) did not increase thyroid hormone production in these patients as compared to their unaffected sibs, suggesting to the authors that the mutant TSH was biologically inactive in vivo. Recombinant TSH harboring the mutation was shown to be biologically inactive in an in vitro bioassay. The mutation was found to be a homozygous 1-bp deletion (T) from codon 105 (TGT) of the TSHB gene, converting a cysteine to a valine residue (C105V) and yielding an additional 8-amino acid nonhomologous peptide extension on the mutant protein.
Doeker et al. (1998) reported a homozygous 1-bp (T) deletion at nucleotide 410 in codon 105 of the TSHB gene in a 5-month-old infant of nonconsanguineous parents. The child had severe central hypothyroidism with undetectable serum levels of T3 and T4 in combination with an undetectable baseline TSH level. The mutation caused a frameshift with a premature stop at codon 114. The truncated TSHB peptide lacked the terminal 5 amino acids.
The nucleotide number in this mutation has variously been described as 313 or 410. Brumm et al. (2002) stated that this mutation, which they referred to as 313delT (C105V), is the most frequent TSHB mutation and had been described in 6 apparently unrelated families. They investigated the frequency and possible monophyletic origin of the different 313delT alleles of 3 affected German families. Haplotype analysis of 5 polymorphic SNP loci in the TSHB region revealed the presence of 7 different haplotypes in the general population. In all 6 parental lines, the mutation occurred on the same haplotype. Extending the haplotype by 2 flanking microsatellite markers led to a mutation age estimate of approximately 150 generations. In 500 unrelated individuals from the general population, the authors did not detect any 313delT alleles, suggesting a population heterozygote carrier frequency of less than 1 in 170 with more than 95% probability. The data suggested a monophyletic origin of the TSHB 313delT mutation from a common ancestor and no significant population prevalence.
Bonomi et al. (2001) reported an Egyptian girl with isolated central hypothyroidism (275100) due to homozygosity for a gln49-to-ter (Q49X) mutation in the TSHB gene. She was referred at 75 days of age for severe clinical signs of hypothyroidism, whose central origin was documented by normal serum TSH, low free T4 and free T3 levels, impaired TSH response to TRH, absence of 99Tc thyroidal uptake, and antithyroid autoantibodies. Ultrasound revealed a hypoplastic thyroid, whereas magnetic resonance imaging showed a hyperplastic pituitary. Interestingly, the sella computed tomography scan showed a completely normalized pituitary size at 21 months of age. At 8 years of age the patient was reinvestigated after 6-week L-T4 withdrawal. TSH values were highly variable depending on the measurement method used, whereas extremely high levels of circulating free glycoprotein alpha-subunit were recorded. Despite the fact that mutant Q49X TSHB lacks 60% of the C-terminal amino acid sequence, it forms with the alpha-subunit a heterodimer with preserved immunoreactivity in some TSH measurement methods, but the mutant heterodimer is completely devoid of bioactivity. The authors concluded that high circulating free glycoprotein alpha-subunit levels, variable TSH levels, and possibly hyperplastic pituitary gland are hallmarks of isolated central hypothyroidism due to mutations of the TSHB gene.
Vuissoz et al. (2001) reported severe isolated TSH deficiency in 2 children from the same consanguineous Turkish kindred. These affected children were homozygous for a C-to-T transition at nucleotide 654 of the TSHB subunit gene, leading to the conversion of a glutamine (CAG) to a premature stop codon (TAG) in codon 49 (Q49X). The resulting nascent peptide did not contain the seatbelt region (amino acid residues 88-105), a TSH-beta subunit region crucial for the dimerization with the alpha-subunit, and, hence, the correct secretion of the mature TSH heterodimer was hampered. Free T3, free T4, and basal TSH levels were extremely low in both affected individuals, and TRH stimulations failed to increase serum TSH, but not PRL, confirming isolated TSH deficiency.
Pohlenz et al. (2002) reported a 4-month-old girl with isolated TSH deficiency (275100) born to consanguineous parents. Sequencing of the TSHB gene revealed a homozygous G-to-A transition at position +5 of the donor splice site of intron 2. TSHB gene transcript could not be obtained from fibroblasts or white blood cells by illegitimate amplification. The mutation at position +5 of the donor splice site produced a skip of exon 2. The putative product of translation from a downstream start site was expected to yield a severely truncated peptide of 25 amino acids. The parents and an unaffected older brother were heterozygous for the mutation.
Borck et al. (2004) reported 4 children from 2 consanguineous Turkish families with isolated TSH deficiency who carried the IVS2+5G-A mutation. Affected children who were screened as newborns had an unremarkable TSH result and a low serum TSH level at diagnosis. Age at diagnosis and clinical phenotype were variable. While this mutation leads to skipping of exon 2 and a loss of the translation start codon without ability to produce a TSH-like protein, the authors detected a very low concentration of authentic, heterodimeric TSH in serum using specific monoclonal antibodies, indicating the production of a small amount of correctly spliced TSH mRNA. By genotyping members of their 2 families and the family reported by Pohlenz et al. (2002) with polymorphic markers at the TSHB locus, they showed that the mutation arose on a common ancestral haplotype in these 3 unrelated Turkish families, indicating a founder mutation in the Turkish population. The authors stressed the need for a biochemical and molecular genetic workup in children with symptoms suggestive of congenital hypothyroidism, even when the neonatal TSH screening is normal.
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Shaki, D., Eskin-Schwartz, M., Hadar, N., Bosin, E., Carmon, L., Refetoff, S., Hershkovitz, E., Birk, O. S., Haim, A. TSHB R75G is a founder variant and prevalent cause of low or undetectable TSH in Indian Jews. Europ. Thyroid J. 11: e210072, 2022. [PubMed: 34981755] [Full Text: https://doi.org/10.1530/ETJ-21-0072]
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