RBCC Red Blood Cell Collection

TSHR (LGR3) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Thyrotropin receptor (Thyroid-stimulating hormone receptor; TSH-R; Flags: Precursor)

hRBCD IPI00028642
IPI00028642 Splice Isoform 1 Of Thyrotropin receptor precursor Splice Isoform 1 Of Thyrotropin receptor precursor membrane n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 1 n/a n/a integral membrane protein splice isoform 1 and 2 found at its expected molecular weight found at molecular weight

UniProt P16473
ID TSHR_HUMAN Reviewed; 764 AA.
AC P16473; A0PJU7; G3V2A9; Q16503; Q8TB90; Q96GT6; Q9P1V4; Q9ULA3;
read moreAC Q9UPH3;
DT 01-AUG-1990, integrated into UniProtKB/Swiss-Prot.
DT 29-MAR-2005, sequence version 2.
DT 22-JAN-2014, entry version 174.
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;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; 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
RT the 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.,
RA 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;
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:
RT regulation 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
RT receptor 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
RT the 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
RT sequenced by 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.,
RA Sun H., Du H., Pepin K., Artiguenave F., Robert C., Cruaud C.,
RA Bruels T., Jaillon O., Friedlander L., Samson G., Brottier P.,
RA Cure S., Segurens B., Aniere F., Samain S., Crespeau H., Abbasi N.,
RA Aiach N., Boscus D., Dickhoff R., Dors M., Dubois I., Friedman C.,
RA Gouyvenoux M., James R., Madan A., Mairey-Estrada B., Mangenot S.,
RA Martins N., Menard M., Oztas S., Ratcliffe A., Shaffer T., Trask B.,
RA Vacherie B., Bellemere C., Belser C., Besnard-Gonnet M.,
RA Bartol-Mavel D., Boutard M., Briez-Silla S., Combette S.,
RA Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., Muselet D.,
RA Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., Trybou A.,
RA 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.,
RA Verdier J., Verdier-Discala C., Hillier L.W., Fulton L., McPherson J.,
RA Matsuda F., Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W.,
RA Quetier F., 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
RT project: 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
RP GLYCOSYLATION 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-
RT terminal extracellular domain of the human thyrotropin receptor.";
RL Biochemistry 40:9860-9869(2001).
RN [11]
RP FUNCTION, AND INTERACTION WITH GPA2/GPB5.
RX PubMed=12045258; DOI=10.1172/JCI0214340;
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 [12]
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-
RT ARF6 pathway.";
RL EMBO J. 24:1364-1374(2005).
RN [13]
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 [14]
RP X-RAY CRYSTALLOGRAPHY (2.55 ANGSTROMS) OF 22-260 IN COMPLEX WITH
RP ANTIBODY, GLYCOSYLATION AT ASN-77; ASN-99; ASN-113; ASN-177 AND
RP ASN-198, AND 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 [15]
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
RT Russian population.";
RL Med. Sci. Monit. 8:CR180-CR184(2002).
RN [16]
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
RT of the human thyrotropin receptor does not have a major effect on the
RT development of Graves' disease.";
RL Thyroid 12:1079-1083(2002).
RN [17]
RP ANALYSIS OF INVOLVEMENT OF VARIANTS HIS-36; THR-52 AND GLU-727 IN
RP GRAVES 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-
RT ethnic origins.";
RL Thyroid 13:523-528(2003).
RN [18]
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-
RT of-function mutations.";
RL Eur. J. Endocrinol. 143:25-30(2000).
RN [19]
RP VARIANT HIS-36.
RX PubMed=1955520;
RA Heldin N.-E., Gustavsson B., Westermark K., Westermark B.;
RT "A somatic point mutation in a putative ligand binding domain of the
RT TSH receptor in a patient with autoimmune hyperthyroidism.";
RL J. Clin. Endocrinol. Metab. 73:1374-1376(1991).
RN [20]
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
RT hyperfunctioning thyroid adenomas.";
RL Nature 365:649-651(1993).
RN [21]
RP VARIANT THR-52.
RX PubMed=7508946; DOI=10.1210/jc.78.2.256;
RA Bahn R.S., Dutton C.M., Heufelder A.E., Sarkar G.;
RT "A genomic point mutation in the extracellular domain of the
RT thyrotropin receptor in patients with Graves' ophthalmopathy.";
RL J. Clin. Endocrinol. Metab. 78:256-260(1994).
RN [22]
RP VARIANTS HYPERTHYROIDISM CYS-631; ILE-632; GLU-633 AND TYR-633.
RX PubMed=8045989; DOI=10.1210/jc.79.2.657;
RA Porcellini A., Ciullo I., Laviola L., Amabile G., Fenzi G.,
RA Avvedimento V.E.;
RT "Novel mutations of thyrotropin receptor gene in thyroid
RT hyperfunctioning adenomas. Rapid identification by fine needle
RT aspiration biopsy.";
RL J. Clin. Endocrinol. Metab. 79:657-661(1994).
RN [23]
RP VARIANTS HYPERTHYROIDISM VAL-623 AND ILE-632.
RX PubMed=7989485; DOI=10.1210/jc.79.6.1785;
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
RT in hyperfunctioning autonomous adenomas of the thyroid.";
RL J. Clin. Endocrinol. Metab. 79:1785-1789(1994).
RN [24]
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.,
RA Schvartz C., Delisle M.-J., Decoulx M., Orgiazzi J., Dumont J.E.,
RA Vassart G.;
RT "Germline mutations in the thyrotropin receptor gene cause non-
RT autoimmune autosomal dominant hyperthyroidism.";
RL Nat. Genet. 7:396-401(1994).
RN [25]
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
RT a family with Graves' disease.";
RL Mol. Cell. Endocrinol. 111:167-173(1995).
RN [26]
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 [27]
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-
RT receptor gene.";
RL N. Engl. J. Med. 332:155-160(1995).
RN [28]
RP VARIANTS PAPILLARY CANCER ILE-197; GLU-219; ASP-715 AND MET-723, AND
RP VARIANT GLU-727.
RX PubMed=7647578;
RA Ohno M., Endo T., Ohta K., Gunji K., Onaya T.;
RT "Point mutations in the thyrotropin receptor in human thyroid
RT tumors.";
RL Thyroid 5:97-100(1995).
RN [29]
RP VARIANT THR-52.
RX PubMed=7488864;
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 [30]
RP VARIANTS HTNA ARG-505; TYR-650 AND SER-670.
RX PubMed=8636266; DOI=10.1210/jc.81.2.547;
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 [31]
RP VARIANT HTNA THR-453.
RX PubMed=8964822; DOI=10.1210/jc.81.6.2023;
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 [32]
RP VARIANTS CHNG1 SER-41; ALA-162; TRP-390; ASN-410 AND LEU-525.
RX PubMed=8954020; DOI=10.1210/jc.81.12.4229;
RA de Roux N., Misrahi M., Brauner R., Houang M., Carel J.-C.,
RA Granier M., Le Bouc Y., Ghinea N., Boumedienne A., Toublanc J.E.,
RA 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 [33]
RP VARIANT INSULAR CARCINOMA HIS-633.
RX PubMed=9062474; DOI=10.1210/jc.82.3.735;
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
RT case of an autonomously hyperfunctioning thyroid insular carcinoma.";
RL J. Clin. Endocrinol. Metab. 82:735-738(1997).
RN [34]
RP VARIANT CHNG1 GLN-109.
RX PubMed=9100579; DOI=10.1210/jc.82.4.1094;
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
RT with resistance to TSH.";
RL J. Clin. Endocrinol. Metab. 82:1094-1100(1997).
RN [35]
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;
RP ALA-633; GLU-633; HIS-633; TYR-633 AND 658-ASN--ILE-661 DEL.
RX PubMed=9253356; DOI=10.1210/jc.82.8.2695;
RA Parma J., Duprez L., van Sande J., Hermans J., Rocmans P.,
RA van Vliet G., Costagliola S., Rodien P., Dumont J.E., Vassart G.;
RT "Diversity and prevalence of somatic mutations in the thyrotropin
RT receptor and Gs alpha genes as a cause of toxic thyroid adenomas.";
RL J. Clin. Endocrinol. Metab. 82:2695-2701(1997).
RN [36]
RP VARIANT CHNG1 TRP-390.
RX PubMed=9329388; DOI=10.1210/jc.82.10.3471;
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 [37]
RP VARIANT HTNA ASN-505.
RX PubMed=9360555; DOI=10.1210/jc.82.11.3879;
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
RT mutation in the thyrotropin receptor gene.";
RL J. Clin. Endocrinol. Metab. 82:3879-3884(1997).
RN [38]
RP VARIANT HTNA PHE-629.
RX PubMed=9398746; DOI=10.1210/jc.82.12.4234;
RA Fuhrer D., Wonerow P., Willgerodt H., Paschke R.;
RT "Identification of a new thyrotropin receptor germline mutation
RT (Leu629Phe) in a family with neonatal onset of autosomal dominant
RT nonautoimmune hyperthyroidism.";
RL J. Clin. Endocrinol. Metab. 82:4234-4238(1997).
RN [39]
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
RT the thyrotropin receptor causing profound hypoplasia of the thyroid
RT gland.";
RL J. Clin. Invest. 99:3018-3024(1997).
RN [40]
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
RT harboring a novel somatic mutation (serine281-->isoleucine) in the
RT extracellular domain of the thyrotropin receptor.";
RL J. Clin. Invest. 100:1634-1639(1997).
RN [41]
RP VARIANT HTNA ILE-632.
RX PubMed=9349581;
RA Kopp P., Jameson J.L., Roe T.F.;
RT "Congenital nonautoimmune hyperthyroidism in a nonidentical twin
RT caused by a sporadic germline mutation in the thyrotropin receptor
RT gene.";
RL Thyroid 7:765-770(1997).
RN [42]
RP VARIANT HTNA ASN-281, AND VARIANT HIS-528.
RX PubMed=9589634; DOI=10.1210/jc.83.5.1431;
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
RT in the extracellular portion of the thyrotropin receptor.";
RL J. Clin. Endocrinol. Metab. 83:1431-1436(1998).
RN [43]
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 [44]
RP VARIANT HTNA SER-639.
RX PubMed=10199795; DOI=10.1210/jc.84.4.1459;
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 [45]
RP VARIANTS MET-606; GLY-703; GLU-720 AND GLU-727.
RX PubMed=10487707; DOI=10.1210/jc.84.9.3328;
RA Gabriel E.M., Bergert E.R., Grant C.S., van Heerden J.A.,
RA Thompson G.B., Morris J.C.;
RT "Germline polymorphism of codon 727 of human thyroid-stimulating
RT hormone receptor is associated with toxic multinodular goiter.";
RL J. Clin. Endocrinol. Metab. 84:3328-3335(1999).
RN [46]
RP VARIANT THYROID CARCINOMA VAL-677.
RX PubMed=10037070;
RA Russo D., Wong M.G., Costante G., Chiefari E., Treseler P.A.,
RA Arturi F., Filetti S., Clark O.H.;
RT "A Val 677 activating mutation of the thyrotropin receptor in a
RT Hurthle cell thyroid carcinoma associated with thyrotoxicosis.";
RL Thyroid 9:13-17(1999).
RN [47]
RP VARIANT HYPERTHYROIDISM LEU-597.
RX PubMed=10560955;
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 [48]
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
RT patient.";
RL Eur. J. Endocrinol. 143:471-477(2000).
RN [49]
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.,
RA Balazs C.;
RT "Analysis of the genetic variability of the 1st (CCC/ACC, P52T) and
RT the 10th exons (bp 1012-1704) of the TSH receptor gene in Graves'
RT disease.";
RL Eur. J. Immunogenet. 27:17-23(2000).
RN [50]
RP VARIANT CHNG1 ILE-477.
RX PubMed=10720030; DOI=10.1210/jc.85.3.1001;
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
RT thyrotropin (TSH) and absent circulating thyroglobulin: evidence for a
RT new inactivating mutation of the TSH receptor gene.";
RL J. Clin. Endocrinol. Metab. 85:1001-1008(2000).
RN [51]
RP VARIANTS HTNA ASN-281; MET-486; PHE-486; PHE-629; ALA-632; ILE-632;
RP GLU-633 AND VAL-647.
RX PubMed=10852462; DOI=10.1210/jc.85.6.2270;
RA Tonacchera M., Agretti P., Chiovato L., Rosellini V., Ceccarini G.,
RA Perri A., Viacava P., Naccarato A.G., Miccoli P., Pinchera A.,
RA Vitti P.;
RT "Activating thyrotropin receptor mutations are present in
RT nonadenomatous hyperfunctioning nodules of toxic or autonomous
RT multinodular goiter.";
RL J. Clin. Endocrinol. Metab. 85:2270-2274(2000).
RN [52]
RP VARIANT GLU-727.
RX PubMed=10946859; DOI=10.1210/jc.85.8.2640;
RA Muehlberg T., Herrmann K., Joba W., Kirchberger M., Heberling H.-J.,
RA Heufelder A.E.;
RT "Lack of association of nonautoimmune hyperfunctioning thyroid
RT disorders and a germline polymorphism of codon 727 of the human
RT thyrotropin receptor in a European Caucasian population.";
RL J. Clin. Endocrinol. Metab. 85:2640-2643(2000).
RN [53]
RP VARIANT CHNG1 CYS-310.
RX PubMed=11095460; DOI=10.1210/jc.85.11.4238;
RA Russo D., Betterle C., Arturi F., Chiefari E., Girelli M.E.,
RA Filetti S.;
RT "A novel mutation in the thyrotropin (TSH) receptor gene causing loss
RT of TSH binding but constitutive receptor activation in a family with
RT resistance to TSH.";
RL J. Clin. Endocrinol. Metab. 85:4238-4242(2000).
RN [54]
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
RT of non-autoimmune hyperthyroidism in childhood.";
RL Langenbecks Arch. Surg. 385:390-392(2000).
RN [55]
RP VARIANT HTNA THR-568.
RX PubMed=11081252;
RA Tonacchera M., Agretti P., Rosellini V., Ceccarini G., Perri A.,
RA Zampolli M., Longhi R., Larizza D., Pinchera A., Vitti P.,
RA 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 [56]
RP VARIANT FOLLICULAR CARCINOMA PHE-486.
RX PubMed=11128715;
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
RT functioning follicular carcinoma that was causing hyperthyroidism.";
RL Thyroid 10:1009-1012(2000).
RN [57]
RP VARIANT HTNA VAL-463.
RX PubMed=11201847;
RA Fuhrer D., Warner J., Sequeira M., Paschke R., Gregory J.W.,
RA Ludgate M.;
RT "Novel TSHR germline mutation (Met463Val) masquerading as Graves'
RT disease in a large Welsh kindred with hyperthyroidism.";
RL Thyroid 10:1035-1041(2000).
RN [58]
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-
RT autoimmune autosomal dominant hyperthyroidism.";
RL Eur. J. Endocrinol. 145:249-254(2001).
RN [59]
RP VARIANT HTNA SER-431, AND CHARACTERIZATION OF VARIANT HTNA SER-431.
RX PubMed=11549687; DOI=10.1210/jc.86.9.4429;
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 [60]
RP VARIANTS TTNS ASN-281; ILE-425; THR-453; PHE-486; ASN-505; ARG-512;
RP GLN-512; THR-568; GLY-619; VAL-623; LEU-631; ALA-632; ILE-632;
RP GLU-633; HIS-633; TYR-633; ALA-639 AND PHE-656, AND CHARACTERIZATION
RP OF VARIANTS TTNS ILE-425 AND GLN-512.
RX PubMed=11434721; DOI=10.1007/s001090000170;
RA Truelzsch B., Krohn K., Wonerow P., Chey S., Holzapfel H.-P.,
RA Ackermann F., Fuehrer D., Paschke R.;
RT "Detection of thyroid-stimulating hormone receptor and G(s)alpha
RT mutations: in 75 toxic thyroid nodules by denaturing gradient gel
RT electrophoresis.";
RL J. Mol. Med. 78:684-691(2001).
RN [61]
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.,
RA Mori M., Morikawa A.;
RT "Novel inactivating missense mutations in the thyrotropin receptor
RT gene in Japanese children with resistance to thyrotropin.";
RL Thyroid 11:551-559(2001).
RN [62]
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 [63]
RP VARIANTS CHNG1 SER-41; ALA-162; PRO-467 AND ARG-600.
RX PubMed=12050212; DOI=10.1210/jc.87.6.2549;
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 [64]
RP VARIANT TOXIC THYROID ADENOMA ASN-593, VARIANT GLU-727,
RP CHARACTERIZATION OF VARIANTS TOXIC THYROID ADENOMA ASN-593 AND
RP ASN-593/GLU-727, AND CHARACTERIZATION OF VARIANT 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
RT polymorphism D727E.";
RL Biochem. Biophys. Res. Commun. 301:1051-1056(2003).
RN [65]
RP VARIANTS HIS-36; THR-52 AND GLU-727, AND ASSOCIATION WITH PLASMA TSH
RP LEVEL.
RX PubMed=12788902; DOI=10.1210/jc.2002-021592;
RA Peeters R.P., van Toor H., Klootwijk W., de Rijke Y.B.,
RA Kuiper G.G.J.M., Uitterlinden A.G., Visser T.J.;
RT "Polymorphisms in thyroid hormone pathway genes are associated with
RT plasma TSH and iodothyronine levels in healthy subjects.";
RL J. Clin. Endocrinol. Metab. 88:2880-2888(2003).
RN [66]
RP VARIANTS HIS-36 AND THR-52, AND RECEPTOR GENETIC ANALYSIS IN CHILDREN
RP WITH DOWN'S SYNDROME.
RX PubMed=14759073;
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 [67]
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
RT hemizygosity for inactivating mutations of the TSH receptor.";
RL Clin. Endocrinol. (Oxf.) 60:220-227(2004).
RN [68]
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.,
RA Ellard S.;
RT "Premature birth and low birth weight associated with nonautoimmune
RT hyperthyroidism due to an activating thyrotropin receptor gene
RT mutation.";
RL Clin. Endocrinol. (Oxf.) 60:711-718(2004).
RN [69]
RP VARIANTS CHNG1 ALA-162 AND PRO-252, AND CHARACTERIZATION OF VARIANT
RP CHNG1 PRO-252.
RX PubMed=15531543; DOI=10.1210/jc.2004-1243;
RA Tonacchera M., Perri A., De Marco G., Agretti P., Banco M.E.,
RA Di Cosmo C., 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).
CC -!- FUNCTION: Receptor for thyrothropin. Plays a central role in
CC controlling thyroid cell metabolism. The activity of this receptor
CC is mediated by G proteins which activate adenylate cyclase. Also
CC acts as a receptor for thyrostimulin (GPA2+GPB5).
CC -!- SUBUNIT: Interacts (via the PDZ-binding motif) with SCRIB;
CC regulates TSHR trafficking and function.
CC -!- SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein.
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 Note=Ref.6 (AAB24246) sequence is in conflict in position:
CC 239:L->F. Ref.5 (AAB23390) and Ref.9 (AAH09237/AAI20974)
CC sequences are in conflict in position: 248:R->S. Ref.5
CC (AAB23390) sequence is in conflict in position: 251:M->T;
CC Name=3;
CC IsoId=P16473-3; Sequence=VSP_044643, VSP_044644;
CC Note=No experimental confirmation available. Ref.9 (AAI27629)
CC sequence is in conflict in position: 269:R->S;
CC -!- TISSUE SPECIFICITY: Expressed in the thyroid.
CC -!- POLYMORPHISM: The Asp727Glu polymorphism is associated with Graves
CC disease in a Russian population. The Glu727 allele and the
CC heterozygous Asp727Glu genotype are related to higher risk of the
CC disease. The Asp727Glu polymorphism significantly ameliorates
CC G(s)alpha protein activation in the presence of the gain-of-
CC function mutation Ala593Asn although it is functionally inert in
CC the context of the wild-type TSHR.
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
CC G(s)alpha mutations have been identified in toxic thyroid nodules
CC (TTNs) that are the predominant cause of hyperthyroidism in iodine
CC deficient areas. These mutations lead to TSH independent
CC activation of the cAMP cascade resulting in thyroid growth and
CC hormone production. TSHR mutations are found in autonomously
CC functioning thyroid nodules (AFTN), toxic multinodular goiter
CC (TMNG) and hyperfunctioning thyroid adenomas (HTA). TMNG
CC encompasses a spectrum of different clinical entities, ranging
CC from a single hyperfunctioning nodule within an enlarged thyroid,
CC to multiple hyperfunctioning areas scattered throughout the gland.
CC HTA are discrete encapsulated neoplasms characterized by TSH-
CC independent autonomous growth, hypersecretion of thyroid hormones,
CC and TSH suppression. Defects in TSHR are also a cause of thyroid
CC neoplasms (papillary and follicular cancers).
CC -!- DISEASE: Note=Autoantibodies against TSHR are directly responsible
CC for the pathogenesis and hyperthyroidism of Graves disease.
CC Antibody interaction with TSHR results in an uncontrolled receptor
CC stimulation.
CC -!- DISEASE: Hypothyroidism, congenital, non-goitrous, 1 (CHNG1)
CC [MIM:275200]: A non-autoimmune condition characterized by
CC resistance to thyroid-stimulating hormone (TSH) leading to
CC increased levels of plasma TSH and low levels of thyroid hormone.
CC It presents variable severity depending on the completeness of the
CC defect. Most patients are euthyroid and asymptomatic, with a
CC normal sized thyroid gland. Only a subset of patients develop
CC hypothyroidism and present a hypoplastic thyroid gland. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Familial gestational hyperthyroidism (HTFG) [MIM:603373]:
CC A condition characterized by abnormally high levels of serum
CC thyroid hormones occurring during early pregnancy. Note=The
CC disease is caused by mutations affecting the gene represented in
CC 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
CC exophthalmia, myxedema, antibodies anti-TSH receptor and
CC lymphocytic infiltration of the thyroid gland are absent. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family.
CC FSH/LSH/TSH subfamily.
CC -!- SIMILARITY: Contains 7 LRR (leucine-rich) repeats.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA70232.1; Type=Frameshift; Positions=130, 135, 612;
CC -!- WEB RESOURCE: Name=TSH receptor database;
CC URL="http://endokrinologie.uniklinikum-leipzig.de/tsh/";
CC -!- WEB RESOURCE: Name=GRIS; Note=Glycoprotein-hormone Receptors
CC Information System;
CC URL="http://gris.ulb.ac.be/";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/TSHR";
CC -!- WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and
CC polymorphism database;
CC URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename;=TSHR";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=TSH receptor entry;
CC URL="http://en.wikipedia.org/wiki/TSH_receptor";
CC -!- WEB RESOURCE: Name=Sequence-structure-function-analysis of
CC glycoprotein hormone receptors;
CC URL="http://www.ssfa-gphr.de/";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/TSHRID290ch14q31.html";
CC -----------------------------------------------------------------------
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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 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.
DR RefSeq; NP_001136098.1; NM_001142626.2.
DR RefSeq; XP_005268096.1; XM_005268039.1.
DR UniGene; Hs.160411; -.
DR PDB; 1XUM; Model; -; A=54-236.
DR PDB; 2XWT; X-ray; 1.90 A; C=22-260.
DR PDB; 3G04; X-ray; 2.55 A; C=22-260.
DR PDBsum; 1XUM; -.
DR PDBsum; 2XWT; -.
DR PDBsum; 3G04; -.
DR ProteinModelPortal; P16473; -.
DR SMR; P16473; 24-305, 411-686.
DR STRING; 9606.ENSP00000298171; -.
DR BindingDB; P16473; -.
DR ChEMBL; CHEMBL1963; -.
DR DrugBank; DB00024; Thyrotropin Alfa.
DR GuidetoPHARMACOLOGY; 255; -.
DR PhosphoSite; P16473; -.
DR DMDM; 62298994; -.
DR PaxDb; P16473; -.
DR PRIDE; P16473; -.
DR DNASU; 7253; -.
DR Ensembl; ENST00000342443; ENSP00000340113; ENSG00000165409.
DR Ensembl; ENST00000554435; ENSP00000450549; ENSG00000165409.
DR GeneID; 7253; -.
DR KEGG; hsa:7253; -.
DR UCSC; uc010tvs.2; human.
DR CTD; 7253; -.
DR GeneCards; GC14P081421; -.
DR H-InvDB; HIX0021925; -.
DR HGNC; HGNC:12373; TSHR.
DR HPA; CAB000473; -.
DR HPA; HPA026680; -.
DR MIM; 275200; phenotype.
DR MIM; 603372; gene+phenotype.
DR MIM; 603373; phenotype.
DR MIM; 609152; phenotype.
DR neXtProt; NX_P16473; -.
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 eggNOG; NOG285844; -.
DR HOVERGEN; HBG052887; -.
DR InParanoid; P16473; -.
DR KO; K04249; -.
DR OrthoDB; EOG73BVCG; -.
DR Reactome; REACT_111102; Signal Transduction.
DR SignaLink; P16473; -.
DR ChiTaRS; TSHR; human.
DR EvolutionaryTrace; P16473; -.
DR GeneWiki; Thyrotropin_receptor; -.
DR GenomeRNAi; 7253; -.
DR NextBio; 28361; -.
DR PRO; PR:P16473; -.
DR ArrayExpress; P16473; -.
DR Bgee; P16473; -.
DR CleanEx; HS_TSHR; -.
DR Genevestigator; P16473; -.
DR GO; GO:0005887; C:integral to plasma membrane; TAS:ProtInc.
DR GO; GO:0004996; F:thyroid-stimulating hormone receptor activity; TAS:ProtInc.
DR GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc.
DR GO; GO:0007187; P:G-protein coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger; TAS:ProtInc.
DR GO; GO:0008284; P:positive regulation of cell proliferation; TAS:ProtInc.
DR InterPro; IPR000276; GPCR_Rhodpsn.
DR InterPro; IPR017452; GPCR_Rhodpsn_7TM.
DR InterPro; IPR002131; Gphrmn_rcpt_fam.
DR InterPro; IPR026906; LRR_5.
DR InterPro; IPR002274; TSH_rcpt.
DR PANTHER; PTHR24372; PTHR24372; 1.
DR PANTHER; PTHR24372:SF0; PTHR24372:SF0; 1.
DR Pfam; PF00001; 7tm_1; 1.
DR Pfam; PF13306; LRR_5; 1.
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; Complete proteome;
KW Congenital hypothyroidism; Direct protein sequencing;
KW Disease mutation; Disulfide bond; G-protein coupled receptor;
KW Glycoprotein; Leucine-rich repeat; Membrane; Polymorphism; Receptor;
KW Reference proteome; Repeat; Signal; Transducer; Transmembrane;
KW Transmembrane helix.
FT SIGNAL 1 20
FT CHAIN 21 764 Thyrotropin receptor.
FT /FTId=PRO_0000012786.
FT TOPO_DOM 21 413 Extracellular (Potential).
FT TRANSMEM 414 441 Helical; Name=1; (Potential).
FT TOPO_DOM 442 450 Cytoplasmic (Potential).
FT TRANSMEM 451 473 Helical; Name=2; (Potential).
FT TOPO_DOM 474 494 Extracellular (Potential).
FT TRANSMEM 495 517 Helical; Name=3; (Potential).
FT TOPO_DOM 518 537 Cytoplasmic (Potential).
FT TRANSMEM 538 560 Helical; Name=4; (Potential).
FT TOPO_DOM 561 580 Extracellular (Potential).
FT TRANSMEM 581 602 Helical; Name=5; (Potential).
FT TOPO_DOM 603 625 Cytoplasmic (Potential).
FT TRANSMEM 626 649 Helical; Name=6; (Potential).
FT TOPO_DOM 650 660 Extracellular (Potential).
FT TRANSMEM 661 682 Helical; Name=7; (Potential).
FT TOPO_DOM 683 764 Cytoplasmic (Potential).
FT REPEAT 100 124 LRR 1.
FT REPEAT 125 150 LRR 2.
FT REPEAT 152 174 LRR 3.
FT REPEAT 176 199 LRR 4.
FT REPEAT 200 223 LRR 5.
FT REPEAT 227 248 LRR 6.
FT REPEAT 250 271 LRR 7.
FT MOTIF 762 764 PDZ-binding.
FT CARBOHYD 77 77 N-linked (GlcNAc...).
FT CARBOHYD 99 99 N-linked (GlcNAc...).
FT CARBOHYD 113 113 N-linked (GlcNAc...).
FT CARBOHYD 177 177 N-linked (GlcNAc...).
FT CARBOHYD 198 198 N-linked (GlcNAc...).
FT CARBOHYD 302 302 N-linked (GlcNAc...).
FT DISULFID 31 41
FT DISULFID 494 569 By similarity.
FT VAR_SEQ 232 274 DVSQTSVTALPSKGLEHLKELIARNTWTLKKLPLSLSFLHL
FT TR -> VENVAVSGKGFCKSLFSWLYRLPLGRKSLSFETQK
FT APRSSMPS (in isoform 3).
FT /FTId=VSP_044643.
FT VAR_SEQ 232 253 DVSQTSVTALPSKGLEHLKELI -> LPLGRKSLSFETQKA
FT PRSSMPS (in isoform Short).
FT /FTId=VSP_001981.
FT VAR_SEQ 254 764 Missing (in isoform Short).
FT /FTId=VSP_001982.
FT VAR_SEQ 275 764 Missing (in isoform 3).
FT /FTId=VSP_044644.
FT VARIANT 34 34 E -> K (in dbSNP:rs45499704).
FT /FTId=VAR_055925.
FT VARIANT 36 36 D -> H (in a patient with Graves disease;
FT dbSNP:rs61747482).
FT /FTId=VAR_003564.
FT VARIANT 41 41 C -> S (in CHNG1).
FT /FTId=VAR_011519.
FT VARIANT 52 52 P -> T (does not contribute to the
FT genetic susceptibility to Graves disease;
FT dbSNP:rs2234919).
FT /FTId=VAR_003565.
FT VARIANT 109 109 R -> Q (in CHNG1).
FT /FTId=VAR_011520.
FT VARIANT 162 162 P -> A (in CHNG1; dbSNP:rs121908863).
FT /FTId=VAR_011521.
FT VARIANT 167 167 I -> N (in CHNG1).
FT /FTId=VAR_011522.
FT VARIANT 183 183 K -> R (in HTFG; enhances receptor
FT response to chorionic gonadotropin).
FT /FTId=VAR_003566.
FT VARIANT 197 197 F -> I (in papillary cancer).
FT /FTId=VAR_003567.
FT VARIANT 219 219 D -> E (in papillary cancer).
FT /FTId=VAR_003568.
FT VARIANT 252 252 L -> P (in CHNG1; displays a low
FT expression at the cell surface and a
FT reduced response to bovine TSH in terms
FT of cAMP production).
FT /FTId=VAR_021495.
FT VARIANT 281 281 S -> I (in hyperthyroidism; congenital;
FT due to a toxic adenoma).
FT /FTId=VAR_003569.
FT VARIANT 281 281 S -> N (in HTNA; gain of function; found
FT in toxic thyroid nodules and
FT hyperfunctioning thyroid adenomas).
FT /FTId=VAR_003570.
FT VARIANT 281 281 S -> T (in hyperthyroidism; associated
FT with hyperfunctioning thyroid adenomas).
FT /FTId=VAR_011523.
FT VARIANT 310 310 R -> C (in CHNG1).
FT /FTId=VAR_011524.
FT VARIANT 390 390 C -> W (in CHNG1; persistent
FT hypothyroidism and defective thyroid
FT development; habolishes high affinity
FT hormone binding).
FT /FTId=VAR_011525.
FT VARIANT 410 410 D -> N (in CHNG1; lack of adenylate
FT cyclase activation).
FT /FTId=VAR_011526.
FT VARIANT 425 425 S -> I (in TTNs; 8 to 9 times higher
FT levels of basal cAMP than wild-type TSHR
FT and similar response to maximal TSH
FT stimulation).
FT /FTId=VAR_021496.
FT VARIANT 431 431 G -> S (in HTNA; gain of function;
FT constitutive activation of the G(s)/
FT adenylyl cyclase system).
FT /FTId=VAR_011527.
FT VARIANT 450 450 R -> H (in CHNG1).
FT /FTId=VAR_011528.
FT VARIANT 453 453 M -> T (in HTNA; sporadic; found in toxic
FT thyroid nodules and hyperfunctioning
FT thyroid adenomas).
FT /FTId=VAR_011529.
FT VARIANT 463 463 M -> V (in HTNA; gain of function).
FT /FTId=VAR_011530.
FT VARIANT 467 467 L -> P (in CHNG1).
FT /FTId=VAR_017295.
FT VARIANT 477 477 T -> I (in CHNG1; severe hypothyroidism).
FT /FTId=VAR_017296.
FT VARIANT 486 486 I -> F (in HTNA; found in thyroid toxic
FT nodules and hyperfunctioning thyroid
FT adenomas; also in hyperfunctioning
FT follicular carcinoma).
FT /FTId=VAR_011531.
FT VARIANT 486 486 I -> M (in HTNA; found in
FT hyperfunctioning thyroid adenomas).
FT /FTId=VAR_011532.
FT VARIANT 498 498 G -> S (in CHNG1).
FT /FTId=VAR_011533.
FT VARIANT 505 505 S -> N (in HTNA; found in toxic thyroid
FT nodules).
FT /FTId=VAR_003571.
FT VARIANT 505 505 S -> R (in HTNA; gain of function).
FT /FTId=VAR_011534.
FT VARIANT 509 509 V -> A (in HTNA; gain of function).
FT /FTId=VAR_011535.
FT VARIANT 512 512 L -> Q (in TTNs; 5 times higher levels of
FT basal cAMP than wild-type TSHR and
FT slightly less response to maximal TSH
FT stimulation).
FT /FTId=VAR_021497.
FT VARIANT 512 512 L -> R (in hyperthyroidism and TTNs;
FT associated with autonomously functioning
FT thyroid nodules; 3.3-fold increase in
FT basal cAMP level).
FT /FTId=VAR_011536.
FT VARIANT 525 525 F -> L (in CHNG1; impairs adenylate
FT cyclase activation).
FT /FTId=VAR_011537.
FT VARIANT 528 528 R -> H.
FT /FTId=VAR_003572.
FT VARIANT 553 553 A -> T (in CHNG1; severe hypothyroidism).
FT /FTId=VAR_011538.
FT VARIANT 568 568 I -> T (in HTNA; found in thyroid toxic
FT nodules and hyperfunctioning thyroid
FT adenomas).
FT /FTId=VAR_011539.
FT VARIANT 593 593 A -> N (in toxic thyroid adenoma;
FT requires 2 nucleotide substitutions;
FT somatic mutation; N-593 and N-593/E-727
FT constitutively activate the cAMP cascade;
FT double mutant's specific constitutive
FT activity is 2.3-fold lower than the N-593
FT mutant).
FT /FTId=VAR_021498.
FT VARIANT 597 597 V -> F (in HTNA; 11-fold increase in
FT specific constitutive activity associated
FT with reduction in receptor protein
FT expression).
FT /FTId=VAR_021499.
FT VARIANT 597 597 V -> L (in hyperthyroidism; congenital
FT with severe thyrotoxicosis).
FT /FTId=VAR_011540.
FT VARIANT 600 600 C -> R (in CHNG1).
FT /FTId=VAR_017297.
FT VARIANT 606 606 I -> M.
FT /FTId=VAR_011541.
FT VARIANT 619 619 D -> G (in hyperthyroidism and TTNs;
FT associated with hyperfunctioning thyroid
FT adenomas).
FT /FTId=VAR_003573.
FT VARIANT 623 623 A -> I (in hyperthyroidism; associated
FT with hyperfunctioning thyroid adenomas;
FT gain of function; requires 2 nucleotide
FT substitutions).
FT /FTId=VAR_003574.
FT VARIANT 623 623 A -> V (in hyperthyroidism and TTNs;
FT associated with hyperfunctioning thyroid
FT adenomas; gain of function).
FT /FTId=VAR_011542.
FT VARIANT 629 629 L -> F (in HTNA; also in hyperfunctioning
FT thyroid adenomas and non-adenomatous
FT nodules).
FT /FTId=VAR_003575.
FT VARIANT 630 630 I -> L (in hyperthyroidism; associated
FT with hyperfunctioning thyroid adenomas).
FT /FTId=VAR_011543.
FT VARIANT 631 631 F -> C (in hyperthyroidism; associated
FT with hyperfunctioning thyroid adenomas).
FT /FTId=VAR_011544.
FT VARIANT 631 631 F -> L (in HTNA; gain of function; found
FT in toxic thyroid nodules and
FT hyperfunctioning thyroid adenomas).
FT /FTId=VAR_011545.
FT VARIANT 632 632 T -> A (in HTNA; gain of function; found
FT in toxic thyroid nodules and
FT hyperfunctioning non-adenomatous
FT nodules).
FT /FTId=VAR_011546.
FT VARIANT 632 632 T -> I (in HTNA; gain of function; found
FT in thyroid toxic nodules and
FT hyperfunctioning thyroid adenomas).
FT /FTId=VAR_011547.
FT VARIANT 633 633 D -> A (in hyperthyroidism; associated
FT with hyperfunctioning thyroid adenomas).
FT /FTId=VAR_011548.
FT VARIANT 633 633 D -> E (in HTNA; found in thyroid toxic
FT nodules and hyperfunctioning thyroid
FT adenomas).
FT /FTId=VAR_011549.
FT VARIANT 633 633 D -> H (in hyperthyroidism and TTNs;
FT associated with hyperfunctioning thyroid
FT adenomas; also in hyperfunctioning
FT insular carcinoma; with severe
FT thyrotoxicosis; gain of function;
FT dbSNP:rs28937584).
FT /FTId=VAR_011550.
FT VARIANT 633 633 D -> Y (in hyperthyroidism and TTNs;
FT associated with hyperfunctioning thyroid
FT adenomas).
FT /FTId=VAR_011551.
FT VARIANT 639 639 P -> A (in TTNs).
FT /FTId=VAR_021500.
FT VARIANT 639 639 P -> S (in HTNA; gain of function).
FT /FTId=VAR_011552.
FT VARIANT 647 647 A -> V (in HTNA; found in non-adenomatous
FT hyperfunctioning nodules).
FT /FTId=VAR_011553.
FT VARIANT 650 650 N -> Y (in HTNA; gain of function).
FT /FTId=VAR_011554.
FT VARIANT 656 656 V -> F (in TTNs).
FT /FTId=VAR_021501.
FT VARIANT 658 661 Missing (in hyperthyroidism; associated
FT with hyperfunctioning thyroid adenomas).
FT /FTId=VAR_011555.
FT VARIANT 670 670 N -> S (in HTNA; gain of function).
FT /FTId=VAR_011556.
FT VARIANT 672 672 C -> Y (in HTNA; gain of function).
FT /FTId=VAR_011557.
FT VARIANT 677 677 L -> V (in thyroid carcinoma; with
FT thyrotoxicosis; gain of function).
FT /FTId=VAR_011558.
FT VARIANT 703 703 A -> G.
FT /FTId=VAR_011559.
FT VARIANT 715 715 N -> D (in papillary cancer).
FT /FTId=VAR_003576.
FT VARIANT 720 720 Q -> E.
FT /FTId=VAR_011560.
FT VARIANT 723 723 K -> M (in papillary cancer).
FT /FTId=VAR_003577.
FT VARIANT 727 727 D -> E (may be a predisposing factor in
FT toxic multinodular goiter pathogenesis;
FT activation of the cAMP cascade does not
FT differ from the wild-type;
FT dbSNP:rs1991517).
FT /FTId=VAR_003578.
FT CONFLICT 87 87 V -> L (in Ref. 2; no nucleotide entry).
FT CONFLICT 196 198 AFN -> DFF (in Ref. 4; AAA70232).
FT CONFLICT 257 257 T -> S (in Ref. 4; AAA70232).
FT CONFLICT 264 264 P -> A (in Ref. 4; AAA70232).
FT CONFLICT 306 308 MQS -> IET (in Ref. 4; AAA70232).
FT CONFLICT 528 528 R -> A (in Ref. 4; AAA70232).
FT CONFLICT 601 601 Y -> H (in Ref. 1; AAA36783).
FT CONFLICT 635 635 I -> T (in Ref. 4; AAA70232).
FT CONFLICT 645 645 L -> V (in Ref. 4; AAA70232).
FT CONFLICT 669 669 L -> I (in Ref. 4; AAA70232).
FT CONFLICT 744 744 N -> K (in Ref. 3; AAA61236).
FT STRAND 26 28
FT STRAND 30 33
FT TURN 35 37
FT STRAND 38 41
FT STRAND 56 61
FT STRAND 65 67
FT TURN 69 74
FT STRAND 80 84
FT TURN 94 96
FT STRAND 97 99
FT STRAND 105 111
FT STRAND 121 123
FT STRAND 130 136
FT STRAND 152 160
FT TURN 169 174
FT STRAND 175 183
FT STRAND 190 192
FT TURN 194 199
FT STRAND 201 206
FT TURN 218 223
FT STRAND 229 232
FT STRAND 250 253
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
//

MIM 275200
*RECORD*
*FIELD* NO
275200
*FIELD* TI
#275200 HYPOTHYROIDISM, CONGENITAL, NONGOITROUS, 1; CHNG1
;;THYROTROPIN RESISTANCE;;
read moreTHYROID-STIMULATING HORMONE, RESISTANCE TO; RTSH;;
TSH RESISTANCE;;
HYPOTHYROIDISM, NONAUTOIMMUNE;;
HYPOTHYROIDISM, CONGENITAL, DUE TO TSH RESISTANCE;;
HYPOTHYROIDISM DUE TO UNRESPONSIVENESS TO THYROTROPIN
*FIELD* TX
A number sign (#) is used with this entry because congenital nongoitrous
hypothyroidism-1 (CHNG1) is caused by mutation in the gene encoding the
thyroid-stimulating hormone receptor (TSHR; 603372) on chromosome 14q31.

DESCRIPTION

Resistance to thyroid-stimulating hormone (TSH; see 188540), a hallmark
of congenital nongoitrous hypothyroidism, causes increased levels of
plasma TSH and low levels of thyroid hormone. Only a subset of patients
develop frank hypothyroidism; the remainder are euthyroid and
asymptomatic (so-called compensated hypothyroidism) and are usually
detected by neonatal screening programs (Paschke and Ludgate, 1997).

- Genetic Heterogeneity of Congenital Nongoitrous Hypothyroidism

CHNG2 (218700) is caused by mutation in the PAX8 gene (167415) on
chromosome 2q12-q14; CHNG3 (609893) maps to a locus on chromosome
15q25.3; CHNG4 (275100) is caused by mutation in the TSHB gene (188540)
on chromosome 1p13; CHNG5 (225250) is caused by mutation in the NKX2-5
gene (600584) on chromosome 5q34; and CHNG6 (614450) is caused by
mutation in the THRA gene (190120) on chromosome 17q21.1.

CLINICAL FEATURES

Stanbury et al. (1968) described an 8-year-old boy with congenital
hypothyroidism who was the offspring of parents related as first cousins
once removed. He showed high serum levels of biologically active
thyrotropin but no response to thyrotropin in vivo or in thyroid tissue
slices in vitro. The findings suggested end-organ unresponsiveness.

Medeiros-Neto et al. (1979) reported a 19-year-old man with congenital
hypothyroidism with thyroglobulin deficiency and high levels of plasma
TSH. No antibodies against thyroid antigens were found. Studies of
thyroid biopsy tissue showed no formation of cAMP after stimulation with
TSH, although the patient's TSH was biologically active in normal tissue
samples.

Codaccioni et al. (1980) described a similar case in a 17-year-old male
born of consanguineous parents. Plasma thyroid hormone levels were very
low and TSH concentrations very high. Uptake of (131)I by the thyroid
was not stimulated by TSH, but was increased by an intravenous injection
of dibutyryl cyclic AMP. Codaccioni et al. (1980) found normal binding
of TSH to thyroid cell membranes, and concluded that the defect lay
somewhere between the receptor binding site and the receptor-cyclase
binding protein. The authors noted that resistance to TSH as well as to
other pituitary trophic hormones is observed in some cases of
pseudohypoparathyroidism (Marx et al., 1971). In some instances,
infantile hypothyroidism is the initial manifestation of
pseudohypoparathyroidism (Levine et al., 1985).

Saldanha and Toledo (1988) reviewed reported cases of inherited
hypothyroidism due to unresponsiveness to thyrotropin; none had goiter,
a feature distinguishing this disorder from the inborn errors of
thyroxine biosynthesis.

Takamatsu et al. (1993) described congenital hypothyroidism due to
unresponsiveness to TSH in a brother and sister, aged 29 and 26 years,
respectively. Congenital hypothyroidism was discovered at ages 5 and 2
years. The parents were first cousins. Takamatsu et al. (1993) claimed
that unresponsiveness to TSH had been identified and sufficiently
studied in only 3 patients and that theirs was the first documentation
of familial occurrence.

Sunthornthepvarakul et al. (1995) reported 3 sibs who were euthyroid and
had normal concentrations of thyroid hormone, but increased plasma
thyrotropin (approximately 20-fold elevation), a situation referred to
as partial thyrotropin resistance or compensated hypothyroidism. The
proband was ascertained by a neonatal screening program; the abnormality
was demonstrated at birth in 2 of the 3 sibs. The persistence of the
high serum thyrotropin concentrations was not compatible with transient
infantile hyperthyrotropinemia, a normal variant. None of the sibs had
symptoms or signs of hypothyroidism at any time. The persistent
hyperthyrotropinemia in the 3 sibs suggested that the disorder was
inherited, and the parents showed borderline elevation of serum
thyrotropin concentrations. There was no parental consanguinity; the
parents were of different ethnic extraction. The normal growth and
development of the eldest girl, who did not receive thyroid hormone
until the age of 5 years, suggested that her increased thyrotropin
secretion was not due to primary hypothyroidism. Sunthornthepvarakul et
al. (1995) concluded that the elevated TSH levels were required to
maintain normal thyroid hormone secretion by cells expressing the mutant
TSH receptor.

Kempers et al. (2009) examined the body surface of 242 Dutch patients
with congenital hypothyroidism (CH) of thyroidal origin with thyroid
agenesis, an ectopic thyroid rudiment, or eutopic thyroid gland, for
visually detectable morphologic abnormalities. The percentage of
patients with 1 or more major anomalies in the total CH cohort (33%) and
in patients with ectopic thyroid (37.2%) was significantly higher than
in 1,007 Dutch controls (21.8%; p less than 0.001), and specific major
malformations such as bilateral ear pits and oligodontia were more
frequent in the group of patients with ectopic thyroid. In addition, the
percentage of patients in the congenital hypothyroidism cohort with 1 or
more minor anomalies (96.3%) was significantly higher than in the
control group (82.5%; p less than 0.001).

DIAGNOSIS

Takeshita et al. (1994) made the diagnosis of TSH unresponsiveness in 3
patients based on the following criteria: (1) congenital primary
hypothyroidism with autosomal recessive inheritance; (2) a nongoitrous
thyroid gland in a normal position with low thyroidal radioactive iodine
uptake; (3) normal in vitro TSH bioactivity or absent in vivo response
to exogenous TSH; and (4) absence of thyroid autoantibodies.

MAPPING

- Genetic Heterogeneity

Some cases of thyrotropin resistance may not be due to mutation in the
TSHR gene on chromosome 14. Ahlbom et al. (1997) investigated 10 Swedish
families, each with 2 cases of congenital hypothyroidism, 11 affected
families from Pakistan, and 1 affected family each from Syria and Egypt.
They mapped the TSHR gene on radiation panels and identified 2 flanking
DNA markers which were analyzed for linkage analysis. Assuming
homogeneity, the 2-point lod score at theta = 0.1 was -4.8 for one
marker and -5.8 for the second, thus excluding linkage to TSHR. Even
when the data were analyzed with allowance for heterogeneity, there was
no evidence of linkage to the TSHR gene. Ahlbom et al. (1997) concluded
that if mutation of the TSHR gene causes familial congenital
hypothyroidism in humans, it affects only a small proportion of cases.

- Associations Pending Confirmation

Carre et al. (2007) analyzed alanine tract length in the FOXE1 gene
(602617) in 115 patients with thyroid dysgenesis and 129 controls and
found suggestive evidence that FOXE1 alanine tract length modulates
genetic susceptibility to thyroid dysgenesis.

Denny et al. (2011) performed a genomewide association study of 1,317
cases of primary hypothyroidism and 5,053 controls that had been
identified by electronic selection algorithms of medical records. Four
SNPs at chromosome 9q22 near the FOXE1 gene were associated with
hypothyroidism at genomewide significance, with the strongest
association at dbSNP rs7850258 (OR, 0.74; p = 3.96 x 10(-9)). A
phenomewide association study performed on this locus identified
associations with additional thyroid-related phenotypes: thyroiditis
(OR, 0.58; p = 1.4 x 10(-5)), nodular goiter (OR, 0.76; p = 3.1 x
10(-5)), multinodular goiter (OR, 0.69; p = 3.9 x 10(-5)), and
thyrotoxicosis (OR, 0.76; p = 1.5 x 10(-3)). Graves disease and thyroid
cancer, however, were not significantly associated with the locus in the
phenomewide study.

MOLECULAR GENETICS

In 3 sibs with normal serum thyroid hormone concentrations but high
serum thyrotropin concentrations ('compensated hypothyroidism'),
Sunthornthepvarakul et al. (1995) identified compound heterozygosity for
2 mutations in the TSHR gene (603372.0005; 603372.0006).
Sunthornthepvarakul et al. (1995) concluded that the elevated TSH levels
were required to maintain normal thyroid hormone secretion by cells
expressing the mutant TSH receptor.

De Roux et al. (1996) studied 4 unrelated French patients with
congenital hypothyroidism found on neonatal screening in whom they
identified loss-of-function mutations in the TSHR gene. One patient was
homozygous, and 3 others were compound heterozygous (see 603372.0006;
603372.0010-603372.0015). The patients showed 'partial thyrotropin
resistance' with increased plasma TSH concentration and normal T3 and T4
concentrations. TSH levels were normal in the heterozygous parents.

In a child with congenital hypothyroidism associated found on neonatal
screening who had markedly increased serum TSH concentrations and low
normal thyroid hormone levels, Clifton-Bligh et al. (1997) identified
compound heterozygosity for 2 mutations in the TSHR gene (603372.0009;
603372.0010).

In a brother and sister, born of consanguineous parents, with congenital
nonautoimmune hypothyroidism, Abramowicz et al. (1997) identified a
homozygous mutation in the TSHR gene (603372.0016). The mutation was
heterozygous in both parents and 2 unaffected sibs. The patients were
initially diagnosed with thyroid agenesis, but cervical ultrasonography
in both patients revealed a very hypoplastic thyroid gland.

In a child with congenital hypothyroidism associated with a reduced
gland volume, Biebermann et al. (1997) identified compound
heterozygosity for 2 mutations in the TSHR gene (603372.0015;
603372.0018).

De Felice and Di Lauro (2004) reviewed the development of the thyroid
gland and the genetic molecular mechanisms leading to thyroid
dysgenesis.

Park and Chatterjee (2005) reviewed the genetics of primary congenital
hypothyroidism, summarizing the different phenotypes associated with
known genetic defects and proposing an algorithm for investigating the
genetic basis of the disorder.

- Genetic Heterogeneity

Takeshita et al. (1994) analyzed the nucleotide sequence of the entire
coding region of the TSHR gene in 3 patients with this disorder. The
TSHR cDNA was obtained from RNA of peripheral mononuclear leukocytes
with reverse transcription and PCR, and was sequenced directly.
Comparison of these nucleotide sequences with the normal TSHR sequence
revealed no difference in the predicted amino acid sequence.

Xie et al. (1997) studied 3 unrelated families with resistance to TSH
that followed a dominant rather than a recessive pattern of inheritance
in 2 families and was not associated with TSHR gene abnormalities. TSHR
gene abnormalities were excluded by sequencing all coding sequences,
exon/intron junctions, and the promoter region of the gene. In addition,
linkage analysis using intragenic polymorphic markers demonstrated that
the TSHR gene did not cosegregate with the disease phenotype in 2
families. Xie et al. (1997) excluded defects in the TSH-beta subunit
(188540) by DNA sequencing and by showing that circulating TSH in
affected subjects from all families had normal bioactivity. Also, no
abnormalities were found in the Gs-alpha gene (GNAS1; 139320) of one
family analyzed by GC-clamped denaturing gradient gel electrophoresis
(DGGE). The authors concluded that resistance to TSH may be a
manifestation of several different genetic defects that requires the
exploration of other candidate genes involved in the TSH/TSHR/Gs-alpha
cascade and genes participating in its regulation.

ANIMAL MODEL

The 'hyt' mouse is a model for autosomal recessive congenital
hypothyroidism (Beamer et al., 1981). The phenotype of the mutant mouse
is very similar to that of human congenital hypothyroidism. Stein et al.
(1994) demonstrated a mutation in the Tshr gene as the cause of the
disease in the hyt mouse.

*FIELD* RF
1. Abramowicz, M. J.; Duprez, L.; Parma, J.; Vassart, G.; Heinrichs,
C.: Familial congenital hypothyroidism due to inactivating mutation
of the thyrotropin receptor causing profound hypoplasia of the thyroid
gland. J. Clin. Invest. 99: 3018-3024, 1997.

2. Ahlbom, B. E.; Yaqoob, M.; Larsson, A.; Ilicki, A.; Anneren, G.;
Wadelius, C.: Genetic and linkage analysis of familial congenital
hypothyroidism: exclusion of linkage to the TSH receptor gene. Hum.
Genet. 99: 186-190, 1997.

3. Beamer, W. G.; Eicher, E. M.; Maltais, L. J.; Southard, J. C.:
Inherited primary hypothyroidism in mice. Science 212: 61-63, 1981.

4. Biebermann, H.; Schoneberg, T.; Krude, H.; Schultz, G.; Gudermann,
T.; Gruters, A.: Mutations of the human thyrotropin receptor gene
causing thyroid hypoplasia and persistent congenital hypothyroidism. J.
Clin. Endocr. Metab. 82: 3471-3480, 1997.

5. Carre, A.; Castanet, M.; Sura-Trueba, S.; Szinnai, G.; Van Vliet,
G.; Trochet, D.; Amiel, J.; Leger, J.; Czernichow, P.; Scotet, V.;
Polak, M.: Polymorphic length of FOXE1 alanine stretch: evidence
for genetic susceptibility to thyroid dysgenesis. Hum. Genet. 122:
467-476, 2007.

6. Clifton-Bligh, R. J.; Gregory, J. W.; Ludgate, M.; John, R.; Persani,
L.; Asteria, C.; Beck-Peccoz, P.; Chatterjee, V. K. K.: Two novel
mutations in the thyrotropin (TSH) receptor gene in a child with resistance
to TSH. J. Clin. Endocr. Metab. 82: 1094-1100, 1997.

7. Codaccioni, J. L.; Carayon, P.; Michel-Bechet, M.; Foucault, F.;
Lefort, G.; Pierron, H.: Congenital hypothyroidism associated with
thyrotropin unresponsiveness and thyroid cell membrane alterations. J.
Clin. Endocr. Metab. 50: 932-937, 1980.

8. De Felice, M.; Di Lauro, R.: Thyroid development and its disorders:
genetics and molecular mechanisms. Endocr. Rev. 25: 722-746, 2004.

9. Denny, J. C.; Crawford, D. C.; Ritchie, M. D.; Bielinski, S. J.;
Basford, M. A.; Bradford, Y.; Chai, H. S.; Bastarache, L.; Zuvich,
R.; Peissig, P.; Carrell, D.; Ramirez, A. H.; and 22 others: Variants
near FOXE1 are associated with hypothyroidism and other thyroid conditions:
using electronic medical records for genome- and phenome-wide studies. Am.
J. Hum. Genet. 89: 529-542, 2011.

10. de Roux, N.; Misrahi, M.; Brauner, R.; Houang, M.; Carel, J. C.;
Granier, M.; le Bouc, Y.; Ghinea, N.; Boumedienne, A.; Toublanc, J.
E.; Milgrom, E.: Four families with loss of function mutations of
the thyrotropin receptor. J. Clin. Endocr. Metab. 81: 4229-4235,
1996.

11. Kempers, M. J. E.; Ozgen, H. M.; Vulsma, T.; Merks, J. H.; Zwinderman,
K. H.; de Vijlder, J. J. M.; Hennekam, R. C. M.: Morphological abnormalities
in children with thyroidal congenital hypothyroidism. Am. J. Med.
Genet. 149A: 943-951, 2009.

12. Levine, M. A.; Jap, T.-S.; Hung, W.: Infantile hypothyroidism
in two sibs: an unusual presentation of pseudohypoparathyroidism type
Ia. J. Pediat. 107: 919-922, 1985.

13. Marx, S. J.; Hershman, J. M.; Aurbach, G. D.: Thyroid dysfunction
in pseudohypoparathyroidism. J. Clin. Endocr. Metab. 33: 822-828,
1971.

14. Medeiros-Neto, G. A.; Knobel, M.; Bronstein, M. D.; Simonetti,
J.; Filho, F. F.; Mattar, E.: Impaired cyclic-AMP response to thyrotrophin
in congenital hypothyroidism with thyroglobulin deficiency. Acta
Endocr. 92: 62-64, 1979.

15. Park, S. M.; Chatterjee, V. K. K.: Genetics of congenital hypothyroidism. J.
Med. Genet. 42: 379-389, 2005.

16. Paschke, R.; Ludgate, M.: The thyrotropin receptor in thyroid
diseases. New Eng. J. Med. 337: 1675-1681, 1997.

17. Saldanha, P. H.; Toledo, S. P. A.: Inherited hypothyroidism unresponsive
to thyrotropin in man. Rev. Brasil. Genet. 11: 803-804, 1988.

18. Stanbury, J. B.; Rocmans, P.; Buhler, U. K.; Ochi, Y.: Congenital
hypothyroidism with impaired thyroid response to thyrotropin. New
Eng. J. Med. 279: 1132-1136, 1968.

19. Stein, S. A.; Oates, E. L.; Hall, C. R.; Grumbles, R. M.; Fernandez,
L. M.; Taylor, N. A.; Puett, D.; Jin, S.: Identification of a point
mutation in the thyrotropin receptor of the hyt/hyt hypothyroid mouse. Molec.
Endocr. 8: 129-138, 1994.

20. Sunthornthepvarakul, T.; Gottschalk, M. E.; Hayashi, Y.; Refetoff,
S.: Resistance to thyrotropin caused by mutations in the thyrotropin-receptor
gene. New Eng. J. Med. 332: 155-160, 1995.

21. Takamatsu, J.; Nishikawa, M.; Horimoto, M.; Ohsawa, N.: Familial
unresponsiveness to thyrotropin by autosomal recessive inheritance. J.
Clin. Endocr. Metab. 77: 1569-1573, 1993.

22. Takeshita, A.; Nagayama, Y.; Yamashita, S.; Takamatsu, J.; Ohsawa,
N.; Maesaka, H.; Tachibana, K.; Tokuhiro, E.; Ashizawa, K.; Yokoyama,
N.; Nagataki, S.: Sequence analysis of the thyrotropin (TSH) receptor
gene in congenital primary hypothyroidism associated with TSH unresponsiveness. Thyroid 4:
255-259, 1994.

23. Xie, J.; Pannain, S.; Pohlenz, J.; Weiss, R. E.; Moltz, K.; Morlot,
M.; Asteria, C.; Persani, L.; Beck-Peccoz, P.; Parma, J.; Vassart,
G.; Refetoff, S.: Resistance to thyrotropin (TSH) in three families
is not associated with mutations in the TSH receptor or TSH. J. Clin.
Endocr. Metab. 82: 3933-3940, 1997.

*FIELD* CS
INHERITANCE:
Autosomal recessive

ENDOCRINE FEATURES:
Euthyroidism;
Normal sized thyroid gland;
No goiter;
Hypothyroidism in subset of patients;
Patients with hypothyroidism have hypoplastic thyroid gland

IMMUNOLOGY:
Absence of anti-thyroid antibodies

LABORATORY ABNORMALITIES:
Increased serum thyroid-stimulating hormone (TSH);
Normal or mildly decreased serum levels of free thyroid hormones

MISCELLANEOUS:
Onset in infancy;
Most patients are asymptomatic and are detected by newborn screening;
Variable severity ranging from asymptomatic euthyroid to severe hypothyroidism

MOLECULAR BASIS:
Caused by mutation in the thyroid-stimulating hormone receptor gene
(TSHR, 603372.0005)

*FIELD* CN
Cassandra L. Kniffin - revised: 01/12/2005

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
ckniffin: 01/12/2005

*FIELD* CN
Marla J. F. O'Neill - updated: 1/26/2012
Marla J. F. O'Neill - updated: 10/28/2011
Marla J. F. O'Neill - updated: 10/30/2009
Marla J. F. O'Neill - updated: 2/17/2006
Marla J. F. O'Neill - updated: 6/23/2005
Cassandra L. Kniffin - reorganized: 1/26/2005
Cassandra L. Kniffin - updated: 1/12/2005
Victor A. McKusick - updated: 12/30/1998
John A. Phillips, III - updated: 7/16/1998
John A. Phillips, III - updated: 6/11/1998
John A. Phillips, III - updated: 5/12/1998
John A. Phillips, III - updated: 3/19/1998
John A. Phillips, III - updated: 3/18/1998
Victor A. McKusick - updated: 1/27/1998
Victor A. McKusick - updated: 1/21/1998
John A. Phillips, III - updated: 12/25/1997
Ada Hamosh - updated: 12/10/1997
Victor A. McKusick - updated: 7/14/1997
John A. Phillips, III - updated: 6/23/1997
John A. Phillips, III - updated: 4/29/1997
John A. Phillips, III - updated: 4/17/1997
John A. Phillips, III - updated: 2/25/1997
Victor A. McKusick - updated: 2/13/1997
John A. Phillips, III - updated: 12/13/1996
John A. Phillips, III - updated: 9/21/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 01/27/2012
terry: 1/26/2012
alopez: 11/2/2011
terry: 10/28/2011
wwang: 11/6/2009
terry: 10/30/2009
carol: 9/5/2008
carol: 2/21/2006
carol: 2/17/2006
wwang: 6/23/2005
carol: 1/26/2005
ckniffin: 1/12/2005
alopez: 10/2/2003
carol: 12/30/1998
dkim: 12/18/1998
dkim: 7/24/1998
carol: 7/20/1998
dholmes: 7/17/1998
dholmes: 7/16/1998
alopez: 6/11/1998
alopez: 5/12/1998
psherman: 3/19/1998
psherman: 3/18/1998
mark: 1/28/1998
terry: 1/27/1998
dholmes: 1/26/1998
alopez: 1/26/1998
mark: 1/25/1998
terry: 1/21/1998
alopez: 1/6/1998
alopez: 1/5/1998
alopez: 12/18/1997
joanna: 12/10/1997
mark: 7/14/1997
terry: 7/14/1997
alopez: 7/10/1997
joanna: 6/23/1997
jenny: 5/28/1997
jenny: 5/27/1997
jenny: 5/21/1997
jenny: 5/20/1997
jenny: 5/14/1997
jenny: 4/29/1997
jenny: 3/4/1997
jenny: 2/25/1997
mark: 2/13/1997
terry: 2/10/1997
jamie: 12/6/1996
terry: 12/4/1996
mark: 11/27/1996
terry: 11/13/1996
carol: 9/25/1996
carol: 9/21/1996
carol: 3/2/1995
mimadm: 3/12/1994
carol: 12/20/1993
carol: 11/5/1993
carol: 9/8/1993
carol: 8/31/1993

MIM 603372
*RECORD*
*FIELD* NO
603372
*FIELD* TI
+603372 THYROID-STIMULATING HORMONE RECEPTOR; TSHR
;;THYROTROPIN RECEPTOR;;
LGR3
THYROID ADENOMA, HYPERFUNCTIONING, INCLUDED;;
read moreTHYROID CARCINOMA WITH THYROTOXICOSIS, INCLUDED
*FIELD* TX

CLONING

Nagayama et al. (1989) isolated a TSHR cDNA from a human thyroid cDNA
library. The deduced 764-amino acid protein has a molecular mass of 86.8
kD and contains a signal peptide, 7 transmembrane regions, 5 potential
glycosylation sites, and a short intracytoplasmic region. The TSHR cDNA
encoded a functional receptor that activated adenylate cyclase in
response to TSH.

Libert et al. (1989) used a dog Tshr cDNA to isolate a human TSHR cDNA
from a thyroid cDNA library. The cDNA encodes a deduced 744-amino acid
protein with 90.3% homology to the dog protein. Two major 4.6- and
4.4-kb mRNA transcripts were identified, suggesting alternative
splicing.

By analyzing several TSHR cDNA clones, Misrahi et al. (1990) determined
that the mature TSHR polypeptide contains 743 amino acids with a
calculated molecular mass of 84.5 kD. The putative TSH receptor has a
394-residue extracellular domain, a 266-residue transmembrane domain,
and an 83-residue intracellular domain. The authors observed a high
degree of homology with the luteinizing hormone/choriogonadotropin
receptor (LHCGR; 152790).

Kakinuma and Nagayama (2002) found that the TSHR gene can express at
least 5 alternatively spliced forms.

GENE FUNCTION

The TSH receptor differs from the LHCG receptor by the presence of 2
unique insertions of 8 and 50 amino acids in the extracellular domain.
Wadsworth et al. (1990) showed that the 8-amino acid tract near the
amino terminus of the TSH receptor is an important site of interaction
with both TSH and autoantibodies against the TSH receptor
(thyroid-stimulating immunoglobulins, TSI). Either deletion or
substitution of this region abolished the interaction, whereas a
deletion of the 50-amino acid tract had no effect.

Contiguous to the 5-prime end of the thyroid transcription factor-1
(TTF1; 600635) element upstream and within the TSHR promoter is an
element on the noncoding strand with single-strand binding activity that
is important for regulation of TSHR expression. Ohmori et al. (1996)
identified a cDNA encoding a single-strand binding protein (SSBP),
referred to as SSBP1, that forms a specific complex with this element on
the noncoding strand of TSHR. SSBP1 is a ubiquitous transcription factor
that contributes to TSHR maximal expression, and mutation analyses
showed that a GXXXXG motif is important for the binding and enhancer
function of SSBP1. The authors concluded that the common transcription
factors regulate TSHR and major histocompatibility gene expression. They
also concluded that SSBP1 is a member of a family of SSBPs that interact
with RNA and with the promoter of retroviruses, and are important in RNA
processing. Members of this family also can interact with c-myc
(190080), a gene linked to growth and DNA replication.

BIOCHEMICAL FEATURES

The high sequence homology with the LHCG receptor, which is composed of
a single polypeptide chain, led many to suppose a similar structure for
the TSH receptor. However, Loosfelt et al. (1992) presented evidence for
a heterodimeric structure of TSHR. The extracellular (hormone-binding)
alpha subunit had an apparent molecular mass of 53 kD, whereas the
membrane-spanning beta subunit seemed heterogeneous and had an apparent
molecular mass of 33 to 42 kD. Human thyroid membranes contained 2.5 to
3 times as many beta subunits as alpha subunits; however, the 2 subunits
probably derive from a single gene since a single reading frame was
demonstrated by cDNA cloning and sequencing. The exact site of cleavage
that results in the 2 subunits was difficult to define.

The TSH receptor is the antigen targeted by autoantibodies in Graves
disease (275000). By PCR amplification of specific cDNA, Feliciello et
al. (1993) demonstrated that mature TSH receptor mRNA is expressed in
the retroorbital tissue of both healthy subjects and patients with
Graves disease. Of other tissues and cells tested, only thyroid tissue
expressed the TSHR mRNA. The findings provided a link between orbital
involvement and thyroid disease in Graves disease.

Graves et al. (1999) used epitope-mapped monoclonal and polyclonal
antibodies to TSHR as immunoblot probes to detect and characterize the
molecular species of the receptor present in normal human thyroid
tissue. In reduced membrane fractions, both full-length (uncleaved)
holoreceptor and cleavage-derived subunits of the holoreceptor were
detected. Uncleaved holoreceptor species included a nonglycosylated form
of apparent molecular mass 85 kD and 2 glycosylated forms of
approximately 110 and 120 kD. The membranes also contained several forms
of cleavage-derived TSHR alpha and beta subunits. Alpha subunits were
detected by antibodies to epitopes localized within the N-terminal end
of the TSHR ectodomain and migrated diffusely between 45 and 55 kD,
reflecting a differentially glycosylated status. Several species of beta
subunit were present, the most abundant having apparent molecular masses
of 50, 40, and 30 kD. The authors concluded that posttranslational
processing of the TSHR occurs in human thyroid tissue and involves
multiple cleavage sites.

Lazar et al. (1999) studied the expression of 4 thyroid-specific genes
(sodium-iodide symporter (NIS, or SLC5A5; 601843), thyroid peroxidase
(TPO; 274500), thyroglobulin (TG; 188450), and TSHR) as well as the gene
encoding glucose transporter-1 (GLUT1, or SLC2A1; 138140) in 90 human
thyroid tissues. Messenger RNAs were extracted from 43 thyroid
carcinomas (38 papillary and 5 follicular), 24 cold adenomas, 5 Graves
thyroid tissues, 8 toxic adenomas, and 5 hyperplastic thyroid tissues; 5
normal thyroid tissues were used as reference. A kinetic quantitative
PCR method, based on the fluorescent TaqMan methodology and real-time
measurement of fluorescence, was used. NIS expression was decreased in
40 of 43 (93%) thyroid carcinomas and in 20 of 24 (83%) cold adenomas;
it was increased in toxic adenomas and Graves thyroid tissues. TPO
expression was decreased in thyroid carcinomas but was normal in cold
adenomas; it was increased in toxic adenomas and Graves thyroid tissues.
TG expression was decreased in thyroid carcinomas but was normal in the
other tissues. TSHR expression was normal in most tissues studied and
was decreased in only some thyroid carcinomas. In thyroid cancer
tissues, a positive relationship was found between the individual levels
of expression of NIS, TPO, TG, and TSHR. No relationship was found with
the age of the patient. Higher tumor stages (stages greater than I vs
stage I) were associated with lower expression of NIS and TPO.
Expression of the GLUT1 gene was increased in 1 of 24 (4%) adenomas and
in 8 of 43 (19%) thyroid carcinomas. In 6 thyroid carcinoma patients,
131-I uptake was studied in vivo. NIS expression was low in all samples,
and 3 patients with normal GLUT1 expression had 131-I uptake in
metastases, whereas the other 3 patients with increased GLUT1 gene
expression had no detectable 131-I uptake. The authors concluded that
(1) reduced NIS gene expression occurs in most hypofunctioning benign
and malignant thyroid tumors; (2) there is differential regulation of
the expression of thyroid-specific genes; and (3) an increased
expression of GLUT1 in some malignant tumors may suggest a role for
glucose-derivative tracers to detect in vivo thyroid cancer metastases
by positron-emission tomography scanning.

Chia et al. (2007) studied the diagnostic value of circulating TSHR mRNA
for preoperative detection of differentiated thyroid cancer (DTC) in
patients with thyroid nodules. Based on cytology/pathology, 88 patients
had DTC and 119 had benign thyroid disease. The TSHR mRNA levels in
cancer patients were significantly higher than in benign disease (P less
than 0.0001). At a cutoff value of 1.02 ng/g total RNA, the TSHR mRNA
correctly classified 78.7% of patients preoperatively (sensitivity =
72.0%; specificity = 82.5%). Chia et al. (2007) concluded that TSHR mRNA
measured with fine needle aspirations enhances the preoperative
detection of cancer in patients with thyroid nodules, reducing
unnecessary surgeries, and immediate postoperative levels can predict
residual/metastatic disease.

GENE STRUCTURE

Kakinuma and Nagayama (2002) determined that the TSHR gene contains 13
exons.

MAPPING

Akamizu et al. (1990) mapped the TSHR gene to human chromosome 14 by
study of somatic cell hybrid DNAs. By in situ hybridization,
Rousseau-Merck et al. (1990) and Libert et al. (1990) regionalized the
gene to 14q31.

Akamizu et al. (1990) mapped the mouse Tshr gene to chromosome 12 using
linkage studies in interspecies backcross mice. Wilkie et al. (1993)
also localized the mouse Tshr gene to chromosome 12.

MOLECULAR GENETICS

Vassart et al. (1991) reviewed the molecular genetics of the thyrotropin
receptor.

Trulzsch et al. (1999) described a database of TSHR mutations. The
desirability of such a database came from the growing number of
mutations identified and the variety of clinical phenotypes associated
with the different mutations: somatic constitutively activating
mutations in toxic thyroid nodules (e.g., 603372.0002); constitutively
activating germline mutations as the cause of sporadic (e.g.,
603372.0004) and familial (e.g., 603372.0019) nonautoimmune autosomal
dominant hyperthyroidism (609152); and inactivating mutations associated
with inherited TSH resistance (275200) (e.g., 603372.0005).

- Hyperfunctioning Thyroid Adenoma and Toxic Multinodular
Goiter

In 3 of 11 hyperfunctioning thyroid adenomas, Parma et al. (1993)
identified somatic mutations in the TSHR gene (603372.0002;
603372.0003). These mutations were restricted to tumor tissue.

By direct sequencing, Fuhrer et al. (1997) screened a consecutive series
of 31 toxic thyroid nodules (TTNs) for mutations in exons 9 and 10 of
the TSHR gene and in exons 7 to 10 of the Gs-alpha protein gene (GNAS1;
139320). Somatic TSHR mutations were identified in 15 of the 31 (48%)
TTNs. The TSHR mutations were localized in the third intracellular loop
(asp619-to-gly (603372.0002), ala623-to-val, and a 27-bp deletion
resulting in deletion of 9 amino acids at codons 613 to 621), the sixth
transmembrane segment (phe631to-leu (603372.0004), thr632-to-ile, and
asp633-to-glu), the second extracellular loop (ile568-to-thr), and the
third extracellular loop (val656-to-phe). One mutation, ser281-to-asn,
was found in the part of the extracellular domain encoded by exon 9. All
of the identified TSHR mutations resulted in constitutive activity. No
mutations were found in exons 7 to 10 of GNAS1. The authors concluded
that constitutively activating TSHR mutations occur in 48% of TTNs,
representing the most frequent molecular mechanism known to cause TTNs.

Parma et al. (1997) investigated 33 different, autonomous hot nodules
from 31 patients for the presence of somatic mutations in the TSHR and
Gs-alpha genes. Twenty-seven mutations (82%) were found in the TSHR
gene, affecting a total of 12 different residues or locations. All but 2
of the mutations studied had previously been identified as activating
mutations. The authors identified the 2 novel mutations as a point
mutation causing a leu629-to-phe substitution (L629F; 603372.0022), a
deletion of 12 bases removing residues 658-661 (asn-ser-lys-ile) at the
C-terminal portion of exoloop 3 (del658-661). Only 2 mutations (6%) were
found in Gs-alpha genes. In 4 nodules, no mutation was detected. Five
residues (ser281, ile486, ile568, phe631, and asp633) were found to be
mutated in 3 or 4 different nodules, making them hotspots for activating
mutations. The authors concluded that in a cohort of patients from a
moderately iodine-deficient area, somatic mutations increasing the
constitutive activity of TSHR are the major cause of autonomous thyroid
adenomas.

Toxic multinodular goiter (TMNG) represents a frequent cause of
endogenous hyperthyroidism, affecting 5 to 15% of such patients. To
search for alterations of TSHR in autonomously functioning thyroid
nodules (AFTN) and TMNG, Gabriel et al. (1999) used bidirectional, dye
primer automated fluorescent DNA sequencing of the entire transmembrane
domain and cytoplasmic tail of TSHR using DNA extracted from nodular
regions of 24 patients with TMNG and 7 patients with AFTN. Eight of the
24 (33.3%) patients with TMNG were heterozygous for an asp727-to-glu
polymorphism (D727E) in the cytoplasmic tail of TSHR. Three of the 24
(12.5%) patients with TMNG were heterozygous for a missense mutation,
and 1 patient had multiple heterozygous mutations. Two patients had
silent polymorphism of codons 460 and 618. The authors found no
mutations in the transmembrane domain and cytoplasmic tail of TSHR in
the 7 patients with AFTN, except for a silent polymorphism of codon 460
in 1. DNA fingerprinting of codon 727 using restriction enzyme NlaIII
and genomic DNA confirmed the sequencing results in all cases,
indicating that the sequence alterations were not somatic in nature.
This technique was also used to examine peripheral blood genomic DNA
from 52 normal individuals and 49 patients with Graves disease; 33.3% of
TMNG (P of 0.019 vs normal subjects), 16.3% of Graves disease patients
(P of 0.10 vs normal subjects), and 9.6% of normal individuals were
heterozygous for the D727E polymorphism. Expression of the D727E variant
in eukaryotic cells resulted in an exaggerated cAMP response to TSH
stimulation compared with that of the wildtype TSHR. The authors
concluded that the germline polymorphism D727E is associated with TMNG,
and suggested that its presence is an important predisposing genetic
factor in TMNG pathogenesis.

Muhlberg et al. (2000) compared the D727E frequencies of 128 European
Caucasian patients with toxic nonautoimmune thyroid disease (83 with
toxic adenoma, 31 with toxic multinodular goiter, and 14 with
disseminated autonomy) with those of 99 healthy controls and 108
patients with Graves disease. They found no significant differences in
codon 727 polymorphism frequencies between patients with autonomously
functioning thyroid disorders (13.3%) and the healthy control group
(16.2%). Moreover, the subtypes of toxic nonautoimmune thyroid disease
were not related to significant differences in codon 727 polymorphism
frequencies compared with the healthy control group. There was no
significant difference between the polymorphism frequency among patients
with Graves disease (21.3%) and that of healthy controls. The authors
concluded that there was no association between the D727E polymorphism
of the TSHR and toxic thyroid adenomas or toxic multinodular goiter in
their study population.

Tonacchera et al. (2000) searched for inactivating TSHR or Gs-alpha
mutations in areas of toxic or functionally autonomous multinodular
goiters that appeared hyperfunctioning at thyroid scintiscan but did not
clearly correspond to definite nodules at physical or ultrasonographic
examination. Activating TSHR mutations were detected in 14 of these 20
hyperfunctioning areas, whereas no mutation was identified in
nonfunctioning nodules or areas contained in the same gland. No Gs-alpha
mutation was found. The authors concluded that activating TSHR mutations
are present in the majority of nonadenomatous hyperfunctioning nodules
scattered throughout the gland in patients with toxic or functionally
autonomous multinodular goiter.

- Nonautoimmune Hyperthyroidism

Duprez et al. (1994) demonstrated heterozygous constitutively activating
germline mutations in the TSHR gene (603372.0019; 603372.0020) in
patients with hereditary nonautoimmune hyperthyroidism (609152). The
functional in vitro characteristics of these 2 mutations were similar to
those already described previously for autonomously functioning thyroid
adenomas (Van Sande et al., 1995), and thus explained the development of
thyroid hyperplasia and hyperthyroidism in the affected patients.

Paschke and Ludgate (1997) found reports of 4 infants with sporadic
congenital hyperthyroidism occurring from a de novo germline mutation.
In all cases, both parents were euthyroid. The authors noted that a
number of gain-of-function mutations had been observed as somatic
mutations in hyperfunctioning thyroid adenomas and in familial autosomal
dominant hyperthyroidism. In their Figure 1, Paschke and Ludgate (1997)
outlined the constitutively activating and inactivating mutations of the
TSHR gene, as well as the location of somatic mutations found in thyroid
carcinomas. At some locations, several different amino acid
substitutions had been described. Most gain-of-function mutations were
in exon 10.

- Nonautoimmune Congenital Thyrotropin Resistance

Alberti et al. (2002) sequenced the entire TSHR gene in a series of 10
unrelated patients with slight (6.6-14.9 mU/liter) to moderate (24-46
mU/liter) elevations of serum TSH, associated with normal free thyroid
hormone concentrations, consistent with a diagnosis of thyrotropin
resistance (275200). Thyroid volume was normal in all patients, except 2
with modest hypoplasia. Autoimmune thyroid disease was excluded in all
patients on the basis of clinical and biochemical parameters. Eight
patients had at least 1 first-degree relative bearing the same
biochemical picture. TSHR mutations were detected in 4 of 10 (40%) cases
by analyzing DNA from peripheral leukocytes (see, e.g., 603372.0006;
603372.0029; 603372.0030; 603372.0031; 603372.0013). The authors
concluded that partial resistance to TSH action is a frequent finding
among patients with slight hyperthyrotropinemia of nonautoimmune origin,
and that heterozygous germline mutations of TSHR may be associated with
serum TSH values fluctuating above the upper limit of the normal range.

Calebiro et al. (2005) cotransfected COS-7 cells with wildtype TSHR and
mutant receptors (C41S, 603372.0013; C600R, 603372.0029; L467P,
603372.0030) found in patients with autosomal dominant partial TSH
resistance. Variable impairment of cAMP response to bovine TSH
stimulation was observed, suggesting that inactive TSHR mutants may
exert a dominant-negative effect on wildtype TSHR. By using chimeric
constructs of wildtype or inactive TSHR mutants fused to different
reporters, the authors documented an intracellular entrapment, mainly in
the endoplasmic reticulum, and reduced maturation of wildtype TSHR in
the presence of inactive TSHR mutants. Fluorescence resonance energy
transfer and coimmunoprecipitation experiments supported the presence of
oligomers formed by wildtype and mutant receptors in the endoplasmic
reticulum. Calebiro et al. (2005) concluded that their findings provide
an explanation for the dominant transmission of partial TSH resistance.

- Familial Gestational Hyperthyroidism

Rodien et al. (1998) described a gain-of-function mutation of the TSHR
gene (603372.0024) as the cause of familial gestational hyperthyroidism
(603373). The mutation rendered the thyrotropin receptor hypersensitive
to chorionic gonadotropin.

- Graves Disease, Susceptibility to

Although Heldin et al. (1991) and Bahn et al. (1994) suggested that
substitutions in the TSHR gene (D36H; 603372.0001 and pro52-to-thr;
P52T) were associated with Graves disease (275000) and Graves
ophthalmopathy, respectively, Simanainen et al. (1999) reported that the
D36H and P52T substitutions were polymorphic variants with a frequency
of approximately 5% and 7.3%, respectively. Simanainen et al. (1999)
found no association between these 2 polymorphisms and Graves disease.
Similarly, Kotsa et al. (1997) found no association between the TSHR
P52T polymorphism and Graves disease among 180 patients with Graves
disease. The variant allele was present in 8.3% of patients and 7.3% of
controls.

For discussion of a possible association between variation in the TSHR
gene and Graves disease, see 275000.

ANIMAL MODEL

Using an adenovirus-mediated mouse model of Graves disease, Chen et al.
(2003) demonstrated that goiter and hyperthyroidism occurred to a
significantly greater extent when the adenovirus expressed the free
alpha subunit as opposed to a genetically modified TSHR that cleaves
minimally into subunits (p less than 0.005). Chen et al. (2003)
concluded that shed alpha subunits induce or amplify the immune response
leading to hyperthyroidism in Graves disease.

Abe et al. (2003) generated Tshr-null mice by replacing exon 1 of Tshr
with a GFP cassette. They detected intense GFP fluorescence in thyroid
follicles. Western blot analysis showed a 50% decrease in Tshr
expression in heterozygotes and no expression in Tshr-null mice.
Tshr-null mice were runted and hypothyroid, and they died by age 10
weeks with severe osteoporosis and significant reduction of calvarial
thickness. Profound osteoporosis and focal osteosclerosis were observed
in heterozygotes. Confocal microscopy demonstrated expression of Tshr in
bone cells. They found 3-fold increased expression of Tnf (191160) in
the bone marrow of Tshr-null mice. Neutralizing anti-Tnf antibody
inhibited enhanced osteoclastogenesis in Tshr-null bone marrow cell
cultures, suggesting that TNF is a proosteoclastic signal mediating the
effects of TSHR deletion. Abe et al. (2003) found that TSH activation of
Tshr resulted in attenuated osteoclast formation by inhibiting Jnk (see
601158) and Nfkb (see 164011) signaling, resorption, and survival. They
showed that TSH regulated osteoblast differentiation through a Runx2
(600211)- and osterix (SP7; 606633)-independent mechanism that involved
downregulation of the prodifferentiation factors Lrp5 (603506) and Flk1
(KDR; 191306). Abe et al. (2003) concluded that TSH acts as a single
molecular switch in the independent control of both bone formation and
resorption. Hase et al. (2006) found that the increased
osteoclastogenesis in homozygous and heterozygous Tshr-null mice was
rescued with graded reductions in the dosage of the Tnf gene.

Rubin et al. (2010) described the use of massively parallel sequencing
to identify selective sweeps of favorable alleles and candidate
mutations that have had a prominent role in the domestication of
chickens and their subsequent specialization into broiler
(meat-producing) and layer (egg-producing) chickens. Rubin et al. (2010)
generated 44.5-fold coverage of the chicken genome using pools of
genomic DNA representing 8 different populations of domestic chickens as
well as red jungle fowl (Gallus gallus), the major wild ancestor. Rubin
et al. (2010) reported more than 7,000,000 SNPs, almost 1,300 deletions,
and a number of putative selective sweeps. One of the most striking
selective sweeps found in all domestic chickens occurred at the locus
for thyroid-stimulating hormone receptor (TSHR), which has a pivotal
role in metabolic regulation and photoperiod control of reproduction in
vertebrates. Several of the selective sweeps detected in broilers
overlapped genes associated with growth, including growth hormone
receptor (600946), appetite, and metabolic regulation. Rubin et al.
(2010) found little evidence that selection for loss-of-function
mutations had a prominent role in chicken domestication, but they
detected 2 deletions in coding sequences, including one in SH3RF2
(613377), that the authors considered functionally important.

*FIELD* AV
.0001
THYROTROPIN RECEPTOR POLYMORPHISM
TSHR, ASP36HIS

In a 29-year-old patient with Graves disease (275000), Heldin et al.
(1991) identified a somatic substitution in the TSHR gene in thyroid
tissue: a G-to-C transversion, resulting in an asp36-to-his (D36H)
substitution. DNA in tissues originating from all 3 germ layers showed
only the germline receptor sequence. Whether the mutation was directly
implicated in the pathogenesis of the patient's autoimmune thyroid
disorder or had functional significance in relation to the
hyperthyroidism was unclear.

In a review article, Paschke and Ludgate (1997) stated that the TSH
receptor is a passive bystander in autoimmune hyperthyroidism, or Graves
disease, and suggested that mutations in the TSHR gene are not involved
in autoimmune disease pathogenesis.

Simanainen et al. (1999) reported that the D36H substitution was not
associated with Graves disease and is a polymorphic variant, with a
frequency of approximately 5%.

.0002
THYROID ADENOMA, HYPERFUNCTIONING, SOMATIC
TSHR, ASP619GLY

In 3 of 11 hyperfunctioning thyroid adenomas, Parma et al. (1993)
identified somatic mutations in the carboxy-terminal portion of a third
cytoplasmic loop of the thyrotropin receptor. These mutations were
restricted to tumor tissue and involved 2 different residues:
asp619-to-gly (D619G) in 2 cases, and ala623-to-ile (A623I; 603372.0003)
in 1. The mutant receptors conferred constitutive activation of adenylyl
cyclase when tested by transfection in COS cells. Parma et al. (1993)
concluded that G protein-coupled receptors are susceptible to
constitutive activation by spontaneous somatic mutations and may
therefore behave as protooncogenes.

.0003
THYROID ADENOMA, HYPERFUNCTIONING, SOMATIC
TSHR, ALA623ILE

See 603372.0002 and Parma et al. (1993).

.0004
HYPERTHYROIDISM, NONAUTOIMMUNE
THYROID ADENOMA, HYPERFUNCTIONING, SOMATIC, INCLUDED
TSHR, PHE631LEU

In a boy with nonautoimmune congenital hyperthyroidism (609152), Kopp et
al. (1995) identified a heterozygous T-to-C germline mutation in the
TSHR gene, resulting in a phe631-to-leu (F631L) substitution. Functional
studies showed that the F631L mutation resulted in constitutive
activation of the receptor. The mother was euthyroid, and repeated tests
for thyroid antibodies in both the mother and patient were always
negative.

Fuhrer et al. (1997) identified the F631L mutation in a toxic thyroid
adenoma.

.0005
HYPOTHYROIDISM, CONGENITAL, NONGOITROUS, 1
TSHR, ILE167ASN

In 3 sisters, 2 of whom were found to have congenital hypothyroidism
(275200) on neonatal screening, Sunthornthepvarakul et al. (1995)
identified compound heterozygosity for 2 mutations in the TSHR gene: the
paternal allele had a 599T-A transversion, resulting in an ile167-to-asn
(I167N) substitution, and the maternal allele had a 583C-G transversion,
resulting in a pro162-to-ala (P162A) substitution (603372.0006). The
mutant thyrotropin receptor inherited from the father had almost no
biologic activity, and that inherited from the mother had reduced
activity. The sisters were euthyroid, with normal serum concentrations
of thyroid hormone but high concentrations of thyrotropin, indicating
so-called partial thyrotropin resistance (also referred to as
'compensated hypothyroidism').

.0006
HYPOTHYROIDISM, CONGENITAL, NONGOITROUS, 1
TSHR, PRO162ALA

See 603372.0005 and Sunthornthepvarakul et al. (1995).

In a patient with nonautoimmune hyperthyrotropinemia and a hypoplastic
thyroid gland on ultrasound (275200), Alberti et al. (2002) identified
compound heterozygosity for 2 mutations in the TSHR gene: the P162A
mutation and a cys600-to-arg (C600R; 603372.0029) substitution.

.0007
HYPERTHYROIDISM, NONAUTOIMMUNE
TSHR, MET453THR

In a newborn with severe nonautoimmune hyperthyroidism (609152), de Roux
et al. (1996) identified a heterozygous T-to-C transition in the TSHR
gene, resulting in a met453-to-thr (M453T) substitution in the second
transmembrane domain of the receptor. The mutation was absent in both
parents, neither of whom had a history of thyroid disease. Functional
expression analysis showed that the M453T mutation resulted in
constitutive activation of adenylate cyclase without enhancement of
phospholipase C activity.

.0008
THYROID CARCINOMA WITH THYROTOXICOSIS
TSHR, ASP633HIS

Russo et al. (1997) reported a case of an insular thyroid carcinoma
presenting as an autonomously functioning thyroid nodule and causing
severe thyrotoxicosis. The tumor was metastatic to a cervical lymph node
and both lungs. An activating mutation of the TSHR gene was found in
both the primary tumor and the lymph node metastasis. A G-to-C mutation,
resulting in an asp633-to-his (D633H) substitution in the TSHR protein,
was identified in the absence of changes in GSP (see 139320), RAS (see
190020), PTC/RET (164761), TRK (see 191315), MET (164860), or P53
(191170). Thus, an activating TSHR mutation was implicated as the cause
of a hyperfunctioning thyroid carcinoma.

.0009
HYPOTHYROIDISM, CONGENITAL, NONGOITROUS, 1
TSHR, ARG109GLN

In a child with congenital hypothyroidism (275200) found on neonatal
screening who had markedly increased serum TSH concentrations and low
normal thyroid hormone levels, Clifton-Bligh et al. (1997) identified
compound heterozygosity for 2 mutations in the TSHR gene: a G-to-A
transition, resulting in an arg109-to-gln (R109Q) substitution in the
extracellular domain of the receptor, and a G-to-A transition, resulting
in a premature termination codon at trp546 (W546X; 603372.0010) in the
fourth transmembrane segment. Each parent was heterozygous for one
mutation, and both parents had normal thyroid function. Cells
transiently transfected with the R109Q mutant protein exhibited reduced
membrane binding of radiolabeled TSH and impaired signal transduction in
response to TSH. In contrast, the W546X mutant protein was
nonfunctional, with negligible membrane radioligand binding. The authors
concluded that a single normal TSHR allele is sufficient for normal
thyroid function, but that the presence of 2 mutant alleles causes TSH
resistance.

.0010
HYPOTHYROIDISM, CONGENITAL, NONGOITROUS, 1
TSHR, TRP546TER

See 603372.0009 and Clifton-Bligh et al. (1997).

Jordan et al. (2003) reported 2 Welsh sibs with congenital
hypothyroidism (275200) identified by neonatal screening. Both had
normal-sized and placed glands but negative isotope uptake. Both sibs
were homozygous for the W546X mutation in the fourth membrane spanning
region of the TSHR protein. The euthyroid parents were heterozygous for
the mutation and unrelated. Jordan et al. (2003) noted that the W546X
had been described in 3 additional families (1 of them Welsh),
suggesting that it may be a relatively common mutation. Jordan et al.
(2003) genotyped 368 euthyroid Welsh individuals using single-nucleotide
primer extension, and found 366 homozygous wildtype and 2 heterozygous
for the mutation. Jordan et al. (2003) suggested that the W546X mutation
may be a major contributor to hypothyroidism in the Welsh population.

.0011
HYPOTHYROIDISM, CONGENITAL, NONGOITROUS, 1
TSHR, GLN324TER

In 4 unrelated French patients with congenital hypoparathyroidism
(275200) found by neonatal screening, de Roux et al. (1996) identified
loss-of-function mutations in the TSHR gene. One patient was homozygous
for a pro162-to-ala substitution (603372.0006). The 3 others were
compound heterozygotes: gln324-to-ter/asp410-to-asn (603372.0012),
cys41-to-ser (603372.0013)/phe525-to-leu (603372.0014), and
cys390-to-trp (603372.0015)/trp546-to-ter (603372.0010). The patients
showed so-called partial thyrotropin resistance, with increased plasma
TSH concentrations and normal T3 and T4 concentrations. TSH levels were
normal in the heterozygous parents. Expression of the various mutated
receptors in transfected COS-7 cells demonstrated their impaired
function. The cys390-to-trp substitution abolished high-affinity hormone
binding; asp410-to-asn bound the hormone normally, but failed to
activate adenylate cyclase; phe525-to-leu also markedly impaired
adenylate cyclase activation, underlining the importance of the second
intracellular loop in receptor signaling.

.0012
HYPOTHYROIDISM, CONGENITAL, NONGOITROUS, 1
TSHR, ASP410ASN

See 603372.0011 and de Roux et al. (1996).

.0013
HYPOTHYROIDISM, CONGENITAL, NONGOITROUS, 1
TSHR, CYS41SER

See 603372.0011 and de Roux et al. (1996).

Alberti et al. (2002) identified heterozygosity for the C41S mutation in
a male infant found to have congenital hypoparathyroidism (275200) on
neonatal screening. His father, who was also heterozygous for the
mutation, had a mildly elevated TSH level.

.0014
HYPOTHYROIDISM, CONGENITAL, NONGOITROUS, 1
TSHR, PHE525LEU

See 603372.0011 and de Roux et al. (1996).

.0015
HYPOTHYROIDISM, CONGENITAL, NONGOITROUS, 1
TSHR, CYS390TRP

See 603372.0011 and de Roux et al. (1996). Also see 603372.0018 and
Biebermann et al. (1997). Biebermann et al. (1997) found that the C390W
mutation resulted in decreased affinity of TSH for the TSHR.

.0016
HYPOTHYROIDISM, CONGENITAL, NONGOITROUS, 1
TSHR, ALA553THR

In a brother and sister, born of consanguineous parents, with congenital
hypothyroidism (275200), Abramowicz et al. (1997) identified a
homozygous mutation in the TSHR gene, resulting in an ala553-to-thr
(A553T) substitution in the fourth transmembrane domain of the protein.
The mutation was heterozygous in both parents and 2 unaffected sibs. The
patients were initially diagnosed with thyroid agenesis, but cervical
ultrasonography in both patients revealed a very hypoplastic thyroid
gland. Functional analysis in transfected COS-7 cells showed that the
mutation resulted in extremely low expression at the cell surface as
compared with the wildtype receptor, in spite of an apparently normal
intracellular synthesis. Blood thyroglobulin was unexpectedly elevated
in the patients at the time of diagnosis; Abramowicz et al. (1997)
speculated as to the possible explanation for this seemingly paradoxical
finding.

.0017
THYROID ADENOMA, HYPERFUNCTIONING, SOMATIC
TSHR, SER281ILE

Kopp et al. (1997) reported an infant with hyperthyroidism caused by a
solitary adenoma harboring a somatic G-to-T transversion in the TSHR
gene, resulting in a ser281-to-ile (S281I) substitution in the carboxy
terminus of the extracellular domain. The mutation was found only in the
adenomatous tissue and not in peripheral leukocytes of the patient or
his parents. Functional expression studies showed that the S281I
mutation resulted in increased basal cAMP levels and increased affinity
for TSH.

.0018
HYPOTHYROIDISM, CONGENITAL, NONGOITROUS, 1
TSHR, 18-BP DEL, 4-BP INS

In a female infant who was found by neonatal screening to have
congenital hypothyroidism with reduced thyroid volume (275200),
Biebermann et al. (1997) identified compound heterozygosity for 2
mutations in exon 10 of the TSHR gene. The maternal allele contained
both an 18-bp deletion (del1217-1234) and a 4-bp insertion, resulting in
a frameshift and premature termination. Transfection studies showed that
this truncated TSHR was trapped intracellularly and completely lacked
cell surface expression. The paternal allele harbored the cys390-to-trp
(C390W; 603372.0015) mutation. The C390W mutation resulted in a drastic
loss of affinity and potency for TSH. In contrast to loss-of-function
mutations of the TSHR that lead to euthyroid hyperthyrotropinemia, these
2 mutations led to persistent congenital hypothyroidism and defective
organ development.

.0019
HYPERTHYROIDISM, NONAUTOIMMUNE
TSHR, VAL509ALA

In affected members of a large kindred from northern France with
autosomal dominant nonautoimmune hyperthyroidism (609152) originally
reported by Thomas et al. (1982), Duprez et al. (1994) identified a
heterozygous T-to-C transition in exon 10 of the TSHR gene, resulting in
a val509-to-ala (V509A) substitution in the third transmembrane domain
of the protein. Functional expression studies of the V509A mutation
showed higher basal intracellular cAMP levels with high constitutive
activation of the receptor. Duprez et al. (1994) noted that autosomal
dominant nonautoimmune hyperthyroidism is the germline counterpart of
hyperfunctioning thyroid adenomas (e.g., 603372.0017), in which
different somatic mutations with similar functional characteristics have
been demonstrated.

.0020
HYPERTHYROIDISM, NONAUTOIMMUNE
TSHR, CYS672TYR

In affected members of a large pedigree from northern France with
nonautoimmune autosomal dominant hyperthyroidism (609152), Duprez et al.
(1994) identified a heterozygous G-to-A transition in exon 10 of the
TSHR gene, resulting in a cys672-to-tyr (C672Y) substitution in the
seventh transmembrane domain of the protein. Functional expression
studies of the C672Y mutation showed higher basal intracellular cAMP
levels with high constitutive activation of the receptor.

.0021
HYPERTHYROIDISM, NONAUTOIMMUNE
TSHR, SER505ASN

In a boy with nonautoimmune hyperthyroidism (609152), Holzapfel et al.
(1997) identified a heterozygous G-to-A transition in the TSHR gene,
resulting in a ser505-to-asn (S505N) substitution in the third
transmembrane region of the protein. No other family members carried the
mutation, indicating it was a de novo event. Transient expression of the
TSHR S505N mutant in COS cells resulted in a constitutively activated
cAMP cascade. The authors noted that patients with sporadic congenital
nonautoimmune hyperthyroidism should be treated with early subtotal to
near-total thyroid resection because of frequent relapses, and that
postoperative radioiodine treatment should be considered for such
patients.

.0022
HYPERTHYROIDISM, NONAUTOIMMUNE
THYROID ADENOMA, HYPERFUNCTIONING, SOMATIC, INCLUDED
TSHR, LEU629PHE

In a 10-year-old boy and his 31-year-old mother with nonautoimmune
hyperthyroidism (609152), Fuhrer et al. (1997) identified a heterozygous
G-to-T transversion in the TSHR gene, resulting in a leu629-to-phe
(L629F) substitution. There was no history of thyroid disease in the
rest of the family. Transient expression of the mutated L629F TSHR
construct confirmed constitutive activity of the TSHR.

Parma et al. (1997) identified the L629F mutation in a toxic
hyperfunctioning thyroid adenoma.

.0023
HYPERTHYROIDISM, NONAUTOIMMUNE
TSHR, SER281ASN

In a child with severe congenital hyperthyroidism (609152), Gruters et
al. (1998) identified a heterozygous mutation in the TSHR gene,
resulting in a ser281-to-asn (S281N) substitution in the extracellular
domain of the protein. Functional studies of the S281N mutation revealed
a marked increase in basal cAMP levels when the mutant receptor was
expressed in COS-7 cells. No other family members had the mutation. The
child's paternal aunt and paternal grandmother had hyperthyroidism and,
like the proband, were heterozygous for an R528H mutation in exon 10 of
the TSHR gene; however, functional expression of the R528H mutation did
not result in constitutive activity, and the authors concluded that
R528H is a polymorphism.

.0024
HYPERTHYROIDISM, FAMILIAL GESTATIONAL
TSHR, LYS183ARG

Rodien et al. (1998) described a woman and her mother who had recurrent
gestational hyperthyroidism (603373). Both women were heterozygous for a
mutation in the TSHR gene, resulting in a lys183-to-arg (K183R)
substitution in the extracellular domain of the thyrotropin receptor.
The mutant receptor was more sensitive than the wildtype receptor to
chorionic gonadotropin, thus accounting for the occurrence of
hyperthyroidism despite the presence of normal chorionic gonadotropin
concentrations. Rodien et al. (1999) referred to this situation as
promiscuity among the glycoprotein hormones.

.0025
HYPERTHYROIDISM, NONAUTOIMMUNE
TSHR, PRO639SER

In affected members of a Chinese family with nonautoimmune familial
thyrotoxicosis (609152), Khoo et al. (1999) identified a C-to-T
transition in the TSHR gene, resulting in a pro639-to-ser (P639S)
substitution. The 3 children in the family developed thyrotoxicosis
during childhood, and the father was diagnosed as thyrotoxic at the age
of 38 years. Two of the children and the father had mitral valve
prolapse associated with mitral regurgitation. The authors concluded
that there was a close temporal relationship between the onset of
thyrotoxicosis and the diagnosis of mitral valvular disease in these
patients.

.0026
HYPOTHYROIDISM, CONGENITAL, NONGOITROUS, 1
TSHR, THR477ILE

Tonacchera et al. (2000) described a 22-year-old female patient with
severe nonautoimmune hypothyroidism (275200) and mental retardation.
Genetic analysis identified a homozygous mutation in the TSHR gene,
resulting in a thr477-to-ile (T477I) substitution in the first
extracellular loop of the receptor of the TSHR protein. Serum T4 and T3
concentrations and thyroglobulin were below the sensitivity of the
methods, with elevated serum TSH levels. A normally shaped hypoplastic
gland was found by scintiscan to be located in the appropriate anatomic
position in the neck. The gland did not respond after administration of
bovine TSH in terms of 131-I uptake, serum thyroid hormones, and
thyroglobulin secretion. The brother, one sister of the father (whose
DNA was not available), the mother of the proposita, one sister, and the
brother were heterozygous for the T477I allele. All of the heterozygotes
were unaffected. After transfection in COS-7 cells, the mutant allele
displayed an extremely low expression at the cell surface. This findings
demonstrated a loss of function TSHR mutation associated with severe
congenital hypothyroidism and absent circulating thyroglobulin due to
TSH unresponsiveness.

.0027
HYPOTHYROIDISM, CONGENITAL, NONGOITROUS, 1
TSHR, ARG310CYS

Russo et al. (2000) reported 2 sibs, born of consanguineous parents, who
had resistance to TSH and euthyroid hyperthyrotropinemia ('compensated
hypothyroidism') (275200). By direct sequencing of the TSHR gene, they
identified a novel mutation in the TSHR gene, resulting in an
arg310-to-cys (R310C) substitution in the extracellular domain of the
protein. The mutation was homozygous in the 2 affected brothers;
heterozygous in both parents, an uncle, and an unaffected brother; and
absent in the other unaffected brother. When stably transfected in
Chinese hamster ovary cells, the mutant allele showed loss of response
to TSH in terms of cAMP stimulation. However, a constitutive activity in
terms of basal cAMP production was detected in the mutant, compared with
wildtype, TSHR. The authors concluded that the R310C TSHR mutant may
determine both the TSH resistance and the clinical euthyroidism detected
in this family.

.0028
HYPERTHYROIDISM, NONAUTOIMMUNE
TSHR, GLY431SER

Biebermann et al. (2001) reported a family in which 3 individuals had
nonautoimmune hyperthyroidism (609152) caused by a mutation in the TSHR
gene, resulting in a gly431-to-ser (G431S) substitution in in
transmembrane domain-1 of the protein. The mutation was found in the
investigated patient, his father, and the paternal grandmother. As
observed in other familial cases of nonautoimmune hyperthyroidism, the
age of onset of the disease was variable, ranging from early childhood
in the patient and his father to adolescence in the grandmother.
Functional characterization of this mutation showed a constitutive
activation of the Gs/adenylyl cyclase system. The authors concluded that
constitutively activating mutations can be found in the entire
transmembrane domain region of the TSHR, indicating the important role
of all parts of the transmembrane domain region for maintaining the
inactive receptor conformation.

.0029
HYPOTHYROIDISM, CONGENITAL, NONGOITROUS, 1
TSHR, CYS600ARG

In a patient with nonautoimmune hyperthyrotropinemia and a hypoplastic
thyroid gland on ultrasound (275200), Alberti et al. (2002) identified
compound heterozygosity for 2 mutations in the TSHR gene: a T-to-C
transition in exon 10, resulting in a cys600-to-arg (C600R) substitution
in the fifth transmembrane segment of the protein, and a pro162-to-ala
(P162A; 603372.0006) substitution.

.0030
HYPOTHYROIDISM, CONGENITAL, NONGOITROUS, 1
TSHR, LEU467PRO

In a 5-year-old girl with nonautoimmune hyperthyrotropinemia (275200)
and her monozygotic twin, Alberti et al. (2002) detected a heterozygous
T-to-C transition in exon 10 of the TSHR gene, resulting in a
leu467-to-pro (L467P) substitution in the second transmembrane segment
of the protein.

.0031
HYPOTHYROIDISM, CONGENITAL, NONGOITROUS, 1
TSHR, 2-BP DEL, 654AC

In a boy who presented with severe congenital hypothyroidism (275200),
the first child of nonconsanguineous French Canadian parents, Gagne et
al. (1998) detected compound heterozygosity for 2 mutations in the TSHR
gene: a deletion of 2 bases from codon 655, designated delAC655, in exon
10, and a splice site mutation, IVS6+3G-C (603372.0032), in intron 6.
The deletion mutation was expected to cause premature termination of
translation at codon 656 within the third extracellular loop of the
receptor, resulting in a truncated protein lacking the last TM7 domain
and the C-terminal tail. The splicing mutation was predicted to cause
skipping of exon 6, resulting in the absence of one leucine-rich motif
from the N-terminal hormone-binding domain of the receptor. Neck
ultrasound revealed a very hypoplastic thyroid gland.

Alberti et al. (2002) identified this mutation, which they referred to
as T655del (stop codon at position 656), in heterozygous state in a
patient with nonautoimmune partial thyrotropin resistance (also referred
to as 'compensated hypothyroidism').

.0032
HYPOTHYROIDISM, CONGENITAL, NONGOITROUS, 1
TSHR, IVS6, G-C, +3

See 603372.0031 and Gagne et al. (1998).

*FIELD* SA
Bahn et al. (1993); Chan et al. (1989); Dechairo et al. (2005); Hiratani
et al. (2005); Murakami and Mori (1990)
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24. Gruters, A.; Schoneberg, T.; Biebermann, H.; Krude, H.; Kron,
H. P.; Dralle, H.; Gudermann, T.: Severe congenital hyperthyroidism
caused by a germ-line neo mutation in the extracellular portion of
the thyrotropin receptor. J. Clin. Endocr. Metab. 83: 1431-1436,
1998.

25. Hase, H.; Ando, T.; Eldeiry, L.; Brebene, A.; Peng, Y.; Liu, L.;
Amano, H.; Davies, T. F.; Sun, L.; Zaidi, M.; Abe, E.: TNF-alpha
mediates the skeletal effects of thyroid-stimulating hormone. Proc.
Nat. Acad. Sci. 103: 12849-12854, 2006.

26. Heldin, N.-E.; Gustavsson, B.; Westermark, K.; Westermark, B.
: A somatic point mutation in a putative ligand binding domain of
the TSH receptor in a patient with autoimmune hyperthyroidism. J.
Clin. Endocr. Metab. 73: 1374-1376, 1991.

27. Hiratani, H.; Bowden, D. W.; Ikegami, S.; Shirasawa, S.; Shimizu,
A.; Iwatani, Y.; Akamizu, T.: Multiple SNPs in intron 7 of thyrotropin
receptor are associated with Graves' disease. J. Clin. Endocr. Metab. 90:
2898-2903, 2005.

28. Holzapfel, H.-P.; Wonerow, P.; von Petrykowski, W.; Henschen,
M.; Scherbaum, W. A.; Paschke, R.: Sporadic congenital hyperthyroidism
due to a spontaneous germline mutation in the thyrotropin receptor
gene. J. Clin. Endocr. Metab. 82: 3879-3884, 1997.

29. Jordan, N.; Williams, N.; Gregory, J. W.; Evans, C.; Owen, M.;
Ludgate, M.: The W546X mutation of the thyrotropin receptor gene:
potential major contributor to thyroid dysfunction in a Caucasian
population. J. Clin. Endocr. Metab. 88: 1002-1005, 2003.

30. Kakinuma, A.; Nagayama, Y.: Multiple messenger ribonucleic acid
transcripts and revised gene organization of the human TSH receptor. Endocr.
J. 49: 175-180, 2002.

31. Khoo, D. H. C.; Parma, J.; Rajasoorya, C.; Ho, S. C.; Vassart,
G.: A germline mutation of the thyrotropin receptor gene associated
with thyrotoxicosis and mitral valve prolapse in a Chinese family. J.
Clin. Endocr. Metab. 84: 1459-1462, 1999.

32. Kopp, P.; Muirhead, S.; Jourdain, N.; Gu, W.-X.; Jameson, J. L.;
Rodd, C.: Congenital hyperthyroidism caused by a solitary toxic adenoma
harboring a novel somatic mutation (serine281-isoleucine) in the extracellular
domain of the thyrotropin receptor. J. Clin. Invest. 100: 1634-1639,
1997.

33. Kopp, P.; van Sande, J.; Parma, J.; Duprez, L.; Gerber, H.; Joss,
E.; Jameson, J. L.; Dumont, J. E.; Vassart, G.: Congenital hyperthyroidism
caused by a mutation in the thyrotropin-receptor gene. New Eng. J.
Med. 332: 150-154, 1995.

34. Kotsa, K. D.; Watson, P. F.; Weetman, A. P.: No association between
a thyrotropin receptor gene polymorphism and Graves' disease in the
female population. Thyroid 7: 31-33, 1997.

35. Lazar, V.; Bidart, J.-M.; Caillou, B.; Mahe, C.; Lacroix, L.;
Filetti, S.; Schlumberger, M.: Expression of the Na(+)/I(-) symporter
gene in human thyroid tumors: a comparison study with other thyroid-specific
genes. J. Clin. Endocr. Metab. 84: 3228-3234, 1999.

36. Libert, F.; Lefort, A.; Gerard, C.; Parmentier, M.; Perret, J.;
Ludgate, M.; Dumont, J. E.; Vassart, G.: Cloning, sequencing and
expression of the human thyrotropin (TSH) receptor: evidence for binding
of autoantibodies. Biochem. Biophys. Res. Commun. 165: 1250-1255,
1989.

37. Libert, F.; Passage, E.; Lefort, A.; Vassart, G.; Mattei, M.-G.
: Localization of human thyrotropin receptor gene to chromosome region
14q31 by in situ hybridization. Cytogenet. Cell Genet. 54: 82-83,
1990.

38. Loosfelt, H.; Pichon, C.; Jolivet, A.; Misrahi, M.; Caillou, B.;
Jamous, M.; Vannier, B.; Milgrom, E.: Two-subunit structure of the
human thyrotropin receptor. Proc. Nat. Acad. Sci. 89: 3765-3769,
1992.

39. Misrahi, M.; Loosfelt, H.; Atger, M.; Sar, S.; Guiochon-Mantel,
A.; Milgrom, E.: Cloning, sequencing and expression of human TSH
receptor. Biochem. Biophys. Res. Commun. 166: 394-403, 1990.

40. Muhlberg, T.; Herrmann, K.; Joba, W.; Kirchberger, M.; Heberling,
H.-J.; Heufelder, A. E.: Lack of association of nonautoimmune hyperfunctioning
thyroid disorders and a germline polymorphism of codon 727 of the
human thyrotropin receptor in a European Caucasian population. J.
Clin. Endocr. Metab. 85: 2640-2643, 2000.

41. Murakami, M.; Mori, M.: Identification of immunogenic regions
in human thyrotropin receptor for immunoglobulin G of patients with
Graves' disease. Biochem. Biophys. Res. Commun. 171: 512-518, 1990.

42. Nagayama, Y.; Kaufman, K. D.; Seto, P.; Rapoport, B.: Molecular
cloning, sequence and functional expression of the cDNA for the human
thyrotropin receptor. Biochem. Biophys. Res. Commun. 165: 1184-1190,
1989.

43. Ohmori, M.; Ohta, M.; Shimura, H.; Shimura, Y.; Suzuki, K.; Kohn,
L. D.: Cloning of the single strand DNA-binding protein important
for maximal expression and thyrotropin (TSH)-induced negative regulation
of the TSH receptor. Molec. Endocr. 10: 1407-1424, 1996.

44. Parma, J.; Duprez, L.; Van Sande, J.; Cochaux, P.; Gervy, C.;
Mockel, J.; Dumont, J.; Vassart, G.: Somatic mutations in the thyrotropin
receptor gene cause hyperfunctioning thyroid adenomas. Nature 365:
649-651, 1993.

45. Parma, J.; Duprez, L.; Van Sande, J.; Hermans, J.; Rocmans, P.;
Van Vliet, G.; Costagliola, S.; Rodien, P.; Dumont, J. E.; Vassart,
G.: Diversity and prevalence of somatic mutations in the thyrotropin
receptor and Gs-alpha genes as a cause of toxic thyroid adenomas. J.
Clin. Endocr. Metab. 82: 2695-2701, 1997.

46. Paschke, R.; Ludgate, M.: The thyrotropin receptor in thyroid
diseases. New Eng. J. Med. 337: 1675-1681, 1997.

47. Rodien, P.; Bremont, C.; Luton, J.-P.; Raffin-Sanson, M.-L.; Parma,
J.; Duprez, L.; Vassart, G.: De la promiscuite chez les hormones
glycoproteiques: hyperthyroidie gestationnelle familiale par mutation
du recepteur de la TSH. Med./Sci. 15: 713-717, 1999.

48. Rodien, P.; Bremont, C.; Raffin Sanson, M.-L.; Parma, J.; Van
Sande, J.; Costagliola, S.; Luton, J.-P.; Vassart, G.; Duprez, L.
: Familial gestational hyperthyroidism caused by a mutant thyrotropin
receptor hypersensitive to human chorionic gonadotropin. New Eng.
J. Med. 339: 1823-1826, 1998.

49. Rousseau-Merck, M. F.; Misrahi, M.; Loosfelt, H.; Atger, M.; Milgrom,
E.; Berger, R.: Assignment of the human thyroid stimulating hormone
receptor (TSHR) gene to chromosome 14q31. Genomics 8: 233-236, 1990.

50. Rubin, C.-J.; Zody, M. C.; Eriksson, J.; Meadows, J. R. S.; Sherwood,
E.; Webster, M. T.; Jiang, L.; Ingman, M.; Sharpe, T.; Ka, S.; Hallbook,
F.; Besnier, F.; Carlborg, O.; Bed'hom, B.; Tixier-Boichard, M.; Jensen,
P.; Siegel, P.; Lindblad-Toh, K.; Andersson, L.: Whole-genome resequencing
reveals loci under selection during chicken domestication. Nature 464:
587-591, 2010.

51. Russo, D.; Betterle, C.; Arturi, F.; Chiefari, E.; Girelli, M.
E.; Filetti, S.: A novel mutation in the thyrotropin (TSH) receptor
gene causing loss of TSH binding but constitutive receptor activation
in a family with resistance to TSH. J. Clin. Endocr. Metab. 85:
4238-4242, 2000.

52. Russo, D.; Tumino, S.; Arturi, F.; Vigneri, P.; Grasso, G.; Pontecorvi,
A.; Filetti, S.; Belfiore, A.: Detection of an activating mutation
of the thyrotropin receptor in a case of an autonomously hyperfunctioning
thyroid insular carcinoma. J. Clin. Endocr. Metab. 82: 735-738,
1997.

53. Simanainen, J.; Kinch, A.; Westermark, K.; Winsa, B.; Bengtsson,
M.; Schuppert, F.; Westermark, B.; Heldin, N.-E.: Analysis of mutations
in exon 1 of the human thyrotropin receptor gene: high frequency of
the D36H and P52T polymorphic variants. Thyroid 9: 7-11, 1999.

54. Sunthornthepvarakul, T.; Gottschalk, M. E.; Hayashi, Y.; Refetoff,
S.: Resistance to thyrotropin caused by mutations in the thyrotropin-receptor
gene. New Eng. J. Med. 332: 155-160, 1995.

55. Thomas, J. L.; Leclere, J.; Hartemann, P.; Duheille, J.; Orgiazzi,
J.; Petersen, M.; Janot, C.; Guedenet, J.-C.: Familial hyperthyroidism
without evidence of autoimmunity. Acta Endocr. 100: 512-518, 1982.

56. Tonacchera, M.; Agretti, P.; Chiovato, L.; Rosellini, V.; Ceccarini,
G.; Perri, A.; Viacava, P.; Naccarato, A. G.; Miccoli, P.; Pinchera,
A.; Vitti, P.: Activating thyrotropin receptor mutations are present
in nonadenomatous hyperfunctioning nodules of toxic or autonomous
multinodular goiter. J. Clin. Endocr. Metab. 85: 2270-2274, 2000.

57. Tonacchera, M.; Agretti, P.; Pinchera, A.; Rosellini, V.; Perri,
A.; Collecchi, P.; Vitti, P.; Chiovato, L.: Congenital hypothyroidism
with impaired thyroid response to thyrotropin (TSH) and absent circulating
thyroglobulin: evidence for a new inactivating mutation of the TSH
receptor gene. J. Clin. Endocr. Metab. 85: 1001-1008, 2000.

58. Trulzsch, B.; Nebel, T.; Paschke, R.: The thyrotropin receptor
mutation database. (Editorial) Thyroid 9: 521-522, 1999.

59. Van Sande, J.; Parma, J.; Tonacchera, M.; Swillens, S.; Dumont,
J.; Vassart, G.: Genetic basis of endocrine disease: Somatic and
germline mutations of the TSH receptor gene in thyroid diseases. J.
Clin. Endocr. Metab. 80: 2577-2585, 1995.

60. Vassart, G.; Parmentier, M.; Libert, F.; Dumont, J.: Molecular
genetics of the thyrotropin receptor. Trends Endocr. Metab. 2: 151-156,
1991.

61. Wadsworth, H. L.; Chazenbalk, G. D.; Nagayama, Y.; Russo, D.;
Rapoport, B.: An insertion in the human thyrotropin receptor critical
for high affinity hormone binding. Science 249: 1423-1425, 1990.

62. Wilkie, T. M.; Chen, Y.; Gilbert, D. J.; Moore, K. J.; Yu, L.;
Simon, M. I.; Copeland, N. G.; Jenkins, N. A.: Identification, chromosomal
location, and genome organization of mammalian G-protein-coupled receptors. Genomics 18:
175-184, 1993.

*FIELD* CN
Ada Hamosh - updated: 4/28/2010
George E. Tiller - updated: 5/13/2009
Patricia A. Hartz - updated: 10/6/2006
Paul J. Converse - updated: 6/20/2006
John A. Phillips, III - updated: 4/25/2006
Marla J. F. O'Neill - updated: 2/17/2006
Marla J. F. O'Neill - updated: 12/1/2005
Marla J. F. O'Neill - updated: 3/18/2005
Cassandra L. Kniffin - reorganized: 1/27/2005
Cassandra L. Kniffin - updated: 1/12/2005
John A. Phillips, III - updated: 9/8/2004
John A. Phillips, III - updated: 1/22/2003
John A. Phillips, III - updated: 3/22/2002
John A. Phillips, III - updated: 10/18/2001
John A. Phillips, III - updated: 10/9/2001
John A. Phillips, III - updated: 2/28/2001
John A. Phillips, III - updated: 2/12/2001
John A. Phillips, III - updated: 8/9/2000
Victor A. McKusick - updated: 7/13/2000
John A. Phillips, III - updated: 3/7/2000
John A. Phillips, III - updated: 9/30/1999
Victor A. McKusick - updated: 9/15/1999
Victor A. McKusick - updated: 12/30/1998
John A. Phillips, III - updated: 9/18/1997

*FIELD* CD
Victor A. McKusick: 12/21/1998

*FIELD* ED
carol: 06/11/2013
terry: 5/11/2010
alopez: 4/30/2010
terry: 4/28/2010
wwang: 6/25/2009
terry: 5/13/2009
carol: 2/20/2009
carol: 8/20/2008
carol: 12/18/2007
wwang: 10/11/2006
terry: 10/6/2006
mgross: 6/20/2006
alopez: 4/25/2006
carol: 2/21/2006
carol: 2/17/2006
carol: 1/27/2006
wwang: 12/1/2005
wwang: 3/21/2005
wwang: 3/18/2005
carol: 1/27/2005
ckniffin: 1/12/2005
alopez: 9/8/2004
joanna: 3/17/2004
alopez: 7/1/2003
alopez: 1/22/2003
joanna: 5/16/2002
alopez: 3/22/2002
alopez: 10/18/2001
alopez: 10/9/2001
alopez: 2/28/2001
terry: 2/12/2001
mgross: 8/9/2000
alopez: 7/21/2000
terry: 7/13/2000
mgross: 3/7/2000
carol: 10/26/1999
mgross: 9/30/1999
mgross: 9/21/1999
terry: 9/15/1999
carol: 12/30/1998

MIM 603373
*RECORD*
*FIELD* NO
603373
*FIELD* TI
#603373 HYPERTHYROIDISM, FAMILIAL GESTATIONAL
*FIELD* TX
A number sign (#) is used with this entry because of evidence that in
read moresome instances familial gestational hyperthyroidism is caused by
heterozygous mutation in the gene encoding the thyroid-stimulating
hormone receptor (TSHR; 603372) on chromosome 14q31.

DESCRIPTION

Some degree of stimulation of the thyroid gland by chorionic
gonadotropin (see 118860) is common during early pregnancy. When serum
chorionic gonadotropin concentrations are abnormally high, e.g., in
women with molar pregnancies (231090), overt hyperthyroidism may ensue.
The pathophysiologic mechanism appears to be promiscuous stimulation of
the thyrotropin receptor by the excess chorionic gonadotropin. The
explanation for this stimulation is the close structural relations
between chorionic gonadotropin and thyrotropin and between their
receptors (Grossmann et al., 1997).

CLINICAL FEATURES

Hyperemesis gravidarum is characterized by excessive vomiting in early
pregnancy, leading to the loss of 5% or more of body weight. It is
usually self-limited and therefore of little clinical consequence. Some
women with the disorder have high serum thyroid hormone concentrations,
and a few have sufficient clinical manifestations of hyperthyroidism to
warrant short-term treatment with antithyroid drugs. Many, but not all,
women with hyperemesis gravidarum and hyperthyroidism have high serum
chorionic gonadotropin concentrations. Rodien et al. (1998) described
mother and daughter with hyperemesis gravidarum associated with
hyperthyroidism and normal serum concentrations of chorionic
gonadotropin. They demonstrated that the thyrotropin receptor gene in
the 2 women carried a heterozygous mutation, K183R (603372.0024), which
rendered the thyrotropin receptor hypersensitive to chorionic
gonadotropin. The daughter was a 27-year-old woman who was 10 weeks'
pregnant when referred for the evaluation and treatment of
hyperthyroidism. This was her third pregnancy, the first and second
having resulted in early miscarriage accompanied by severe nausea and
vomiting. In the third pregnancy, she again suffered severe nausea and
vomiting and had a weight loss of 5 kg. She had tachycardia, excessive
sweating, and tremor of the hands with a small, diffuse goiter and no
ophthalmopathy. She was treated with propylthiouracil for 8 weeks with
good results. After delivery of a normal girl at 38 weeks' gestation,
propylthiouracil was discontinued. After an asymptomatic period, she
returned 18 months later with recurrence of hyperthyroidism associated
with hyperemesis gravidarum and was found to be pregnant again.
Treatment with propylthiouracil was accompanied by a good response and
delivery of a normal boy at 38 weeks' gestation. The mother was 27 years
old when she gave birth to her daughter, 2 years after having a
miscarriage. Both pregnancies were complicated by nausea, vomiting, and
weight loss. The same symptoms recurred during a subsequent pregnancy,
and the woman was treated with carbimazole for what was believed to be
hyperthyroidism due to Graves disease, despite the absence of goiter and
ophthalmopathy. After a normal delivery, the medication was discontinued
and the patient remained euthyroid and had no further pregnancies.

*FIELD* RF
1. Grossmann, M.; Weintraub, B. D.; Szkudinski, M. W.: Novel insights
into the molecular mechanisms of human thyrotropin action: structural,
physiological, and therapeutic implications for the glycoprotein hormone
family. Endocr. Rev. 18: 476-501, 1997.

2. Rodien, P.; Bremont, C.; Raffin Sanson, M.-L.; Parma, J.; Van Sande,
J.; Costagliola, S.; Luton, J.-P.; Vassart, G.; Duprez, L.: Familial
gestational hyperthyroidism caused by a mutant thyrotropin receptor
hypersensitive to human chorionic gonadotropin. New Eng. J. Med. 339:
1823-1826, 1998.

*FIELD* CD
Victor A. McKusick: 12/21/1998

*FIELD* ED
carol: 12/16/2013
carol: 12/21/1998

MIM 609152
*RECORD*
*FIELD* NO
609152
*FIELD* TI
#609152 HYPERTHYROIDISM, NONAUTOIMMUNE
;;HYPERTHYROIDISM, CONGENITAL NONAUTOIMMUNE;;
read moreHYPERTHYROIDISM, NONAUTOIMMUNE, AUTOSOMAL DOMINANT;;
TOXIC THYROID HYPERPLASIA, AUTOSOMAL DOMINANT
*FIELD* TX
A number sign (#) is used with this entry because nonautoimmune
hyperthyroidism is caused by mutation in the gene encoding the
thyroid-stimulating hormone receptor (TSHR; 603372).

Mutation in the same gene can also cause thyrotropin resistance and
nonautoimmune hypothyroidism (275200).

Congenital nonautoimmune hyperthyroidism is distinct from autoimmune
hyperthyroidism, or Graves disease (275000), and from transient neonatal
hyperthyroidism due to passive transfer of maternal autoantibodies.

CLINICAL FEATURES

Graves disease in the neonate is usually described as a transient
disorder in the newborn offspring of women who have or have had
hyperthyroidism. Hollingsworth and Mabry (1976) reported a subset of
patients with 'congenital Graves disease' in whom the disorder was not
caused by immunoglobulins. The authors favored autosomal dominant
inheritance with female predilection. They quoted an experience of Dr.
A. M. DiGeorge (Philadelphia) who had seen affected father and son. The
father had symptoms from age 3 years and the son from birth; both had
required antithyroid medication.

Thomas et al. (1982) reported a large family in which 9 of 34 members
had hyperthyroidism associated with diffuse goiter. Exophthalmos was
absent, and there were no antithyroid antibodies. Examination of thyroid
tissue showed rare lymphocytic infiltration and absence of immune
complexes.

Kopp et al. (1995) described a boy in whom hyperthyroidism was suspected
at birth because of tachycardia, tachypnea, and a diffuse goiter.
Laboratory tests confirmed the diagnosis and did not demonstrate any
antithyroid antibodies. The patient was initially treated with
propylthiouracil, and later had a subtotal thyroidectomy at the age of 8
years. Although almost all thyroid tissue was removed, the patient
remained hyperthyroid after surgery and radioiodine therapy was
administered at the age of 9 years. Thereafter, the patient became
euthyroid. Neuropsychologic testing revealed hyperactivity and mental
retardation with an IQ between 75 and 85. The patient's mother was
euthyroid, and repeated tests for thyroid antibodies were always
negative.

De Roux et al. (1996) reported a newborn who presented with severe
hyperthyroidism, diffuse goiter, eyelid retraction, and possibly
proptosis. The absence of thyroid pathology in the parents and the lack
of antithyroid antibodies in the mother and the patient suggested a
nonimmune etiology.

In a review, Paschke and Ludgate (1997) noted that the thyroid gland was
enlarged in most patients with nonautoimmune hyperthyroidism, but that
features of Graves disease, such as thyroid-associated ophthalmopathy,
pretibial myxedema, lymphocytic infiltration of the thyroid, and thyroid
antibodies, were absent. Hyperthyroidism occurred at any time from the
neonatal period to adulthood; the variability in age at onset probably
resulted from other genetic components and environmental factors such as
iodine intake and dietary goitrogens. Patients required ablative
treatment (surgery or radioiodine) because there had been reports in
many families of recurrent hyperthyroidism after subtotal thyroidectomy,
mandating a second thyroidectomy or radioiodine treatment.

MOLECULAR GENETICS

In affected members of 2 large unrelated kindreds from northern France
with autosomal dominant nonautoimmune hyperthyroidism, Duprez et al.
(1994) identified 2 different heterozygous mutations in the TSHR gene
(603372.0019; 603372.0020). One of the families had been reported by
Thomas et al. (1982).

In a boy with nonautoimmune congenital hyperthyroidism, Kopp et al.
(1995) identified a heterozygous mutation in the TSHR gene (603372.0004)
that resulted in constitutive activation of the receptor.

In an infant with nonautoimmune hyperthyroidism, de Roux et al. (1996)
identified a heterozygous mutation in the TSHR gene (603372.0007).

*FIELD* SA
Hollingsworth et al. (1972)
*FIELD* RF
1. de Roux, N.; Polak, M.; Couet, J.; Leger, J.; Czernichow, P.; Milgrom,
E.; Misrahi, M.: A neomutation of the thyroid-stimulating hormone
receptor in a severe neonatal hyperthyroidism. J. Clin. Endocr. Metab. 81:
2023-2026, 1996.

2. Duprez, L.; Parma, J.; Van Sande, J.; Allgeier, A.; Leclere, J.;
Schvartz, C.; Delisle, M.-J.; Decoulx, M.; Orgiazzi, J.; Dumont, J.;
Vassart, G.: Germline mutations in the thyrotropin receptor gene
cause non-autoimmune autosomal dominant hyperthyroidism. Nature Genet. 7:
396-401, 1994.

3. Hollingsworth, D. R.; Mabry, C. C.: Congenital Graves disease:
four familial cases with long-term follow-up and perspective. Am.
J. Dis. Child. 130: 148-155, 1976.

4. Hollingsworth, D. R.; Mabry, C. C.; Eckerd, J. M.: Hereditary
aspects of Graves' disease in infancy and childhood. J. Pediat. 81:
446-459, 1972.

5. Kopp, P.; van Sande, J.; Parma, J.; Duprez, L.; Gerber, H.; Joss,
E.; Jameson, J. L.; Dumont, J. E.; Vassart, G.: Congenital hyperthyroidism
caused by a mutation in the thyrotropin-receptor gene. New Eng. J.
Med. 332: 150-154, 1995.

6. Paschke, R.; Ludgate, M.: The thyrotropin receptor in thyroid
diseases. New Eng. J. Med. 337: 1675-1681, 1997.

7. Thomas, J. L.; Leclere, J.; Hartemann, P.; Duheille, J.; Orgiazzi,
J.; Petersen, M.; Janot, C.; Guedenet, J.-C.: Familial hyperthyroidism
without evidence of autoimmunity. Acta Endocr. 100: 512-518, 1982.

*FIELD* CS
INHERITANCE:
Autosomal dominant;
Isolated cases

GROWTH:
[Weight];
Low birth weight

HEAD AND NECK:
[Eyes];
Absence of exophthalmos

CARDIOVASCULAR:
[Heart];
Tachycardia

SKELETAL:
Advanced bone age

SKIN, NAILS, HAIR:
[Skin];
Absence of dermopathy;
Absence of pretibial myxedema

NEUROLOGIC:
[Central nervous system];
Delayed motor development;
Delayed speech development;
Mental retardation;
Sleep difficulties;
[Behavioral/psychiatric manifestations];
Hyperactivity

ENDOCRINE FEATURES:
Hyperthyroidism;
Goiter;
Thyroid hyperplasia;
Absence of immune complexes and lymphocytes in thyroid tissue

IMMUNOLOGY:
Absence of anti-thyroid antibodies

PRENATAL MANIFESTATIONS:
[Delivery];
Premature delivery of affected infants

LABORATORY ABNORMALITIES:
Decreased serum thyroid-stimulating hormone (TSH);
Increased serum levels of free plasma thyroid hormones

MISCELLANEOUS:
Age at onset ranges from neonatal to adulthood;
Phenotypic variation;
Patients usually require total thyroidectomy;
Distinct disorder from transient neonatal hyperthyroidism due to maternal
Graves disease (see 275000)

MOLECULAR BASIS:
Caused by mutation in the thyroid-stimulating hormone receptor gene
(TSHR, 603372.0004)

*FIELD* CD
Cassandra L. Kniffin: 1/10/2005

*FIELD* ED
ckniffin: 01/12/2005

*FIELD* CD
Cassandra L. Kniffin: 1/7/2005

*FIELD* ED
carol: 01/27/2005
ckniffin: 1/12/2005