TSHR (thyroid stimulating hormone receptor)

2009-11-01   Carmela Iosco , Kerry J Rhoden 

Medical Genetics Unit, Department of Gynaecologic, Obstetric, Pediatric Sciences, University of Bologna, Bologna, Italy

Identity

HGNC
LOCATION
14q31.1
LOCUSID
ALIAS
CHNG1,LGR3,hTSHR-I
FUSION GENES

DNA/RNA

Atlas Image
Structure of the TSHR gene and coding sequence (CDS). Boxes represent exons numbered 1 to 10 and proportional to length, red representing the coding sequence, grey representing untranslated regions (UTR); the horizontal line joining exons represents introns, shrunk to minimal length. Positions below the CDS are numbered relative to the transcription start.

Description

Spans 190,778 bp, contains 10 exons. Kakinuma and Nagayama (2002) identified 13 exons, but most findings relate to the 10-exon pattern.

Transcription

Regulated by a TATA-less promoter containing binding sites for GABP, TTF1, CREB, ATF2, TR/RXR, SSBP and ICER.
Major transcript (TSHR isoform 1 precursor, NM_000369.2) encoded by 10 exons, transcript length 4410 bp, 2295 bp ORF, ~100 bp 5 UTR and 1.6 kb 3 UTR; the coding region spans positions 157-2451 bp, with a signal peptide at 157-216 bp, mature peptide from 217 to 2448 bp, poly-A signal at 4371-4376. Encodes the canonical protein, 764 aa.
NCBI Entrez Gene describes two alternatively spliced variants, TSHR isoform 2 precursor (NM_001018036.1) and TSHR isoform 3 precursor (NM_001142626.1). Additional transcripts are possible; according to NCBI/Aceview, there are 10 alternatively spliced variants, based upon cDNAs deposited in GenBank derived from normal and neoplastic human tissues and cell lines. There are 3 probable alternative promoters, 6 non overlapping alternative last exons and 6 validated alternative polyadenylation sites. The mRNAs appear to differ by truncation of the 5 end, truncation of the 3 end, overlapping exons with different boundaries, alternative splicing or retention of 2 introns. There is no evidence for protein expression of splice variants.
Transcription variant *Exons in CDSmRNAPredicted proteinProtein evidence
a; isoform 1 precursor104570 bp764 aayes
b; isoform 3 precursor91089 bp274 aano
c; isoform 2 precursor91281 bp253 aano
d81184 bp231 aano
e9901 bp229 aano
f2699 bp167 aano
g61018 bp160 aano
h6445 bp141 aano
i3561 bp106 aano
j-unspliced12541 bp69 aano
k2333 bp57 aano
Table 1: TSHR transcript variants. *Letters refer to NCBI Aceview nomenclature as of April 2007; names in italics refer to NCBI Entrez Gene nomenclature.

Proteins

Atlas Image
TSHR localization and structure. Left, thyroid follicle where the TSH-stimulated synthesis of thyroid hormone (T3 and T4) occurs following iodide uptake and organification into thyroglobulin (Tg). Right, TSHR protein structure, showing the A subunit composed of leucine-rich repeats (LRR) and the N-terminus, and the B subunit composed of 7 transmembrane domains (TMD), the intracellular and extracellular loops (ICL and ECL respectively) and the C-terminus.

Description

G-protein coupled receptor (GPCR), 764 aa membrane glycoprotein. Predicted MW 84.5 kDa; apparent MW of glycosylated protein 95-120 kDa.
Consists of two subunits:
(i) A or α subunit: encoded by exons 1-8 of TSHR gene; glycosylated extracellular ectodomain containing 9 leucine-rich repeats (LRR) and the N-terminus; binds TSH and other ligands (hCG and LH),
(ii) B or β subunit: encoded by exons 9-10 of TSHR gene; consists of 7 trans-membrane domains (TMD) connected by extracellular loops (important for basal and activated function) and intracellular loops (important for G protein coupling), and an intracellular C terminus.
A and B subunits are produced by posttranslational proteolytic cleavage of single-chain TSHR at the cell surface, with removal of a 50 aa peptide, and subsequent joining of A and B subunits by disulfide bridges. The B subunit is thought to be constitutionally active, and interaction with the A subunit ectodomain maintains the B subunit in an inactive state.

Expression

Thyroid follicular epithelial cells; to a lesser degree in thymus, pituitary gland, lymphocytes, testis, retro-ocular fibroblasts, adipocytes, brain, heart and kidney.

Localisation

Plasma membrane.

Function

Regulation of thyroid metabolism.
TSHR is the receptor for thyrotropin (thyroid stimulating hormone or TSH), a member of the glycoprotein hormone family. TSH is released by the anterior pituitary gland and is the main regulator of thyroid gland growth and development. Binding of TSH to TSHR stimulates thyroid epithelial cell proliferation, and regulates the expression of differentiation markers such as thyroglobulin, thyroperoxidase and the sodium iodide symporter (NIS), necessary for the synthesis of thyroid hormones.
TSHR is coupled to heterotrimetric G proteins, regulatory proteins associated with the inner surface of the plasma membrane. Binding of TSH to TSHR causes a conformational change in TSHR, provoking the GTP-dependent dissociation of the Gα subunit from GβGγ dimers. Gα activates distinct signal transduction pathways to stimulate gene transcription and cell proliferation.
Two G protein-dependent pathways are activated by TSHR:
(i) Gαs activates adenylate cyclase to increase cAMP levels; cAMP activates protein kinase A (PKA) causing translocation of its catalytic subunit to the nucleus; PKA phosphorylates, among others, the transcription factor CREB thereby increasing its transcriptional activity.
(ii) Gαq activates phospholipase C to increase phosphoinositide turnover, releasing inositol triphosphate (IP3) and diacylglycerol (DAG); DAG activates protein kinase C, which promotes proliferation via the RAF/MEK/ERK pathway.
Complex cross-talk occurs between these pathways and other signaling pathways including the PI3/Akt, PKC/NFkB and JAK/STAT pathways (for reviews see García-Jiménez and Santisteban (2007) and Latif et al. (2009)).
TSHR is also activated by other members of the glycoprotein hormone family, including human chorionic gonadotropin (hCG), luteinizing hormone (LH) and thyrostimulin (a heterodimer composed of A2 and B5 glycoprotein hormone subunits).

Homology

LHCGR (Luteinizing Hormone, Choriogonadotropin receptor) 51% amino acid identity; FSHR (Follicle Stimulating Hormone receptor) 48% amino acid identity.

Mutations

Note

Over 90 naturally occurring TSHR mutations have been identified, and are catalogued in the GRIS database and TSHR mutation database. Mutations are gain-of-function resulting in constitutional activation of the receptor independently of TSH, or loss-of-function resulting in loss of TSH sensitivity.
Polymorphisms: Coding missense SNPs: Pro27Thr, Glu34Lys, Asp36His, Pro52Thr, Thr574Ser, Tyr601His, Val721Phe, Glu727Asp, Asn 744Lys.
Atlas Image
Table 2: TSHR mutations in thyroid disease. Mutations are listed in terms of the amino acid residues altered and their respective location (α = A subunit, β = B subunit, TM = transmembrane domain, ICL = intracellular loop, ECL = extracellular loop, LRR = leucine-rich repeat, hinge = domain connecting leucine-rich repeats to first transmembrane domain).
Note: * unknown functional status of mutations (Ohno et al., 1995).

Germinal

Germinal TSHR mutations include missense mutations, nonsense mutations, insertion/deletions, and exon skipping due to alternative splicing. Germinal activating mutations are associated with hereditary or sporadic congenital hyperthyroidism, whereas germinal inactivating mutations are a cause of TSH resistance associated with congenital hypothyroidism and euthyroid hyperthyrotropinaemia.

Somatic

Somatic TSHR mutations include missense mutations and in-frame deletions. Activating mutations have been identified in hyperfunctioning thyroid adenoma and toxic multinodular goiter; few cases are associated with thyroid carcinoma. No somatic inactivating mutations have been described so far.

Implicated in

Entity name
Thyroid adenoma
Disease
Somatic activating TSHR mutations are a major cause of hyperfunctioning thyroid adenomas, benign neoplasms of thyroid follicular cells:
- 10-80% of hyperfunctioning or hot adenomas (i.e. ademomas with active radioiodide uptake and thyroid hormone synthesis) harbor somatic activating mutations (Parma et al., 1993; Russo et al., 1996; Führer et al., 2007). The highly variable frequency of mutations may reflect geographic differences.
- Activating mutations are largely located in exon 10 encoding the TSHR β-subunit, and are particularly frequent in the sixth transmembrane segment (TM6) important for coupling to G proteins.
- Mutations result in the constitutive activation of adenylate cyclase, stimulating thyrocyte proliferation and thyroid hormone synthesis. As a consequence, hyperfunctioning nodules provoke hyperthyroidism and thyrotoxicosis.
- Nonfunctioning or cold adenomas (i.e. not able to accumulate radioiodide or synthesize thyroid hormones) do not harbor TSHR mutations.
Entity name
Toxic multinodular goiter (Plummers disease)
Disease
Somatic activating TSHR mutations are a major cause of Toxic Multinodular Goiter (TMNG), a hyperplastic thyroid enlargement with multiple bilateral nodules:
- 70-80% of hyperfunctioning nodules of TMNG harbor somatic activating mutations, many of which are shared with hyperfunctioning thyroid adenoma suggesting a common pathogenic event (Tonacchera et al., 1998; Tonacchera et al., 2000).
- Different hyperfunctioning nodules within a goiter harbor may distinct TSHR activating mutations, confirming the polyclonal etiology of TMNG. In contrast, nonfunctioning nodules within the same goiter do not harbor mutations.
- TMNG is most common in iodine-deficient areas, and this may reflect the increased mutagenic load associated with chronic TSH stimulation and thyrocyte proliferation.
- A germline polymorphism of codon 727 of TSHR was reported to be associated with TMNG (Gabriel et al., 1999), however a subsequent study failed to substantiate this finding in a European population (Mulhberg et al., 2000).
Entity name
Thyroid carcinoma
Prognosis
TSHR mRNA in thyroid tumours: Reduced or absent TSHR mRNA in thyroid tumours is a negative prognostic marker, indicative of reduced effectiveness of radioiodine therapy. TSHR expression in thyroid carcinoma correlates with the state of differentiation of tumours, with loss of differentiation resulting in a loss of mRNA expression. Thus, well-differentiated carcinomas (papillary and follicular) show variable TSHR mRNA levels ranging from normal to markedly reduced, whereas undifferentiated anaplastic carcinoma shows absent TSHR mRNA (Brabant et al., 2001; Brönnegård et al., 1994; Shiels et al., 1999). TSHR regulates the thyroid expression of the iodide transporter NIS, and decreased TSHR expression impairs the iodine-concentrating capacity of thyroid tumours.
Circulating TSHR mRNA: TSHR mRNA in peripheral blood has been suggested as a potential molecular marker of circulating thyroid carcinoma cells to aid in the differential diagnosis of malignant and benign thyroid disease preoperatively, and to detect residual, recurrent or metastatic thyroid cancer (Barzon et al., 2004; Chinnappa et al., 2004).
TSHR promoter methylation: TSHR promoter methylation may be a marker for malignancy in thyroid carcinoma (Xing et al., 2003).
Oncogenesis
TSHR mutations: Mutagenic screening of thyroid carcinomas reveals a low incidence of somatic TSHR mutations ranging from 0-22%, suggesting a limited role for TSHR mutations in the pathogenesis of thyroid carcinoma (Matsuo et al., 1993; Russo et al., 1995; Ohno et al., 1995; Spambalg et al., 1996; Esapa et al., 1997; Cetani et al., 1999).
- Thr632Ile in thyroid hormone-producing follicular carcinoma (Spambalg et al., 1996).
Rare cases of TSHR mutations in nonfunctioning thyroid carcinoma have also been reported:
- Ile486Phe in an autonomously functioning follicular carcinoma presenting a hot nodule causing hyperthyroidism (Camacho et al., 2000).
- Leu512Arg in autonomously functioning papillary carcinoma with hot nodule (Gozu et al., 2004).
- Leu677Val in autonomously functioning Hürthle cell thyroid carcinoma causing thyrotoxicosis (Russo et al., 1999).
- Phe631Ile and Asp633Tyr in toxic metastasizing follicular thyroid carcinoma; no TSHR mutations in non-functioning lung metastases (Führer et al., 2003).
- Asp633His in aggressive insular thyroid carcinoma (poorly-differentiated carcinoma) presenting as an autonomously functioning thyroid nodule and causing severe thyrotoxicosis; TSHR mutation also present in lymph node metastasis (Russo et al., 1997).
- Thr632Ala in nonfunctioning follicular carcinoma (Spambalg et al., 1996).
- Ala623Ser activating mutation in papillary carcinoma with cold nodule, in patient with past history of Graves disease (De Cross et al., 2008).
The role of activating TSHR mutations in neoplastic transformation is unclear. Although TSHR activation stimulates thyrocyte proliferation, hyperfunctioning nodules (adenoma or toxic multinodular goiter) are rarely malignant, suggesting that constitutive activation of the cAMP cascade alone is insufficient for the malignant transformation of thyroid follicular cells.
Epigenetics: The TSHR gene promoter is frequently hypermethylated in thyroid carcinoma, with preferential methylation in undifferentiated carcinoma (Xing et al., 2003; Schagdarsurengin et al., 2006). In contrast, TSHR gene promoter is unmethylated in the normal thyroid and in benign tumours (thyroid adenoma). Hypermethylation results in TSHR gene silencing and reduced TSHR expression in some malignant thyroid tumours. In thyroid cancer cell lines, demethylating agents partially restore TSHR expression.
Entity name
Congenital nongoitrous hypothyroidism-1 (CHNG1)
Disease
Germline inactivation TSHR mutations are a cause of hereditary congenital nongoitrous hypothyroidism. Inactivating mutations result in variable degrees of TSH resistance, with clinical consequences ranging from euthyroid hyperthyrotropinemia to mild or severe hypothyroidism. CHNG1 is inherited in an autosomal recessive manner, manifesting in homozygotes or compound heterozygotes. However, subclinical hypothyroidism may also manifest in heterozygotes, suggesting autosomal dominant inheritance.
Entity name
Hereditary nonautoimmune hyperthyroidism
Disease
Germline activating TSHR mutations are a cause of hereditary nonautoimmune congenital hyperthyroidism (autosomal dominant inheritance). Sporadic cases of nonautoimmune congenital hyperthyroidism result from de novo germinal mutations. Activating germline mutations result in constitutive activation of the cAMP pathway in thyrocytes. Mutations are predominantly in exon 10 encoding the transmembrane domains. One activating mutation (Arg183Lys) increases sensitivity towards hCG and manifests in women during pregnancy (familial gestational hyperthyroidism).

Bibliography

Pubmed IDLast YearTitleAuthors
151706762004Evaluation of circulating thyroid-specific transcripts as markers of thyroid cancer relapse.Barzon L et al
17611611991Human thyrotropin receptor gene: expression in thyroid tumors and correlation to markers of thyroid differentiation and dedifferentiation.Brabant G et al
80459521994Expression of thyrotropin receptor and thyroid hormone receptor messenger ribonucleic acid in normal, hyperplastic, and neoplastic human thyroid tissue.Brönnegård M et al
111287152000A Phe 486 thyrotropin receptor mutation in an autonomously functioning follicular carcinoma that was causing hyperthyroidism.Camacho P et al
103423611999Genetic analysis of the TSH receptor gene in differentiated human thyroid carcinomas.Cetani F et al
171189942007Thyroid-stimulating hormone receptor messenger ribonucleic acid measurement in blood as a marker for circulating thyroid cancer cells and its role in the preoperative diagnosis of thyroid cancer.Chia SY et al
152922932004Detection of thyrotropin-receptor messenger ribonucleic acid (mRNA) and thyroglobulin mRNA transcripts in peripheral blood of patients with thyroid disease: sensitive and specific markers for thyroid cancer.Chinnappa P et al
160750372005Thyrotropin receptor-associated diseases: from adenomata to Graves disease.Davies TF et al
187277132009Functional studies of new TSH receptor (TSHr) mutations identified in patients affected by hypothyroidism or isolated hyperthyrotrophinaemia.De Marco G et al
90242421997G protein and thyrotropin receptor mutations in thyroid neoplasia.Esapa C et al
93605561997Somatic mutations in the thyrotropin receptor gene and not in the Gs alpha protein gene in 31 toxic thyroid nodules.Führer D et al
147132692003Two somatic TSH receptor mutations in a patient with toxic metastasising follicular thyroid carcinoma and non-functional lung metastases.Führer D et al
104877071999Germline polymorphism of codon 727 of human thyroid-stimulating hormone receptor is associated with toxic multinodular goiter.Gabriel EM et al
178912292007TSH signalling and cancer.García-Jiménez C et al
156717792004Does a Leu 512 Arg thyrotropin receptor mutation cause an autonomously functioning papillary carcinoma?Gozu H et al
120812362002Multiple messenger ribonucleic acid transcripts and revised gene organization of the human TSH receptor.Kakinuma A et al
193284142009The thyroid-stimulating hormone receptor: impact of thyroid-stimulating hormone and thyroid-stimulating hormone receptor antibodies on multimerization, cleavage, and signaling.Latif R et al
198268302010United detection GNAS and TSHR mutations in subclinical toxic multinodular goiter.Liu C et al
85011491993The thyrotropin receptor (TSH-R) is not an oncogene for thyroid tumors: structural studies of the TSH-R and the alpha-subunit of Gs in human thyroid neoplasms.Matsuo K et al
190159222009Effectiveness of peripheral thyrotropin receptor mRNA in follow-up of differentiated thyroid cancer.Milas M et al
110358452000Hyperfunctioning malignant thyroid nodule in an 11-year-old girl: pathologic and molecular studies.Mircescu H et al
150126102004Decreased expression of thyrotropin receptor gene suggests a high-risk subgroup for oncocytic adenoma.Mirebeau-Prunier D et al
109468592000Lack of association of nonautoimmune hyperfunctioning thyroid disorders and a germline polymorphism of codon 727 of the human thyrotropin receptor in a European Caucasian population.Mühlberg T et al
167564732006Follicular carcinoma presenting as autonomous functioning thyroid nodule and containing an activating mutation of the TSH receptor (T620I) and a mutation of the Ki-RAS (G12C) genes.Niepomniszcze H et al
76475781995Point mutations in the thyrotropin receptor in human thyroid tumors.Ohno M et al
84136271993Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas.Parma J et al
86363651996Thyrotropin receptor gene alterations in thyroid hyperfunctioning adenomas.Russo D et al
90624741997Detection of an activating mutation of the thyrotropin receptor in a case of an autonomously hyperfunctioning thyroid insular carcinoma.Russo D et al
100370701999A Val 677 activating mutation of the thyrotropin receptor in a Hürthle cell thyroid carcinoma associated with thyrotoxicosis.Russo D et al
168894862006CpG island methylation of tumor-related promoters occurs preferentially in undifferentiated carcinoma.Schagdarsurengin U et al
103981461999TSH receptor status of thyroid neoplasms--TaqMan RT-PCR analysis of archival material.Sheils OM et al
179383242007Methylation status of genes in papillary thyroid carcinoma.Smith JA et al
89238351996Structural studies of the thyrotropin receptor and Gs alpha in human thyroid cancers: low prevalence of mutations predicts infrequent involvement in malignant transformation.Spambalg D et al
108524622000Activating thyrotropin receptor mutations are present in nonadenomatous hyperfunctioning nodules of toxic or autonomous multinodular goiter.Tonacchera M et al
165434052006GRIS: glycoprotein-hormone receptor information system.Van Durme J et al
127278562003Methylation of the thyroid-stimulating hormone receptor gene in epithelial thyroid tumors: a marker of malignancy and a cause of gene silencing.Xing M et al
190823102008Fatal outcome of a young woman with papillary thyroid carcinoma and graves' disease: possible implication of "cross-signalling" mechanism.Cross GA et al

Other Information

Locus ID:

NCBI: 7253
MIM: 603372
HGNC: 12373
Ensembl: ENSG00000165409

Variants:

dbSNP: 7253
ClinVar: 7253
TCGA: ENSG00000165409
COSMIC: TSHR

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000165409ENST00000298171A0A0A0MTJ0
ENSG00000165409ENST00000342443P16473
ENSG00000165409ENST00000541158A0A0A0MTJ0
ENSG00000165409ENST00000554263Q0VAP8
ENSG00000165409ENST00000554435P16473
ENSG00000165409ENST00000555326G3V381
ENSG00000165409ENST00000637447A0A1B0GUJ5
ENSG00000165409ENST00000642209A0A2R8Y709

Expression (GTEx)

0
50
100
150
200

Pathways

PathwaySourceExternal ID
Neuroactive ligand-receptor interactionKEGGko04080
Autoimmune thyroid diseaseKEGGko05320
Neuroactive ligand-receptor interactionKEGGhsa04080
Autoimmune thyroid diseaseKEGGhsa05320
Thyroid hormone synthesisKEGGhsa04918
Thyroid hormone synthesisKEGGko04918
cAMP signaling pathwayKEGGhsa04024
cAMP signaling pathwayKEGGko04024
Regulation of lipolysis in adipocytesKEGGhsa04923
Signal TransductionREACTOMER-HSA-162582
Signaling by GPCRREACTOMER-HSA-372790
GPCR ligand bindingREACTOMER-HSA-500792
Class A/1 (Rhodopsin-like receptors)REACTOMER-HSA-373076
Hormone ligand-binding receptorsREACTOMER-HSA-375281
GPCR downstream signalingREACTOMER-HSA-388396
G alpha (s) signalling eventsREACTOMER-HSA-418555

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
158891382005Glycoprotein hormone receptors: link between receptor homodimerization and negative cooperativity.91
187688992008Evidence for an association between thyroid-stimulating hormone and insulin-like growth factor 1 receptors: a tale of two antigens implicated in Graves' disease.74
128130252003The thyrotropin receptor autoantigen in Graves disease is the culprit as well as the victim.73
119170952002Thyroid-stimulating hormone and thyroid-stimulating hormone receptor structure-function relationships.66
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
197306832009The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors.59
127889022003Polymorphisms in thyroid hormone pathway genes are associated with plasma TSH and iodothyronine levels in healthy subjects.58
124320932002Role of the thyroid-stimulating hormone receptor signaling in development and differentiation of the thyroid gland.57
264276602016Long noncoding RNA PVT1 modulates thyroid cancer cell proliferation by recruiting EZH2 and regulating thyroid-stimulating hormone receptor (TSHR).54
198379332009Genetic predisposition to elevated serum thyrotropin is associated with exceptional longevity.49

Citation

Carmela Iosco ; Kerry J Rhoden

TSHR (thyroid stimulating hormone receptor)

Atlas Genet Cytogenet Oncol Haematol. 2009-11-01

Online version: http://atlasgeneticsoncology.org/gene/290/tshr-(thyroid-stimulating-hormone-receptor)