TSHR_HUMAN
ID TSHR_HUMAN Reviewed; 764 AA.
AC P16473; A0PJU7; F5GYU5; G3V2A9; Q16503; Q8TB90; Q96GT6; Q9P1V4; Q9ULA3;
AC Q9UPH3;
DT 01-AUG-1990, integrated into UniProtKB/Swiss-Prot.
DT 29-MAR-2005, sequence version 2.
DT 03-AUG-2022, entry version 245.
DE RecName: Full=Thyrotropin receptor;
DE AltName: Full=Thyroid-stimulating hormone receptor;
DE Short=TSH-R;
DE Flags: Precursor;
GN Name=TSHR; Synonyms=LGR3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG).
RX PubMed=2558651; DOI=10.1016/0006-291x(89)92727-7;
RA Nagayama Y., Kaufman K.D., Seto P., Rapoport B.;
RT "Molecular cloning, sequence and functional expression of the cDNA for the
RT human thyrotropin receptor.";
RL Biochem. Biophys. Res. Commun. 165:1184-1190(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG), AND TISSUE SPECIFICITY.
RC TISSUE=Thyroid;
RX PubMed=2610690; DOI=10.1016/0006-291x(89)92736-8;
RA Libert F., Lefort A., Gerard C., Parmentier M., Perret J., Ludgate M.,
RA Dumont J.E., Vassart G.;
RT "Cloning, sequencing and expression of the human thyrotropin (TSH)
RT receptor: evidence for binding of autoantibodies.";
RL Biochem. Biophys. Res. Commun. 165:1250-1255(1989).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG), AND VARIANT GLU-727.
RX PubMed=2302212; DOI=10.1016/0006-291x(90)91958-u;
RA Misrahi M., Loosfelt H., Atger M., Sar S., Guiochon-Mantel A., Milgrom E.;
RT "Cloning, sequencing and expression of human TSH receptor.";
RL Biochem. Biophys. Res. Commun. 166:394-403(1990).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG).
RC TISSUE=Thyroid;
RX PubMed=2293030; DOI=10.1210/mend-4-8-1264;
RA Frazier A.L., Robbins L.S., Stork P.J., Sprengel R., Segaloff D.L.,
RA Cone R.D.;
RT "Isolation of TSH and LH/CG receptor cDNAs from human thyroid: regulation
RT by tissue specific splicing.";
RL Mol. Endocrinol. 4:1264-1276(1990).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM SHORT).
RX PubMed=1530609; DOI=10.1016/0006-291x(92)91315-h;
RA Graves P.N., Tomer Y., Davies T.F.;
RT "Cloning and sequencing of a 1.3 KB variant of human thyrotropin receptor
RT mRNA lacking the transmembrane domain.";
RL Biochem. Biophys. Res. Commun. 187:1135-1143(1992).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM SHORT).
RC TISSUE=Thyroid;
RX PubMed=1445355; DOI=10.1016/0006-291x(92)91360-3;
RA Takeshita A., Nagayama Y., Fujiyama K., Yokoyama N., Namba H.,
RA Yamashita S., Izumi M., Nagataki S.;
RT "Molecular cloning and sequencing of an alternatively spliced form of the
RT human thyrotropin receptor transcript.";
RL Biochem. Biophys. Res. Commun. 188:1214-1219(1992).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM LONG).
RC TISSUE=Thyroid;
RA Kopatz S.A., Aronstam R.S., Sharma S.V.;
RT "cDNA clones of human proteins involved in signal transduction sequenced by
RT the Guthrie cDNA resource center (www.cdna.org).";
RL Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT GLU-727.
RX PubMed=12508121; DOI=10.1038/nature01348;
RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C.,
RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A.,
RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H.,
RA Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T.,
RA Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B.,
RA Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D.,
RA Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R.,
RA Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S.,
RA Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C.,
RA Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S.,
RA Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C.,
RA Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P.,
RA Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M.,
RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V.,
RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J.,
RA Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F.,
RA Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F.,
RA Waterston R., Hood L., Weissenbach J.;
RT "The DNA sequence and analysis of human chromosome 14.";
RL Nature 421:601-607(2003).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS SHORT AND 3).
RC TISSUE=Ovarian adenocarcinoma;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [10]
RP PROTEIN SEQUENCE OF 66-80; 113-123; 184-210 AND 294-310, AND GLYCOSYLATION
RP AT ASN-77; ASN-113; ASN-198 AND ASN-302.
RX PubMed=11502179; DOI=10.1021/bi0107389;
RA Cornelis S., Uttenweiler-Joseph S., Panneels V., Vassart G.,
RA Costagliola S.;
RT "Purification and characterization of a soluble bioactive amino-terminal
RT extracellular domain of the human thyrotropin receptor.";
RL Biochemistry 40:9860-9869(2001).
RN [11]
RP FUNCTION, GLYCOSYLATION, SUBCELLULAR LOCATION, SULFATION AT TYR-385, TISSUE
RP SPECIFICITY, AND MUTAGENESIS OF CYS-283; TYR-385 AND TYR-387.
RX PubMed=11847099; DOI=10.1093/emboj/21.4.504;
RA Costagliola S., Panneels V., Bonomi M., Koch J., Many M.C., Smits G.,
RA Vassart G.;
RT "Tyrosine sulfation is required for agonist recognition by glycoprotein
RT hormone receptors.";
RL EMBO J. 21:504-513(2002).
RN [12]
RP FUNCTION, AND INTERACTION WITH HETERODIMER GPHA2-GPHB5.
RX PubMed=12045258; DOI=10.1172/jci14340;
RA Nakabayashi K., Matsumi H., Bhalla A., Bae J., Mosselman S., Hsu S.Y.,
RA Hsueh A.J.W.;
RT "Thyrostimulin, a heterodimer of two new human glycoprotein hormone
RT subunits, activates the thyroid-stimulating hormone receptor.";
RL J. Clin. Invest. 109:1445-1452(2002).
RN [13]
RP INTERACTION WITH SCRIB.
RX PubMed=15775968; DOI=10.1038/sj.emboj.7600616;
RA Lahuna O., Quellari M., Achard C., Nola S., Meduri G., Navarro C.,
RA Vitale N., Borg J.-P., Misrahi M.;
RT "Thyrotropin receptor trafficking relies on the hScrib-betaPIX-GIT1-ARF6
RT pathway.";
RL EMBO J. 24:1364-1374(2005).
RN [14]
RP 3D-STRUCTURE MODELING OF 54-236.
RX PubMed=8747461; DOI=10.1016/s0969-2126(01)00272-6;
RA Jiang X., Dreano M., Buckler D.R., Cheng S., Ythier A., Wu H.,
RA Hendrickson W.A., el Tayar N.;
RT "Structural predictions for the ligand-binding region of glycoprotein
RT hormone receptors and the nature of hormone-receptor interactions.";
RL Structure 3:1341-1353(1995).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (2.55 ANGSTROMS) OF 22-260 IN COMPLEX WITH ANTIBODY,
RP GLYCOSYLATION AT ASN-77; ASN-99; ASN-113; ASN-177 AND ASN-198, AND
RP N-TERMINAL DISULFIDE BOND.
RX PubMed=17542669; DOI=10.1089/thy.2007.0034;
RA Sanders J., Chirgadze D.Y., Sanders P., Baker S., Sullivan A.,
RA Bhardwaja A., Bolton J., Reeve M., Nakatake N., Evans M., Richards T.,
RA Powell M., Miguel R.N., Blundell T.L., Furmaniak J., Smith B.R.;
RT "Crystal structure of the TSH receptor in complex with a thyroid-
RT stimulating autoantibody.";
RL Thyroid 17:395-410(2007).
RN [16]
RP ANALYSIS OF INVOLVEMENT OF VARIANT GLU-727 IN GRAVES DISEASE.
RX PubMed=11887032;
RA Chistiakov D.A., Savost'anov K.V., Turakulov R.I., Petunina N.,
RA Balabolkin M.I., Nosikov V.V.;
RT "Further studies of genetic susceptibility to Graves' disease in a Russian
RT population.";
RL Med. Sci. Monit. 8:CR180-CR184(2002).
RN [17]
RP ANALYSIS OF INVOLVEMENT OF VARIANT GLU-727 IN GRAVES DISEASE.
RX PubMed=12593721; DOI=10.1089/105072502321085171;
RA Ban Y., Greenberg D.A., Concepcion E.S., Tomer Y.;
RT "A germline single nucleotide polymorphism at the intracellular domain of
RT the human thyrotropin receptor does not have a major effect on the
RT development of Graves' disease.";
RL Thyroid 12:1079-1083(2002).
RN [18]
RP ANALYSIS OF INVOLVEMENT OF VARIANTS HIS-36; THR-52 AND GLU-727 IN GRAVES
RP DISEASE.
RX PubMed=12930595; DOI=10.1089/105072503322238773;
RA Ho S.-C., Goh S.-S., Khoo D.H.;
RT "Association of Graves' disease with intragenic polymorphism of the
RT thyrotropin receptor gene in a cohort of Singapore patients of multi-ethnic
RT origins.";
RL Thyroid 13:523-528(2003).
RN [19]
RP REVIEW ON VARIANTS.
RX PubMed=10870027; DOI=10.1530/eje.0.1430025;
RA Farid N.R., Kascur V., Balazs C.;
RT "The human thyrotropin receptor is highly mutable: a review of gain-of-
RT function mutations.";
RL Eur. J. Endocrinol. 143:25-30(2000).
RN [20]
RP VARIANT HIS-36.
RX PubMed=1955520; DOI=10.1210/jcem-73-6-1374;
RA Heldin N.-E., Gustavsson B., Westermark K., Westermark B.;
RT "A somatic point mutation in a putative ligand binding domain of the TSH
RT receptor in a patient with autoimmune hyperthyroidism.";
RL J. Clin. Endocrinol. Metab. 73:1374-1376(1991).
RN [21]
RP VARIANTS HYPERTHYROIDISM GLY-619 AND ILE-623.
RX PubMed=8413627; DOI=10.1038/365649a0;
RA Parma J., Duprez L., van Sande J., Cochaux P., Gervy C., Mockel J.,
RA Dumont J.E., Vassart G.;
RT "Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning
RT thyroid adenomas.";
RL Nature 365:649-651(1993).
RN [22]
RP VARIANT THR-52.
RX PubMed=7508946; DOI=10.1210/jcem.78.2.7508946;
RA Bahn R.S., Dutton C.M., Heufelder A.E., Sarkar G.;
RT "A genomic point mutation in the extracellular domain of the thyrotropin
RT receptor in patients with Graves' ophthalmopathy.";
RL J. Clin. Endocrinol. Metab. 78:256-260(1994).
RN [23]
RP VARIANTS HYPERTHYROIDISM CYS-631; ILE-632; GLU-633 AND TYR-633.
RX PubMed=8045989; DOI=10.1210/jcem.79.2.8045989;
RA Porcellini A., Ciullo I., Laviola L., Amabile G., Fenzi G.,
RA Avvedimento V.E.;
RT "Novel mutations of thyrotropin receptor gene in thyroid hyperfunctioning
RT adenomas. Rapid identification by fine needle aspiration biopsy.";
RL J. Clin. Endocrinol. Metab. 79:657-661(1994).
RN [24]
RP VARIANTS HYPERTHYROIDISM VAL-623 AND ILE-632.
RX PubMed=7989485; DOI=10.1210/jcem.79.6.7989485;
RA Paschke R., Tonacchera M., van Sande J., Parma J., Vassart G.;
RT "Identification and functional characterization of two new somatic
RT mutations causing constitutive activation of the thyrotropin receptor in
RT hyperfunctioning autonomous adenomas of the thyroid.";
RL J. Clin. Endocrinol. Metab. 79:1785-1789(1994).
RN [25]
RP VARIANTS HTNA ALA-509 AND TYR-672.
RX PubMed=7920658; DOI=10.1038/ng0794-396;
RA Duprez L., Parma J., van Sande J., Allgeier A., Leclere J., Schvartz C.,
RA Delisle M.-J., Decoulx M., Orgiazzi J., Dumont J.E., Vassart G.;
RT "Germline mutations in the thyrotropin receptor gene cause non-autoimmune
RT autosomal dominant hyperthyroidism.";
RL Nat. Genet. 7:396-401(1994).
RN [26]
RP CHARACTERIZATION OF VARIANT HIS-36.
RX PubMed=7556878; DOI=10.1016/0303-7207(95)03562-l;
RA Gustavsson B., Eklof C., Westermark K., Westermark B., Heldin N.-E.;
RT "Functional analysis of a variant of the thyrotropin receptor gene in a
RT family with Graves' disease.";
RL Mol. Cell. Endocrinol. 111:167-173(1995).
RN [27]
RP VARIANT HTNA LEU-631.
RX PubMed=7800007; DOI=10.1056/nejm199501193320304;
RA Kopp P., van Sande J., Parma J., Duprez L., Gerber H., Joss E.,
RA Jameson J.L., Dumont J.E., Vassart G.;
RT "Congenital hyperthyroidism caused by a mutation in the thyrotropin-
RT receptor gene.";
RL N. Engl. J. Med. 332:150-154(1995).
RN [28]
RP VARIANTS CHNG1 ALA-162 AND ASN-167, AND VARIANT THR-52.
RX PubMed=7528344; DOI=10.1056/nejm199501193320305;
RA Sunthornthepvarakul T., Gottschalk M.E., Hayashi Y., Refetoff S.;
RT "Resistance to thyrotropin caused by mutations in the thyrotropin-receptor
RT gene.";
RL N. Engl. J. Med. 332:155-160(1995).
RN [29]
RP VARIANTS PAPILLARY CANCER ILE-197; GLU-219; ASP-715 AND MET-723, AND
RP VARIANT GLU-727.
RX PubMed=7647578; DOI=10.1089/thy.1995.5.97;
RA Ohno M., Endo T., Ohta K., Gunji K., Onaya T.;
RT "Point mutations in the thyrotropin receptor in human thyroid tumors.";
RL Thyroid 5:97-100(1995).
RN [30]
RP VARIANT THR-52.
RX PubMed=7488864; DOI=10.1089/thy.1995.5.255;
RA Cuddihy R.M., Bryant W.P., Bahn R.S.;
RT "Normal function in vivo of a homozygotic polymorphism in the human
RT thyrotropin receptor.";
RL Thyroid 5:255-257(1995).
RN [31]
RP VARIANTS HTNA ARG-505; TYR-650 AND SER-670.
RX PubMed=8636266; DOI=10.1210/jcem.81.2.8636266;
RA Tonacchera M., van Sande J., Cetani F., Swillens S., Schvartz C.,
RA Winiszewski P., Portmann L., Dumont J.E., Vassart G., Parma J.;
RT "Functional characteristics of three new germline mutations of the
RT thyrotropin receptor gene causing autosomal dominant toxic thyroid
RT hyperplasia.";
RL J. Clin. Endocrinol. Metab. 81:547-554(1996).
RN [32]
RP VARIANT HTNA THR-453.
RX PubMed=8964822; DOI=10.1210/jcem.81.6.8964822;
RA de Roux N., Polak M., Couet J., Leger J., Czernichow P., Milgrom E.,
RA Misrahi M.;
RT "A neomutation of the thyroid-stimulating hormone receptor in a severe
RT neonatal hyperthyroidism.";
RL J. Clin. Endocrinol. Metab. 81:2023-2026(1996).
RN [33]
RP VARIANTS CHNG1 SER-41; ALA-162; TRP-390; ASN-410 AND LEU-525.
RX PubMed=8954020; DOI=10.1210/jcem.81.12.8954020;
RA de Roux N., Misrahi M., Brauner R., Houang M., Carel J.-C., Granier M.,
RA Le Bouc Y., Ghinea N., Boumedienne A., Toublanc J.E., Milgrom E.;
RT "Four families with loss of function mutations of the thyrotropin
RT receptor.";
RL J. Clin. Endocrinol. Metab. 81:4229-4235(1996).
RN [34]
RP VARIANT INSULAR CARCINOMA HIS-633.
RX PubMed=9062474; DOI=10.1210/jcem.82.3.3838;
RA Russo D., Tumino S., Arturi F., Vigneri P., Grasso G., Pontecorvi A.,
RA Filetti S., Belfiore A.;
RT "Detection of an activating mutation of the thyrotropin receptor in a case
RT of an autonomously hyperfunctioning thyroid insular carcinoma.";
RL J. Clin. Endocrinol. Metab. 82:735-738(1997).
RN [35]
RP VARIANT CHNG1 GLN-109.
RX PubMed=9100579; DOI=10.1210/jcem.82.4.3863;
RA Clifton-Bligh R.J., Gregory J.W., Ludgate M., John R., Persani L.,
RA Asteria C., Beck-Peccoz P., Chatterjee V.K.K.;
RT "Two novel mutations in the thyrotropin (TSH) receptor gene in a child with
RT resistance to TSH.";
RL J. Clin. Endocrinol. Metab. 82:1094-1100(1997).
RN [36]
RP VARIANTS HYPERTHYROIDISM ASN-281; THR-281; THR-453; PHE-486; MET-486;
RP THR-568; GLY-619; ILE-623; PHE-629; LEU-630; LEU-631; ILE-632; ALA-633;
RP GLU-633; HIS-633; TYR-633 AND 658-ASN--ILE-661 DEL.
RX PubMed=9253356; DOI=10.1210/jcem.82.8.4144;
RA Parma J., Duprez L., van Sande J., Hermans J., Rocmans P., van Vliet G.,
RA Costagliola S., Rodien P., Dumont J.E., Vassart G.;
RT "Diversity and prevalence of somatic mutations in the thyrotropin receptor
RT and Gs alpha genes as a cause of toxic thyroid adenomas.";
RL J. Clin. Endocrinol. Metab. 82:2695-2701(1997).
RN [37]
RP VARIANT CHNG1 TRP-390.
RX PubMed=9329388; DOI=10.1210/jcem.82.10.4286;
RA Biebermann H., Schoeneberg T., Krude H., Schultz G., Gudermann T.,
RA Grueters A.;
RT "Mutations of the human thyrotropin receptor gene causing thyroid
RT hypoplasia and persistent congenital hypothyroidism.";
RL J. Clin. Endocrinol. Metab. 82:3471-3480(1997).
RN [38]
RP VARIANT HTNA ASN-505.
RX PubMed=9360555; DOI=10.1210/jcem.82.11.4378;
RA Holzapfel H.P., Wonerow P., von Petrykowski W., Henschen M.,
RA Scherbaum W.A., Paschke R.;
RT "Sporadic congenital hyperthyroidism due to a spontaneous germline mutation
RT in the thyrotropin receptor gene.";
RL J. Clin. Endocrinol. Metab. 82:3879-3884(1997).
RN [39]
RP VARIANT HTNA PHE-629.
RX PubMed=9398746; DOI=10.1210/jcem.82.12.4405;
RA Fuhrer D., Wonerow P., Willgerodt H., Paschke R.;
RT "Identification of a new thyrotropin receptor germline mutation (Leu629Phe)
RT in a family with neonatal onset of autosomal dominant nonautoimmune
RT hyperthyroidism.";
RL J. Clin. Endocrinol. Metab. 82:4234-4238(1997).
RN [40]
RP VARIANT CHNG1 THR-553.
RX PubMed=9185526; DOI=10.1172/jci119497;
RA Abramowicz M.J., Duprez L., Parma J., Vassart G., Heinrichs C.;
RT "Familial congenital hypothyroidism due to inactivating mutation of the
RT thyrotropin receptor causing profound hypoplasia of the thyroid gland.";
RL J. Clin. Invest. 99:3018-3024(1997).
RN [41]
RP VARIANT HYPERTHYROIDISM ILE-281.
RX PubMed=9294132; DOI=10.1172/jci119687;
RA Kopp P., Muirhead S., Jourdain N., Gu W.X., Jameson J.L., Rodd C.;
RT "Congenital hyperthyroidism caused by a solitary toxic adenoma harboring a
RT novel somatic mutation (serine281-->isoleucine) in the extracellular domain
RT of the thyrotropin receptor.";
RL J. Clin. Invest. 100:1634-1639(1997).
RN [42]
RP VARIANT HTNA ILE-632.
RX PubMed=9349581; DOI=10.1089/thy.1997.7.765;
RA Kopp P., Jameson J.L., Roe T.F.;
RT "Congenital nonautoimmune hyperthyroidism in a nonidentical twin caused by
RT a sporadic germline mutation in the thyrotropin receptor gene.";
RL Thyroid 7:765-770(1997).
RN [43]
RP VARIANT HTNA ASN-281, AND VARIANT HIS-528.
RX PubMed=9589634; DOI=10.1210/jcem.83.5.4776;
RA Grueters A., Schoeneberg T., Biebermann H., Krude H., Krohn H.P.,
RA Dralle H., Gudermann T.;
RT "Severe congenital hyperthyroidism caused by a germ-line neo mutation in
RT the extracellular portion of the thyrotropin receptor.";
RL J. Clin. Endocrinol. Metab. 83:1431-1436(1998).
RN [44]
RP VARIANT HTFG ARG-183.
RX PubMed=9854118; DOI=10.1056/nejm199812173392505;
RA Rodien P., Bremont C., Raffin Sanson M.-L., Parma J., van Sande J.,
RA Costagliola S., Luton J.-P., Vassart G., Duprez L.;
RT "Familial gestational hyperthyroidism caused by a mutant thyrotropin
RT receptor hypersensitive to human chorionic gonadotropin.";
RL N. Engl. J. Med. 339:1823-1826(1998).
RN [45]
RP VARIANT HTNA SER-639.
RX PubMed=10199795; DOI=10.1210/jcem.84.4.5620;
RA Khoo D.H.C., Parma J., Rajasoorya C., Ho S.C., Vassart G.;
RT "A germline mutation of the thyrotropin receptor gene associated with
RT thyrotoxicosis and mitral valve prolapse in a Chinese family.";
RL J. Clin. Endocrinol. Metab. 84:1459-1462(1999).
RN [46]
RP VARIANTS MET-606; GLY-703; GLU-720 AND GLU-727.
RX PubMed=10487707; DOI=10.1210/jcem.84.9.5966;
RA Gabriel E.M., Bergert E.R., Grant C.S., van Heerden J.A., Thompson G.B.,
RA Morris J.C.;
RT "Germline polymorphism of codon 727 of human thyroid-stimulating hormone
RT receptor is associated with toxic multinodular goiter.";
RL J. Clin. Endocrinol. Metab. 84:3328-3335(1999).
RN [47]
RP VARIANT THYROID CARCINOMA VAL-677.
RX PubMed=10037070; DOI=10.1089/thy.1999.9.13;
RA Russo D., Wong M.G., Costante G., Chiefari E., Treseler P.A., Arturi F.,
RA Filetti S., Clark O.H.;
RT "A Val 677 activating mutation of the thyrotropin receptor in a Hurthle
RT cell thyroid carcinoma associated with thyrotoxicosis.";
RL Thyroid 9:13-17(1999).
RN [48]
RP VARIANT HYPERTHYROIDISM LEU-597.
RX PubMed=10560955; DOI=10.1089/thy.1999.9.1005;
RA Esapa C.T., Duprez L., Ludgate M., Mustafa M.S., Kendall-Taylor P.,
RA Vassart G., Harris P.E.;
RT "A novel thyrotropin receptor mutation in an infant with severe
RT thyrotoxicosis.";
RL Thyroid 9:1005-1010(1999).
RN [49]
RP VARIANT HYPERTHYROIDISM ARG-512, AND CHARACTERIZATION OF VARIANT
RP HYPERTHYROIDISM ARG-512.
RX PubMed=11022192; DOI=10.1530/eje.0.1430471;
RA Kosugi S., Hai N., Okamoto H., Sugawa H., Mori T.;
RT "A novel activating mutation in the thyrotropin receptor gene in an
RT autonomously functioning thyroid nodule developed by a Japanese patient.";
RL Eur. J. Endocrinol. 143:471-477(2000).
RN [50]
RP VARIANT THR-52.
RX PubMed=10651846; DOI=10.1046/j.1365-2370.2000.00187.x;
RA Kaczur V., Takacs M., Szalai C., Falus A., Nagy Z., Berencsi G., Balazs C.;
RT "Analysis of the genetic variability of the 1st (CCC/ACC, P52T) and the
RT 10th exons (bp 1012-1704) of the TSH receptor gene in Graves' disease.";
RL Eur. J. Immunogenet. 27:17-23(2000).
RN [51]
RP VARIANT CHNG1 ILE-477.
RX PubMed=10720030; DOI=10.1210/jcem.85.3.6460;
RA Tonacchera M., Agretti P., Pinchera A., Rosellini V., Perri A.,
RA Collecchi P., Vitti P., Chiovato L.;
RT "Congenital hypothyroidism with impaired thyroid response to thyrotropin
RT (TSH) and absent circulating thyroglobulin: evidence for a new inactivating
RT mutation of the TSH receptor gene.";
RL J. Clin. Endocrinol. Metab. 85:1001-1008(2000).
RN [52]
RP VARIANTS HTNA ASN-281; MET-486; PHE-486; PHE-629; ALA-632; ILE-632; GLU-633
RP AND VAL-647.
RX PubMed=10852462; DOI=10.1210/jcem.85.6.6634;
RA Tonacchera M., Agretti P., Chiovato L., Rosellini V., Ceccarini G.,
RA Perri A., Viacava P., Naccarato A.G., Miccoli P., Pinchera A., Vitti P.;
RT "Activating thyrotropin receptor mutations are present in nonadenomatous
RT hyperfunctioning nodules of toxic or autonomous multinodular goiter.";
RL J. Clin. Endocrinol. Metab. 85:2270-2274(2000).
RN [53]
RP VARIANT GLU-727.
RX PubMed=10946859; DOI=10.1210/jcem.85.8.6704;
RA Muehlberg T., Herrmann K., Joba W., Kirchberger M., Heberling H.-J.,
RA Heufelder A.E.;
RT "Lack of association of nonautoimmune hyperfunctioning thyroid disorders
RT and a germline polymorphism of codon 727 of the human thyrotropin receptor
RT in a European Caucasian population.";
RL J. Clin. Endocrinol. Metab. 85:2640-2643(2000).
RN [54]
RP VARIANT CHNG1 CYS-310.
RX PubMed=11095460; DOI=10.1210/jcem.85.11.6985;
RA Russo D., Betterle C., Arturi F., Chiefari E., Girelli M.E., Filetti S.;
RT "A novel mutation in the thyrotropin (TSH) receptor gene causing loss of
RT TSH binding but constitutive receptor activation in a family with
RT resistance to TSH.";
RL J. Clin. Endocrinol. Metab. 85:4238-4242(2000).
RN [55]
RP VARIANTS HTNA ASN-281; SER-431 AND ILE-632.
RX PubMed=11127522; DOI=10.1007/s004230000145;
RA Biebermann H., Schoeneberg T., Krude H., Gudermann T., Grueters A.;
RT "Constitutively activating TSH-receptor mutations as a molecular cause of
RT non-autoimmune hyperthyroidism in childhood.";
RL Langenbecks Arch. Surg. 385:390-392(2000).
RN [56]
RP VARIANT HTNA THR-568.
RX PubMed=11081252; DOI=10.1089/thy.2000.10.859;
RA Tonacchera M., Agretti P., Rosellini V., Ceccarini G., Perri A.,
RA Zampolli M., Longhi R., Larizza D., Pinchera A., Vitti P., Chiovato L.;
RT "Sporadic nonautoimmune congenital hyperthyroidism due to a strong
RT activating mutation of the thyrotropin receptor gene.";
RL Thyroid 10:859-863(2000).
RN [57]
RP VARIANT FOLLICULAR CARCINOMA PHE-486.
RX PubMed=11128715; DOI=10.1089/thy.2000.10.1009;
RA Camacho P., Gordon D., Chiefari E., Yong S., DeJong S., Pitale S.,
RA Russo D., Filetti S.;
RT "A Phe 486 thyrotropin receptor mutation in an autonomously functioning
RT follicular carcinoma that was causing hyperthyroidism.";
RL Thyroid 10:1009-1012(2000).
RN [58]
RP VARIANT HTNA VAL-463.
RX PubMed=11201847; DOI=10.1089/thy.2000.10.1035;
RA Fuhrer D., Warner J., Sequeira M., Paschke R., Gregory J.W., Ludgate M.;
RT "Novel TSHR germline mutation (Met463Val) masquerading as Graves' disease
RT in a large Welsh kindred with hyperthyroidism.";
RL Thyroid 10:1035-1041(2000).
RN [59]
RP VARIANT HTNA PHE-597, AND CHARACTERIZATION OF VARIANT HTNA PHE-597.
RX PubMed=11517004; DOI=10.1530/eje.0.1450249;
RA Alberti L., Proverbio M.C., Costagliola S., Weber G., Beck-Peccoz P.,
RA Chiumello G., Persani L.;
RT "A novel germline mutation in the TSH receptor gene causes non-autoimmune
RT autosomal dominant hyperthyroidism.";
RL Eur. J. Endocrinol. 145:249-254(2001).
RN [60]
RP VARIANT HTNA SER-431, AND CHARACTERIZATION OF VARIANT HTNA SER-431.
RX PubMed=11549687; DOI=10.1210/jcem.86.9.7888;
RA Biebermann H., Schoeneberg T., Hess C., Germak J., Gudermann T.,
RA Grueters A.;
RT "The first activating TSH receptor mutation in transmembrane domain 1
RT identified in a family with nonautoimmune hyperthyroidism.";
RL J. Clin. Endocrinol. Metab. 86:4429-4433(2001).
RN [61]
RP VARIANTS ASN-281; ILE-425; THR-453; PHE-486; ASN-505; ARG-512; GLN-512;
RP THR-568; GLY-619; VAL-623; LEU-631; ALA-632; ILE-632; GLU-633; HIS-633;
RP TYR-633; ALA-639 AND PHE-656, AND CHARACTERIZATION OF VARIANTS ILE-425 AND
RP GLN-512.
RX PubMed=11434721; DOI=10.1007/s001090000170;
RA Truelzsch B., Krohn K., Wonerow P., Chey S., Holzapfel H.-P., Ackermann F.,
RA Fuehrer D., Paschke R.;
RT "Detection of thyroid-stimulating hormone receptor and G(s)alpha mutations:
RT in 75 toxic thyroid nodules by denaturing gradient gel electrophoresis.";
RL J. Mol. Med. 78:684-691(2001).
RN [62]
RP VARIANTS CHNG1 HIS-450 AND SER-498.
RX PubMed=11442002; DOI=10.1089/105072501750302859;
RA Nagashima T., Murakami M., Onigata K., Morimura T., Nagashima K., Mori M.,
RA Morikawa A.;
RT "Novel inactivating missense mutations in the thyrotropin receptor gene in
RT Japanese children with resistance to thyrotropin.";
RL Thyroid 11:551-559(2001).
RN [63]
RP VARIANTS HYPERTHYROIDISM THR-453; MET-486; ARG-512 AND ALA-632.
RX PubMed=12213664; DOI=10.1530/eje.0.1470287;
RA Vanvooren V., Uchino S., Duprez L., Costa M.J., Vandekerckhove J.,
RA Parma J., Vassart G., Dumont J.E., van Sande J., Noguchi S.;
RT "Oncogenic mutations in the thyrotropin receptor of autonomously
RT functioning thyroid nodules in the Japanese population.";
RL Eur. J. Endocrinol. 147:287-291(2002).
RN [64]
RP VARIANTS CHNG1 SER-41; ALA-162; PRO-467 AND ARG-600.
RX PubMed=12050212; DOI=10.1210/jcem.87.6.8536;
RA Alberti L., Proverbio M.C., Costagliola S., Romoli R., Boldrighini B.,
RA Vigone M.C., Weber G., Chiumello G., Beck-Peccoz P., Persani L.;
RT "Germline mutations of TSH receptor gene as cause of nonautoimmune
RT subclinical hypothyroidism.";
RL J. Clin. Endocrinol. Metab. 87:2549-2555(2002).
RN [65]
RP VARIANT TOXIC THYROID ADENOMA ASN-593, VARIANT GLU-727, CHARACTERIZATION OF
RP VARIANT TOXIC THYROID ADENOMA ASN-593, AND CHARACTERIZATION OF VARIANT
RP GLU-727.
RX PubMed=12589819; DOI=10.1016/s0006-291x(03)00071-8;
RA Sykiotis G.P., Neumann S., Georgopoulos N.A., Sgourou A.,
RA Papachatzopoulou A., Markou K.B., Kyriazopoulou V., Paschke R.,
RA Vagenakis A.G., Papavassiliou A.G.;
RT "Functional significance of the thyrotropin receptor germline polymorphism
RT D727E.";
RL Biochem. Biophys. Res. Commun. 301:1051-1056(2003).
RN [66]
RP VARIANTS HIS-36; THR-52 AND GLU-727, AND ASSOCIATION WITH PLASMA TSH LEVEL.
RX PubMed=12788902; DOI=10.1210/jc.2002-021592;
RA Peeters R.P., van Toor H., Klootwijk W., de Rijke Y.B., Kuiper G.G.J.M.,
RA Uitterlinden A.G., Visser T.J.;
RT "Polymorphisms in thyroid hormone pathway genes are associated with plasma
RT TSH and iodothyronine levels in healthy subjects.";
RL J. Clin. Endocrinol. Metab. 88:2880-2888(2003).
RN [67]
RP VARIANTS HIS-36 AND THR-52, AND RECEPTOR GENETIC ANALYSIS IN CHILDREN WITH
RP DOWN'S SYNDROME.
RX PubMed=14759073; DOI=10.1007/bf03348198;
RA Tonacchera M., Perri A., De Marco G., Agretti P., Montanelli L.,
RA Banco M.E., Corrias A., Bellone J., Tosi M.T., Vitti P., Martino E.,
RA Pinchera A., Chiovato L.;
RT "TSH receptor and Gs(alpha) genetic analysis in children with Down's
RT syndrome and subclinical hypothyroidism.";
RL J. Endocrinol. Invest. 26:997-1000(2003).
RN [68]
RP VARIANT CHNG1 THR-553.
RX PubMed=14725684; DOI=10.1111/j.1365-2265.2004.01967.x;
RA Park S.-M., Clifton-Bligh R.J., Betts P., Chatterjee V.K.K.;
RT "Congenital hypothyroidism and apparent athyreosis with compound
RT heterozygosity or compensated hypothyroidism with probable hemizygosity for
RT inactivating mutations of the TSH receptor.";
RL Clin. Endocrinol. (Oxf.) 60:220-227(2004).
RN [69]
RP VARIANT HTNA ASN-505.
RX PubMed=15163335; DOI=10.1111/j.1365-2265.2004.02040.x;
RA Vaidya B., Campbell V., Tripp J.H., Spyer G., Hattersley A.T., Ellard S.;
RT "Premature birth and low birth weight associated with nonautoimmune
RT hyperthyroidism due to an activating thyrotropin receptor gene mutation.";
RL Clin. Endocrinol. (Oxf.) 60:711-718(2004).
RN [70]
RP VARIANTS CHNG1 ALA-162 AND PRO-252, AND CHARACTERIZATION OF VARIANT CHNG1
RP PRO-252.
RX PubMed=15531543; DOI=10.1210/jc.2004-1243;
RA Tonacchera M., Perri A., De Marco G., Agretti P., Banco M.E., Di Cosmo C.,
RA Grasso L., Vitti P., Chiovato L., Pinchera A.;
RT "Low prevalence of thyrotropin receptor mutations in a large series of
RT subjects with sporadic and familial nonautoimmune subclinical
RT hypothyroidism.";
RL J. Clin. Endocrinol. Metab. 89:5787-5793(2004).
RN [71]
RP VARIANTS CHNG1 ALA-162; ASP-432 AND LEU-449, AND CHARACTERIZATION OF
RP VARIANTS CHNG1 ASP-432 AND LEU-449.
RX PubMed=25978107; DOI=10.1210/jc.2014-4511;
RA Labadi A., Grassi E.S., Gellen B., Kleinau G., Biebermann H., Ruzsa B.,
RA Gelmini G., Rideg O., Miseta A., Kovacs G.L., Patocs A., Felszeghy E.,
RA Nagy E.V., Mezosi E., Persani L.;
RT "Loss-of-function variants in a Hungarian cohort reveal structural insights
RT on TSH receptor maturation and signaling.";
RL J. Clin. Endocrinol. Metab. 100:E1039-E1045(2015).
CC -!- FUNCTION: Receptor for the thyroid-stimulating hormone (TSH) or
CC thyrotropin (PubMed:11847099, PubMed:12045258). Also acts as a receptor
CC for the heterodimeric glycoprotein hormone (GPHA2:GPHB5) or
CC thyrostimulin (PubMed:12045258). The activity of this receptor is
CC mediated by G proteins which activate adenylate cyclase
CC (PubMed:11847099). Plays a central role in controlling thyroid cell
CC metabolism (By similarity). {ECO:0000250|UniProtKB:P21463,
CC ECO:0000269|PubMed:11847099, ECO:0000269|PubMed:12045258}.
CC -!- SUBUNIT: Interacts with heterodimer GPHA2:GPHB5; this interaction
CC stimulates cAMP production (PubMed:12045258). Interacts (via the PDZ-
CC binding motif) with SCRIB; regulates TSHR trafficking and function
CC (PubMed:15775968). {ECO:0000269|PubMed:12045258,
CC ECO:0000269|PubMed:15775968}.
CC -!- INTERACTION:
CC P16473; P30542: ADORA1; NbExp=2; IntAct=EBI-13939599, EBI-2903663;
CC P16473; Q9NPA3: MID1IP1; NbExp=2; IntAct=EBI-13939599, EBI-750096;
CC P16473; Q14160: SCRIB; NbExp=3; IntAct=EBI-13939599, EBI-357345;
CC P16473; P21579: SYT1; NbExp=2; IntAct=EBI-13939599, EBI-524909;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:11847099};
CC Multi-pass membrane protein {ECO:0000305}. Basolateral cell membrane
CC {ECO:0000269|PubMed:11847099}; Multi-pass membrane protein
CC {ECO:0000305}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Comment=Additional isoforms seem to exist.;
CC Name=Long;
CC IsoId=P16473-1; Sequence=Displayed;
CC Name=Short;
CC IsoId=P16473-2; Sequence=VSP_001981, VSP_001982;
CC Name=3;
CC IsoId=P16473-3; Sequence=VSP_044643, VSP_044644;
CC -!- TISSUE SPECIFICITY: Expressed in thyroide cells (at protein level)
CC (PubMed:11847099). Expressed in the thyroid (PubMed:2610690).
CC {ECO:0000269|PubMed:11847099, ECO:0000269|PubMed:2610690}.
CC -!- PTM: Glycosylated. {ECO:0000269|PubMed:11847099}.
CC -!- PTM: Sulfated. Sulfation on Tyr-385 plays a role in thyrotropin
CC receptor binding and activation. {ECO:0000269|PubMed:11847099}.
CC -!- POLYMORPHISM: The Asp727Glu polymorphism is associated with Graves
CC disease in a Russian population. The Glu727 allele and the heterozygous
CC Asp727Glu genotype are related to higher risk of the disease. The
CC Asp727Glu polymorphism significantly ameliorates G(s)alpha protein
CC activation in the presence of the gain-of-function mutation Ala593Asn
CC although it is functionally inert in the context of the wild-type TSHR.
CC {ECO:0000269|PubMed:11887032}.
CC -!- DISEASE: Note=Defects in TSHR are found in patients affected by
CC hyperthyroidism with different etiologies. Somatic, constitutively
CC activating TSHR mutations and/or constitutively activating G(s)alpha
CC mutations have been identified in toxic thyroid nodules (TTNs) that are
CC the predominant cause of hyperthyroidism in iodine deficient areas.
CC These mutations lead to TSH independent activation of the cAMP cascade
CC resulting in thyroid growth and hormone production. TSHR mutations are
CC found in autonomously functioning thyroid nodules (AFTN), toxic
CC multinodular goiter (TMNG) and hyperfunctioning thyroid adenomas (HTA).
CC TMNG encompasses a spectrum of different clinical entities, ranging
CC from a single hyperfunctioning nodule within an enlarged thyroid, to
CC multiple hyperfunctioning areas scattered throughout the gland. HTA are
CC discrete encapsulated neoplasms characterized by TSH-independent
CC autonomous growth, hypersecretion of thyroid hormones, and TSH
CC suppression. Defects in TSHR are also a cause of thyroid neoplasms
CC (papillary and follicular cancers).
CC -!- DISEASE: Note=Autoantibodies against TSHR are directly responsible for
CC the pathogenesis and hyperthyroidism of Graves disease. Antibody
CC interaction with TSHR results in an uncontrolled receptor stimulation.
CC -!- DISEASE: Hypothyroidism, congenital, non-goitrous, 1 (CHNG1)
CC [MIM:275200]: A non-autoimmune condition characterized by resistance to
CC thyroid-stimulating hormone (TSH) leading to increased levels of plasma
CC TSH and low levels of thyroid hormone. It presents variable severity
CC depending on the completeness of the defect. Most patients are
CC euthyroid and asymptomatic, with a normal sized thyroid gland. Only a
CC subset of patients develop hypothyroidism and present a hypoplastic
CC thyroid gland. {ECO:0000269|PubMed:10720030,
CC ECO:0000269|PubMed:11095460, ECO:0000269|PubMed:11442002,
CC ECO:0000269|PubMed:12050212, ECO:0000269|PubMed:14725684,
CC ECO:0000269|PubMed:15531543, ECO:0000269|PubMed:25978107,
CC ECO:0000269|PubMed:7528344, ECO:0000269|PubMed:8954020,
CC ECO:0000269|PubMed:9100579, ECO:0000269|PubMed:9185526,
CC ECO:0000269|PubMed:9329388}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Familial gestational hyperthyroidism (HTFG) [MIM:603373]: A
CC condition characterized by abnormally high levels of serum thyroid
CC hormones occurring during early pregnancy.
CC {ECO:0000269|PubMed:9854118}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Hyperthyroidism, non-autoimmune (HTNA) [MIM:609152]: A
CC condition characterized by abnormally high levels of serum thyroid
CC hormones, thyroid hyperplasia, goiter and lack of anti-thyroid
CC antibodies. Typical features of Graves disease such as exophthalmia,
CC myxedema, antibodies anti-TSH receptor and lymphocytic infiltration of
CC the thyroid gland are absent. {ECO:0000269|PubMed:10199795,
CC ECO:0000269|PubMed:10852462, ECO:0000269|PubMed:11081252,
CC ECO:0000269|PubMed:11127522, ECO:0000269|PubMed:11201847,
CC ECO:0000269|PubMed:11517004, ECO:0000269|PubMed:11549687,
CC ECO:0000269|PubMed:15163335, ECO:0000269|PubMed:7800007,
CC ECO:0000269|PubMed:7920658, ECO:0000269|PubMed:8636266,
CC ECO:0000269|PubMed:8964822, ECO:0000269|PubMed:9349581,
CC ECO:0000269|PubMed:9360555, ECO:0000269|PubMed:9398746,
CC ECO:0000269|PubMed:9589634}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family.
CC FSH/LSH/TSH subfamily. {ECO:0000255|PROSITE-ProRule:PRU00521}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA70232.1; Type=Frameshift; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=TSH receptor database;
CC URL="https://endokrinologie.uniklinikum-leipzig.de/tsh/";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=TSH receptor entry;
CC URL="https://en.wikipedia.org/wiki/TSH_receptor";
CC -!- WEB RESOURCE: Name=Sequence-structure-function-analysis of glycoprotein
CC hormone receptors;
CC URL="http://www.ssfa-gphr.de/";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/TSHRID290ch14q31.html";
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; M31774; AAA36783.1; -; mRNA.
DR EMBL; M32215; AAA61236.1; -; mRNA.
DR EMBL; M73747; AAA70232.1; ALT_FRAME; mRNA.
DR EMBL; S45272; AAB23390.2; -; mRNA.
DR EMBL; S49816; AAB24246.1; -; mRNA.
DR EMBL; AY429111; AAR07906.1; -; mRNA.
DR EMBL; AC007262; AAD31568.1; -; Genomic_DNA.
DR EMBL; AC010072; AAF09032.1; -; Genomic_DNA.
DR EMBL; AC010582; AAF26775.1; -; Genomic_DNA.
DR EMBL; AL136040; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC009237; AAH09237.1; -; mRNA.
DR EMBL; BC024205; AAH24205.1; -; mRNA.
DR EMBL; BC063613; AAH63613.1; -; mRNA.
DR EMBL; BC108653; AAI08654.1; -; mRNA.
DR EMBL; BC120973; AAI20974.1; -; mRNA.
DR EMBL; BC127628; AAI27629.1; -; mRNA.
DR EMBL; BC141970; AAI41971.1; -; mRNA.
DR CCDS; CCDS32131.1; -. [P16473-2]
DR CCDS; CCDS55935.1; -. [P16473-3]
DR CCDS; CCDS9872.1; -. [P16473-1]
DR PIR; A33789; QRHURH.
DR PIR; JC1319; JC1319.
DR PIR; T01787; T01787.
DR RefSeq; NP_000360.2; NM_000369.2.
DR RefSeq; NP_001018046.1; NM_001018036.2. [P16473-2]
DR RefSeq; NP_001136098.1; NM_001142626.2. [P16473-3]
DR RefSeq; XP_005268096.1; XM_005268039.1. [P16473-2]
DR RefSeq; XP_006720308.1; XM_006720245.1. [P16473-3]
DR PDB; 2XWT; X-ray; 1.90 A; C=22-260.
DR PDB; 3G04; X-ray; 2.55 A; C=22-260.
DR PDBsum; 2XWT; -.
DR PDBsum; 3G04; -.
DR AlphaFoldDB; P16473; -.
DR SMR; P16473; -.
DR BioGRID; 113104; 109.
DR IntAct; P16473; 25.
DR MINT; P16473; -.
DR STRING; 9606.ENSP00000441235; -.
DR BindingDB; P16473; -.
DR ChEMBL; CHEMBL1963; -.
DR DrugBank; DB00024; Thyrotropin alfa.
DR DrugCentral; P16473; -.
DR GuidetoPHARMACOLOGY; 255; -.
DR GlyGen; P16473; 6 sites.
DR iPTMnet; P16473; -.
DR PhosphoSitePlus; P16473; -.
DR SwissPalm; P16473; -.
DR BioMuta; TSHR; -.
DR DMDM; 62298994; -.
DR MassIVE; P16473; -.
DR PaxDb; P16473; -.
DR PeptideAtlas; P16473; -.
DR PRIDE; P16473; -.
DR ProteomicsDB; 24847; -.
DR ProteomicsDB; 32578; -.
DR ProteomicsDB; 53374; -. [P16473-1]
DR ProteomicsDB; 53375; -. [P16473-2]
DR ABCD; P16473; 14 sequenced antibodies.
DR Antibodypedia; 4379; 1130 antibodies from 38 providers.
DR DNASU; 7253; -.
DR Ensembl; ENST00000342443.10; ENSP00000340113.6; ENSG00000165409.18. [P16473-2]
DR Ensembl; ENST00000554435.1; ENSP00000450549.1; ENSG00000165409.18. [P16473-3]
DR GeneID; 7253; -.
DR KEGG; hsa:7253; -.
DR UCSC; uc001xvc.4; human. [P16473-1]
DR CTD; 7253; -.
DR DisGeNET; 7253; -.
DR GeneCards; TSHR; -.
DR HGNC; HGNC:12373; TSHR.
DR HPA; ENSG00000165409; Tissue enriched (thyroid).
DR MalaCards; TSHR; -.
DR MIM; 275200; phenotype.
DR MIM; 603372; gene+phenotype.
DR MIM; 603373; phenotype.
DR MIM; 609152; phenotype.
DR neXtProt; NX_P16473; -.
DR OpenTargets; ENSG00000165409; -.
DR Orphanet; 95713; Athyreosis.
DR Orphanet; 99819; Familial gestational hyperthyroidism.
DR Orphanet; 424; Familial hyperthyroidism due to mutations in TSH receptor.
DR Orphanet; 90673; Hypothyroidism due to TSH receptor mutations.
DR Orphanet; 95720; Thyroid hypoplasia.
DR PharmGKB; PA37042; -.
DR VEuPathDB; HostDB:ENSG00000165409; -.
DR eggNOG; KOG2087; Eukaryota.
DR GeneTree; ENSGT00940000156510; -.
DR InParanoid; P16473; -.
DR PhylomeDB; P16473; -.
DR TreeFam; TF316814; -.
DR PathwayCommons; P16473; -.
DR Reactome; R-HSA-375281; Hormone ligand-binding receptors.
DR Reactome; R-HSA-418555; G alpha (s) signalling events.
DR Reactome; R-HSA-9660821; ADORA2B mediated anti-inflammatory cytokines production.
DR SignaLink; P16473; -.
DR SIGNOR; P16473; -.
DR BioGRID-ORCS; 7253; 11 hits in 1068 CRISPR screens.
DR ChiTaRS; TSHR; human.
DR EvolutionaryTrace; P16473; -.
DR GeneWiki; Thyrotropin_receptor; -.
DR GenomeRNAi; 7253; -.
DR Pharos; P16473; Tclin.
DR PRO; PR:P16473; -.
DR Proteomes; UP000005640; Chromosome 14.
DR RNAct; P16473; protein.
DR Bgee; ENSG00000165409; Expressed in left lobe of thyroid gland and 108 other tissues.
DR ExpressionAtlas; P16473; baseline and differential.
DR Genevisible; P16473; HS.
DR GO; GO:0016323; C:basolateral plasma membrane; IDA:UniProtKB.
DR GO; GO:0009986; C:cell surface; ISS:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0043235; C:receptor complex; IDA:MGI.
DR GO; GO:0008528; F:G protein-coupled peptide receptor activity; IBA:GO_Central.
DR GO; GO:0044877; F:protein-containing complex binding; IDA:UniProtKB.
DR GO; GO:0038023; F:signaling receptor activity; IMP:UniProtKB.
DR GO; GO:0004996; F:thyroid-stimulating hormone receptor activity; IMP:UniProtKB.
DR GO; GO:0007190; P:activation of adenylate cyclase activity; IBA:GO_Central.
DR GO; GO:0007189; P:adenylate cyclase-activating G protein-coupled receptor signaling pathway; IMP:UniProtKB.
DR GO; GO:0007166; P:cell surface receptor signaling pathway; IMP:UniProtKB.
DR GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc.
DR GO; GO:1904588; P:cellular response to glycoprotein; IMP:UniProtKB.
DR GO; GO:1905229; P:cellular response to thyrotropin-releasing hormone; IMP:UniProtKB.
DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; TAS:ProtInc.
DR GO; GO:0007187; P:G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger; TAS:ProtInc.
DR GO; GO:0009755; P:hormone-mediated signaling pathway; IBA:GO_Central.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; TAS:ProtInc.
DR GO; GO:0120162; P:positive regulation of cold-induced thermogenesis; ISS:YuBioLab.
DR GO; GO:0038194; P:thyroid-stimulating hormone signaling pathway; IMP:UniProtKB.
DR Gene3D; 3.80.10.10; -; 1.
DR InterPro; IPR000276; GPCR_Rhodpsn.
DR InterPro; IPR017452; GPCR_Rhodpsn_7TM.
DR InterPro; IPR002131; Gphrmn_rcpt_fam.
DR InterPro; IPR026906; LRR_5.
DR InterPro; IPR032675; LRR_dom_sf.
DR InterPro; IPR002274; TSH_rcpt.
DR PANTHER; PTHR24372:SF0; PTHR24372:SF0; 1.
DR Pfam; PF00001; 7tm_1; 1.
DR Pfam; PF13306; LRR_5; 2.
DR PRINTS; PR00373; GLYCHORMONER.
DR PRINTS; PR00237; GPCRRHODOPSN.
DR PRINTS; PR01145; TSHRECEPTOR.
DR PROSITE; PS00237; G_PROTEIN_RECEP_F1_1; 1.
DR PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane;
KW Congenital hypothyroidism; Direct protein sequencing; Disease variant;
KW Disulfide bond; G-protein coupled receptor; Glycoprotein;
KW Leucine-rich repeat; Membrane; Receptor; Reference proteome; Repeat;
KW Signal; Sulfation; Transducer; Transmembrane; Transmembrane helix.
FT SIGNAL 1..20
FT CHAIN 21..764
FT /note="Thyrotropin receptor"
FT /id="PRO_0000012786"
FT TOPO_DOM 21..413
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 414..441
FT /note="Helical; Name=1"
FT /evidence="ECO:0000255"
FT TOPO_DOM 442..450
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 451..473
FT /note="Helical; Name=2"
FT /evidence="ECO:0000255"
FT TOPO_DOM 474..494
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 495..517
FT /note="Helical; Name=3"
FT /evidence="ECO:0000255"
FT TOPO_DOM 518..537
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 538..560
FT /note="Helical; Name=4"
FT /evidence="ECO:0000255"
FT TOPO_DOM 561..580
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 581..602
FT /note="Helical; Name=5"
FT /evidence="ECO:0000255"
FT TOPO_DOM 603..625
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 626..649
FT /note="Helical; Name=6"
FT /evidence="ECO:0000255"
FT TOPO_DOM 650..660
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 661..682
FT /note="Helical; Name=7"
FT /evidence="ECO:0000255"
FT TOPO_DOM 683..764
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REPEAT 100..124
FT /note="LRR 1"
FT REPEAT 125..150
FT /note="LRR 2"
FT REPEAT 152..174
FT /note="LRR 3"
FT REPEAT 176..199
FT /note="LRR 4"
FT REPEAT 200..223
FT /note="LRR 5"
FT REPEAT 227..248
FT /note="LRR 6"
FT REPEAT 250..271
FT /note="LRR 7"
FT MOTIF 762..764
FT /note="PDZ-binding"
FT MOD_RES 385
FT /note="Sulfotyrosine"
FT /evidence="ECO:0000305|PubMed:11847099"
FT CARBOHYD 77
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:11502179,
FT ECO:0000269|PubMed:17542669"
FT CARBOHYD 99
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:17542669"
FT CARBOHYD 113
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:11502179,
FT ECO:0000269|PubMed:17542669"
FT CARBOHYD 177
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:17542669"
FT CARBOHYD 198
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:11502179,
FT ECO:0000269|PubMed:17542669"
FT CARBOHYD 302
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:11502179"
FT DISULFID 31..41
FT DISULFID 494..569
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00521"
FT VAR_SEQ 232..274
FT /note="DVSQTSVTALPSKGLEHLKELIARNTWTLKKLPLSLSFLHLTR -> VENVA
FT VSGKGFCKSLFSWLYRLPLGRKSLSFETQKAPRSSMPS (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_044643"
FT VAR_SEQ 232..253
FT /note="DVSQTSVTALPSKGLEHLKELI -> LPLGRKSLSFETQKAPRSSMPS (in
FT isoform Short)"
FT /evidence="ECO:0000303|PubMed:1445355,
FT ECO:0000303|PubMed:1530609, ECO:0000303|PubMed:15489334"
FT /id="VSP_001981"
FT VAR_SEQ 254..764
FT /note="Missing (in isoform Short)"
FT /evidence="ECO:0000303|PubMed:1445355,
FT ECO:0000303|PubMed:1530609, ECO:0000303|PubMed:15489334"
FT /id="VSP_001982"
FT VAR_SEQ 275..764
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_044644"
FT VARIANT 34
FT /note="E -> K (in dbSNP:rs45499704)"
FT /id="VAR_055925"
FT VARIANT 36
FT /note="D -> H (in a patient with Graves disease;
FT dbSNP:rs61747482)"
FT /evidence="ECO:0000269|PubMed:12788902,
FT ECO:0000269|PubMed:12930595, ECO:0000269|PubMed:14759073,
FT ECO:0000269|PubMed:1955520, ECO:0000269|PubMed:7556878"
FT /id="VAR_003564"
FT VARIANT 41
FT /note="C -> S (in CHNG1)"
FT /evidence="ECO:0000269|PubMed:12050212,
FT ECO:0000269|PubMed:8954020"
FT /id="VAR_011519"
FT VARIANT 52
FT /note="P -> T (does not contribute to the genetic
FT susceptibility to Graves disease; dbSNP:rs2234919)"
FT /evidence="ECO:0000269|PubMed:10651846,
FT ECO:0000269|PubMed:12788902, ECO:0000269|PubMed:12930595,
FT ECO:0000269|PubMed:14759073, ECO:0000269|PubMed:7488864,
FT ECO:0000269|PubMed:7508946, ECO:0000269|PubMed:7528344"
FT /id="VAR_003565"
FT VARIANT 109
FT /note="R -> Q (in CHNG1)"
FT /evidence="ECO:0000269|PubMed:9100579"
FT /id="VAR_011520"
FT VARIANT 162
FT /note="P -> A (in CHNG1; dbSNP:rs121908863)"
FT /evidence="ECO:0000269|PubMed:12050212,
FT ECO:0000269|PubMed:15531543, ECO:0000269|PubMed:25978107,
FT ECO:0000269|PubMed:7528344, ECO:0000269|PubMed:8954020"
FT /id="VAR_011521"
FT VARIANT 167
FT /note="I -> N (in CHNG1)"
FT /evidence="ECO:0000269|PubMed:7528344"
FT /id="VAR_011522"
FT VARIANT 183
FT /note="K -> R (in HTFG; enhances receptor response to
FT chorionic gonadotropin)"
FT /evidence="ECO:0000269|PubMed:9854118"
FT /id="VAR_003566"
FT VARIANT 197
FT /note="F -> I (in papillary cancer)"
FT /evidence="ECO:0000269|PubMed:7647578"
FT /id="VAR_003567"
FT VARIANT 219
FT /note="D -> E (in papillary cancer)"
FT /evidence="ECO:0000269|PubMed:7647578"
FT /id="VAR_003568"
FT VARIANT 252
FT /note="L -> P (in CHNG1; displays a low expression at the
FT cell surface and a reduced response to bovine TSH in terms
FT of cAMP production)"
FT /evidence="ECO:0000269|PubMed:15531543"
FT /id="VAR_021495"
FT VARIANT 281
FT /note="S -> I (in hyperthyroidism; congenital; due to a
FT toxic adenoma)"
FT /evidence="ECO:0000269|PubMed:9294132"
FT /id="VAR_003569"
FT VARIANT 281
FT /note="S -> N (in HTNA; gain of function; found in toxic
FT thyroid nodules and hyperfunctioning thyroid adenomas)"
FT /evidence="ECO:0000269|PubMed:10852462,
FT ECO:0000269|PubMed:11127522, ECO:0000269|PubMed:11434721,
FT ECO:0000269|PubMed:9253356, ECO:0000269|PubMed:9589634"
FT /id="VAR_003570"
FT VARIANT 281
FT /note="S -> T (in hyperthyroidism; associated with
FT hyperfunctioning thyroid adenomas)"
FT /evidence="ECO:0000269|PubMed:9253356"
FT /id="VAR_011523"
FT VARIANT 310
FT /note="R -> C (in CHNG1)"
FT /evidence="ECO:0000269|PubMed:11095460"
FT /id="VAR_011524"
FT VARIANT 390
FT /note="C -> W (in CHNG1; persistent hypothyroidism and
FT defective thyroid development; abolishes high affinity
FT hormone binding)"
FT /evidence="ECO:0000269|PubMed:8954020,
FT ECO:0000269|PubMed:9329388"
FT /id="VAR_011525"
FT VARIANT 410
FT /note="D -> N (in CHNG1; lack of adenylate cyclase
FT activation)"
FT /evidence="ECO:0000269|PubMed:8954020"
FT /id="VAR_011526"
FT VARIANT 425
FT /note="S -> I (found in toxic thyroid nodules; 8 to 9 times
FT higher levels of basal cAMP than wild-type TSHR and similar
FT response to maximal TSH stimulation)"
FT /evidence="ECO:0000269|PubMed:11434721"
FT /id="VAR_021496"
FT VARIANT 431
FT /note="G -> S (in HTNA; gain of function; constitutive
FT activation of the G(s)/adenylyl cyclase system)"
FT /evidence="ECO:0000269|PubMed:11127522,
FT ECO:0000269|PubMed:11549687"
FT /id="VAR_011527"
FT VARIANT 432
FT /note="N -> D (in CHNG1; abolishes cell membrane location;
FT abolishes adenylate cyclase-activating G-protein coupled
FT receptor signaling pathway; abolishes phospholipase C-
FT activating G-protein coupled receptor signaling pathway)"
FT /evidence="ECO:0000269|PubMed:25978107"
FT /id="VAR_075585"
FT VARIANT 449
FT /note="P -> L (in CHNG1; no effect on cell membrane
FT location; upon TSH stimulation decreases more phospholipase
FT C-activating G-protein coupled receptor signaling pathway
FT than adenylate cyclase-activating G-protein coupled
FT receptor signaling pathway)"
FT /evidence="ECO:0000269|PubMed:25978107"
FT /id="VAR_075586"
FT VARIANT 450
FT /note="R -> H (in CHNG1)"
FT /evidence="ECO:0000269|PubMed:11442002"
FT /id="VAR_011528"
FT VARIANT 453
FT /note="M -> T (in HTNA; sporadic; found in toxic thyroid
FT nodules and hyperfunctioning thyroid adenomas)"
FT /evidence="ECO:0000269|PubMed:11434721,
FT ECO:0000269|PubMed:12213664, ECO:0000269|PubMed:8964822,
FT ECO:0000269|PubMed:9253356"
FT /id="VAR_011529"
FT VARIANT 463
FT /note="M -> V (in HTNA; gain of function)"
FT /evidence="ECO:0000269|PubMed:11201847"
FT /id="VAR_011530"
FT VARIANT 467
FT /note="L -> P (in CHNG1)"
FT /evidence="ECO:0000269|PubMed:12050212"
FT /id="VAR_017295"
FT VARIANT 477
FT /note="T -> I (in CHNG1; severe hypothyroidism)"
FT /evidence="ECO:0000269|PubMed:10720030"
FT /id="VAR_017296"
FT VARIANT 486
FT /note="I -> F (in HTNA; found in thyroid toxic nodules and
FT hyperfunctioning thyroid adenomas; also in hyperfunctioning
FT follicular carcinoma)"
FT /evidence="ECO:0000269|PubMed:10852462,
FT ECO:0000269|PubMed:11128715, ECO:0000269|PubMed:11434721,
FT ECO:0000269|PubMed:9253356"
FT /id="VAR_011531"
FT VARIANT 486
FT /note="I -> M (in HTNA; found in hyperfunctioning thyroid
FT adenomas)"
FT /evidence="ECO:0000269|PubMed:10852462,
FT ECO:0000269|PubMed:12213664, ECO:0000269|PubMed:9253356"
FT /id="VAR_011532"
FT VARIANT 498
FT /note="G -> S (in CHNG1)"
FT /evidence="ECO:0000269|PubMed:11442002"
FT /id="VAR_011533"
FT VARIANT 505
FT /note="S -> N (in HTNA; found in toxic thyroid nodules)"
FT /evidence="ECO:0000269|PubMed:11434721,
FT ECO:0000269|PubMed:15163335, ECO:0000269|PubMed:9360555"
FT /id="VAR_003571"
FT VARIANT 505
FT /note="S -> R (in HTNA; gain of function)"
FT /evidence="ECO:0000269|PubMed:8636266"
FT /id="VAR_011534"
FT VARIANT 509
FT /note="V -> A (in HTNA; gain of function)"
FT /evidence="ECO:0000269|PubMed:7920658"
FT /id="VAR_011535"
FT VARIANT 512
FT /note="L -> Q (found in toxic thyroid nodules; 5 times
FT higher levels of basal cAMP than wild-type TSHR and
FT slightly less response to maximal TSH stimulation)"
FT /evidence="ECO:0000269|PubMed:11434721"
FT /id="VAR_021497"
FT VARIANT 512
FT /note="L -> R (in hyperthyroidism; associated with
FT autonomously functioning thyroid nodules; 3.3-fold increase
FT in basal cAMP level)"
FT /evidence="ECO:0000269|PubMed:11022192,
FT ECO:0000269|PubMed:11434721, ECO:0000269|PubMed:12213664"
FT /id="VAR_011536"
FT VARIANT 525
FT /note="F -> L (in CHNG1; impairs adenylate cyclase
FT activation)"
FT /evidence="ECO:0000269|PubMed:8954020"
FT /id="VAR_011537"
FT VARIANT 528
FT /note="R -> H"
FT /evidence="ECO:0000269|PubMed:9589634"
FT /id="VAR_003572"
FT VARIANT 553
FT /note="A -> T (in CHNG1; severe hypothyroidism)"
FT /evidence="ECO:0000269|PubMed:14725684,
FT ECO:0000269|PubMed:9185526"
FT /id="VAR_011538"
FT VARIANT 568
FT /note="I -> T (in HTNA; found in thyroid toxic nodules and
FT hyperfunctioning thyroid adenomas)"
FT /evidence="ECO:0000269|PubMed:11081252,
FT ECO:0000269|PubMed:11434721, ECO:0000269|PubMed:9253356"
FT /id="VAR_011539"
FT VARIANT 593
FT /note="A -> N (in toxic thyroid adenoma; requires 2
FT nucleotide substitutions; somatic mutation; constitutively
FT activates the cAMP cascade)"
FT /evidence="ECO:0000269|PubMed:12589819"
FT /id="VAR_021498"
FT VARIANT 597
FT /note="V -> F (in HTNA; 11-fold increase in specific
FT constitutive activity associated with reduction in receptor
FT protein expression)"
FT /evidence="ECO:0000269|PubMed:11517004"
FT /id="VAR_021499"
FT VARIANT 597
FT /note="V -> L (in hyperthyroidism; congenital with severe
FT thyrotoxicosis)"
FT /evidence="ECO:0000269|PubMed:10560955"
FT /id="VAR_011540"
FT VARIANT 600
FT /note="C -> R (in CHNG1)"
FT /evidence="ECO:0000269|PubMed:12050212"
FT /id="VAR_017297"
FT VARIANT 606
FT /note="I -> M"
FT /evidence="ECO:0000269|PubMed:10487707"
FT /id="VAR_011541"
FT VARIANT 619
FT /note="D -> G (in hyperthyroidism; found in toxic thyroid
FT nodules; associated with hyperfunctioning thyroid
FT adenomas)"
FT /evidence="ECO:0000269|PubMed:11434721,
FT ECO:0000269|PubMed:8413627, ECO:0000269|PubMed:9253356"
FT /id="VAR_003573"
FT VARIANT 623
FT /note="A -> I (in hyperthyroidism; associated with
FT hyperfunctioning thyroid adenomas; gain of function;
FT requires 2 nucleotide substitutions)"
FT /evidence="ECO:0000269|PubMed:8413627,
FT ECO:0000269|PubMed:9253356"
FT /id="VAR_003574"
FT VARIANT 623
FT /note="A -> V (in hyperthyroidism; found in toxic thyroid
FT nodules; associated with hyperfunctioning thyroid adenomas;
FT gain of function)"
FT /evidence="ECO:0000269|PubMed:11434721,
FT ECO:0000269|PubMed:7989485"
FT /id="VAR_011542"
FT VARIANT 629
FT /note="L -> F (in HTNA; also in hyperfunctioning thyroid
FT adenomas and non-adenomatous nodules)"
FT /evidence="ECO:0000269|PubMed:10852462,
FT ECO:0000269|PubMed:9253356, ECO:0000269|PubMed:9398746"
FT /id="VAR_003575"
FT VARIANT 630
FT /note="I -> L (in hyperthyroidism; associated with
FT hyperfunctioning thyroid adenomas)"
FT /evidence="ECO:0000269|PubMed:9253356"
FT /id="VAR_011543"
FT VARIANT 631
FT /note="F -> C (in hyperthyroidism; associated with
FT hyperfunctioning thyroid adenomas)"
FT /evidence="ECO:0000269|PubMed:8045989"
FT /id="VAR_011544"
FT VARIANT 631
FT /note="F -> L (in HTNA; gain of function; found in toxic
FT thyroid nodules and hyperfunctioning thyroid adenomas)"
FT /evidence="ECO:0000269|PubMed:11434721,
FT ECO:0000269|PubMed:7800007, ECO:0000269|PubMed:9253356"
FT /id="VAR_011545"
FT VARIANT 632
FT /note="T -> A (in HTNA; found in toxic thyroid nodules and
FT hyperfunctioning non-adenomatous nodules)"
FT /evidence="ECO:0000269|PubMed:10852462,
FT ECO:0000269|PubMed:11434721, ECO:0000269|PubMed:12213664"
FT /id="VAR_011546"
FT VARIANT 632
FT /note="T -> I (in HTNA; gain of function; found in thyroid
FT toxic nodules and hyperfunctioning thyroid adenomas)"
FT /evidence="ECO:0000269|PubMed:10852462,
FT ECO:0000269|PubMed:11127522, ECO:0000269|PubMed:11434721,
FT ECO:0000269|PubMed:7989485, ECO:0000269|PubMed:8045989,
FT ECO:0000269|PubMed:9253356, ECO:0000269|PubMed:9349581"
FT /id="VAR_011547"
FT VARIANT 633
FT /note="D -> A (in hyperthyroidism; associated with
FT hyperfunctioning thyroid adenomas)"
FT /evidence="ECO:0000269|PubMed:9253356"
FT /id="VAR_011548"
FT VARIANT 633
FT /note="D -> E (in HTNA; found in thyroid toxic nodules and
FT hyperfunctioning thyroid adenomas)"
FT /evidence="ECO:0000269|PubMed:10852462,
FT ECO:0000269|PubMed:11434721, ECO:0000269|PubMed:8045989,
FT ECO:0000269|PubMed:9253356"
FT /id="VAR_011549"
FT VARIANT 633
FT /note="D -> H (in hyperthyroidism; found in toxic thyroid
FT nodules; associated with hyperfunctioning thyroid adenomas;
FT also in hyperfunctioning insular carcinoma; with severe
FT thyrotoxicosis; gain of function; dbSNP:rs28937584)"
FT /evidence="ECO:0000269|PubMed:11434721,
FT ECO:0000269|PubMed:9062474, ECO:0000269|PubMed:9253356"
FT /id="VAR_011550"
FT VARIANT 633
FT /note="D -> Y (in hyperthyroidism; found in toxic thyroid
FT nodules; associated with hyperfunctioning thyroid
FT adenomas)"
FT /evidence="ECO:0000269|PubMed:11434721,
FT ECO:0000269|PubMed:8045989, ECO:0000269|PubMed:9253356"
FT /id="VAR_011551"
FT VARIANT 639
FT /note="P -> A (found in toxic thyroid nodules)"
FT /evidence="ECO:0000269|PubMed:11434721"
FT /id="VAR_021500"
FT VARIANT 639
FT /note="P -> S (in HTNA; gain of function)"
FT /evidence="ECO:0000269|PubMed:10199795"
FT /id="VAR_011552"
FT VARIANT 647
FT /note="A -> V (in HTNA; found in non-adenomatous
FT hyperfunctioning nodules)"
FT /evidence="ECO:0000269|PubMed:10852462"
FT /id="VAR_011553"
FT VARIANT 650
FT /note="N -> Y (in HTNA; gain of function)"
FT /evidence="ECO:0000269|PubMed:8636266"
FT /id="VAR_011554"
FT VARIANT 656
FT /note="V -> F (found in toxic thyroid nodules)"
FT /evidence="ECO:0000269|PubMed:11434721"
FT /id="VAR_021501"
FT VARIANT 658..661
FT /note="Missing (in hyperthyroidism; associated with
FT hyperfunctioning thyroid adenomas)"
FT /evidence="ECO:0000269|PubMed:9253356"
FT /id="VAR_011555"
FT VARIANT 670
FT /note="N -> S (in HTNA; gain of function)"
FT /evidence="ECO:0000269|PubMed:8636266"
FT /id="VAR_011556"
FT VARIANT 672
FT /note="C -> Y (in HTNA; gain of function)"
FT /evidence="ECO:0000269|PubMed:7920658"
FT /id="VAR_011557"
FT VARIANT 677
FT /note="L -> V (in thyroid carcinoma; with thyrotoxicosis;
FT gain of function)"
FT /evidence="ECO:0000269|PubMed:10037070"
FT /id="VAR_011558"
FT VARIANT 703
FT /note="A -> G"
FT /evidence="ECO:0000269|PubMed:10487707"
FT /id="VAR_011559"
FT VARIANT 715
FT /note="N -> D (in papillary cancer)"
FT /evidence="ECO:0000269|PubMed:7647578"
FT /id="VAR_003576"
FT VARIANT 720
FT /note="Q -> E"
FT /evidence="ECO:0000269|PubMed:10487707"
FT /id="VAR_011560"
FT VARIANT 723
FT /note="K -> M (in papillary cancer)"
FT /evidence="ECO:0000269|PubMed:7647578"
FT /id="VAR_003577"
FT VARIANT 727
FT /note="D -> E (may be a predisposing factor in toxic
FT multinodular goiter pathogenesis; activation of the cAMP
FT cascade does not differ from the wild-type;
FT dbSNP:rs1991517)"
FT /evidence="ECO:0000269|PubMed:10487707,
FT ECO:0000269|PubMed:10946859, ECO:0000269|PubMed:12508121,
FT ECO:0000269|PubMed:12589819, ECO:0000269|PubMed:12788902,
FT ECO:0000269|PubMed:2302212, ECO:0000269|PubMed:7647578"
FT /id="VAR_003578"
FT MUTAGEN 283
FT /note="C->S: Abolishes cell surface expression."
FT /evidence="ECO:0000269|PubMed:11847099"
FT MUTAGEN 385..387
FT /note="YDY->EDE: Inhibits intracellular cAMP accumulation."
FT /evidence="ECO:0000269|PubMed:11847099"
FT MUTAGEN 385..387
FT /note="YDY->FDF: Abolishes sulfation. Inhibits
FT intracellular cAMP accumulation."
FT /evidence="ECO:0000269|PubMed:11847099"
FT MUTAGEN 385
FT /note="Y->E: Reduces binding with thyrotropin. Inhibits
FT intracellular cAMP accumulation."
FT /evidence="ECO:0000269|PubMed:11847099,
FT ECO:0000305|PubMed:11847099"
FT MUTAGEN 385
FT /note="Y->F: Reduces sulfation. Reduces binding with
FT thyrotropin. Inhibits intracellular cAMP accumulation."
FT /evidence="ECO:0000269|PubMed:11847099,
FT ECO:0000305|PubMed:11847099"
FT MUTAGEN 387
FT /note="Y->E: No change in intracellular cAMP accumulation."
FT /evidence="ECO:0000269|PubMed:11847099"
FT MUTAGEN 387
FT /note="Y->F: Reduces sulfation. No change in intracellular
FT cAMP accumulation."
FT /evidence="ECO:0000269|PubMed:11847099"
FT CONFLICT 87
FT /note="V -> L (in Ref. 2; no nucleotide entry)"
FT /evidence="ECO:0000305"
FT CONFLICT 196..198
FT /note="AFN -> DFF (in Ref. 4; AAA70232)"
FT /evidence="ECO:0000305"
FT CONFLICT 257
FT /note="T -> S (in Ref. 4; AAA70232)"
FT /evidence="ECO:0000305"
FT CONFLICT 264
FT /note="P -> A (in Ref. 4; AAA70232)"
FT /evidence="ECO:0000305"
FT CONFLICT 306..308
FT /note="MQS -> IET (in Ref. 4; AAA70232)"
FT /evidence="ECO:0000305"
FT CONFLICT 528
FT /note="R -> A (in Ref. 4; AAA70232)"
FT /evidence="ECO:0000305"
FT CONFLICT 601
FT /note="Y -> H (in Ref. 1; AAA36783)"
FT /evidence="ECO:0000305"
FT CONFLICT 635
FT /note="I -> T (in Ref. 4; AAA70232)"
FT /evidence="ECO:0000305"
FT CONFLICT 645
FT /note="L -> V (in Ref. 4; AAA70232)"
FT /evidence="ECO:0000305"
FT CONFLICT 669
FT /note="L -> I (in Ref. 4; AAA70232)"
FT /evidence="ECO:0000305"
FT CONFLICT 744
FT /note="N -> K (in Ref. 3; AAA61236)"
FT /evidence="ECO:0000305"
FT STRAND 26..28
FT /evidence="ECO:0007829|PDB:2XWT"
FT STRAND 30..33
FT /evidence="ECO:0007829|PDB:2XWT"
FT TURN 35..37
FT /evidence="ECO:0007829|PDB:3G04"
FT STRAND 38..41
FT /evidence="ECO:0007829|PDB:2XWT"
FT STRAND 56..61
FT /evidence="ECO:0007829|PDB:2XWT"
FT STRAND 65..67
FT /evidence="ECO:0007829|PDB:2XWT"
FT TURN 69..74
FT /evidence="ECO:0007829|PDB:2XWT"
FT STRAND 80..84
FT /evidence="ECO:0007829|PDB:2XWT"
FT TURN 94..96
FT /evidence="ECO:0007829|PDB:2XWT"
FT STRAND 97..99
FT /evidence="ECO:0007829|PDB:2XWT"
FT STRAND 105..111
FT /evidence="ECO:0007829|PDB:2XWT"
FT STRAND 121..123
FT /evidence="ECO:0007829|PDB:2XWT"
FT STRAND 130..136
FT /evidence="ECO:0007829|PDB:2XWT"
FT STRAND 152..160
FT /evidence="ECO:0007829|PDB:2XWT"
FT TURN 169..174
FT /evidence="ECO:0007829|PDB:2XWT"
FT STRAND 175..183
FT /evidence="ECO:0007829|PDB:2XWT"
FT STRAND 190..192
FT /evidence="ECO:0007829|PDB:3G04"
FT TURN 194..199
FT /evidence="ECO:0007829|PDB:2XWT"
FT STRAND 201..206
FT /evidence="ECO:0007829|PDB:2XWT"
FT TURN 218..223
FT /evidence="ECO:0007829|PDB:2XWT"
FT STRAND 229..232
FT /evidence="ECO:0007829|PDB:2XWT"
FT STRAND 250..253
FT /evidence="ECO:0007829|PDB:2XWT"
FT CONFLICT P16473-2:239
FT /note="L -> F (in Ref. 6; AAB24246)"
FT /evidence="ECO:0000305"
FT CONFLICT P16473-2:248
FT /note="R -> S (in Ref. 5; AAB23390 and 9; AAH09237/
FT AAI20974)"
FT /evidence="ECO:0000305"
FT CONFLICT P16473-2:251
FT /note="M -> T (in Ref. 5; AAB23390)"
FT /evidence="ECO:0000305"
FT CONFLICT P16473-3:269
FT /note="R -> S (in Ref. 9; AAI27629)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 764 AA; 86830 MW; D2EE9CEBFD64A65F CRC64;
MRPADLLQLV LLLDLPRDLG GMGCSSPPCE CHQEEDFRVT CKDIQRIPSL PPSTQTLKLI
ETHLRTIPSH AFSNLPNISR IYVSIDVTLQ QLESHSFYNL SKVTHIEIRN TRNLTYIDPD
ALKELPLLKF LGIFNTGLKM FPDLTKVYST DIFFILEITD NPYMTSIPVN AFQGLCNETL
TLKLYNNGFT SVQGYAFNGT KLDAVYLNKN KYLTVIDKDA FGGVYSGPSL LDVSQTSVTA
LPSKGLEHLK ELIARNTWTL KKLPLSLSFL HLTRADLSYP SHCCAFKNQK KIRGILESLM
CNESSMQSLR QRKSVNALNS PLHQEYEENL GDSIVGYKEK SKFQDTHNNA HYYVFFEEQE
DEIIGFGQEL KNPQEETLQA FDSHYDYTIC GDSEDMVCTP KSDEFNPCED IMGYKFLRIV
VWFVSLLALL GNVFVLLILL TSHYKLNVPR FLMCNLAFAD FCMGMYLLLI ASVDLYTHSE
YYNHAIDWQT GPGCNTAGFF TVFASELSVY TLTVITLERW YAITFAMRLD RKIRLRHACA
IMVGGWVCCF LLALLPLVGI SSYAKVSICL PMDTETPLAL AYIVFVLTLN IVAFVIVCCC
YVKIYITVRN PQYNPGDKDT KIAKRMAVLI FTDFICMAPI SFYALSAILN KPLITVSNSK
ILLVLFYPLN SCANPFLYAI FTKAFQRDVF ILLSKFGICK RQAQAYRGQR VPPKNSTDIQ
VQKVTHDMRQ GLHNMEDVYE LIENSHLTPK KQGQISEEYM QTVL
