TSHR (thyroid stimulating hormone receptor)

	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 CDS mRNA Predicted protein Protein evidence a; isoform 1 precursor 10 4570 bp 764 aa yes b; isoform 3 precursor 9 1089 bp 274 aa no c; isoform 2 precursor 9 1281 bp 253 aa no d 8 1184 bp 231 aa no e 9 901 bp 229 aa no f 2 699 bp 167 aa no g 6 1018 bp 160 aa no h 6 445 bp 141 aa no i 3 561 bp 106 aa no j-unspliced 1 2541 bp 69 aa no k 2 333 bp 57 aa no Table 1: TSHR transcript variants. *Letters refer to NCBI Aceview nomenclature as of April 2007; names in italics refer to NCBI Entrez Gene nomenclature.

	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.

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.
	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.

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