ID FSHR_HUMAN Reviewed; 695 AA. AC P23945; A8K947; G5CBS7; G5E967; J3KQ00; Q05AH0; Q16225; Q4QRJ3; AC Q4ZFZ2; Q53RW2; DT 01-MAR-1992, integrated into UniProtKB/Swiss-Prot. DT 02-NOV-2010, sequence version 3. DT 09-DEC-2015, entry version 183. DE RecName: Full=Follicle-stimulating hormone receptor; DE Short=FSH-R; DE AltName: Full=Follitropin receptor; DE Flags: Precursor; GN Name=FSHR; Synonyms=LGR1; 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), AND VARIANT SER-680. RC TISSUE=Ovary; RX PubMed=1709010; DOI=10.1016/0006-291X(91)91682-3; RA Minegish T., Nakamura K., Takakura Y., Ibuki Y., Igarashi M.; RT "Cloning and sequencing of human FSH receptor cDNA."; RL Biochem. Biophys. Res. Commun. 175:1125-1130(1991). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG), AND VARIANT THR-307. RX PubMed=1322283; DOI=10.1210/en.131.2.799; RA Tilly J.L., Aihara T., Nishimori K., Jia X.-C., Billig H., RA Kowalski K.I., Perlas E.A., Hsueh A.J.; RT "Expression of recombinant human follicle-stimulating hormone RT receptor: species-specific ligand binding, signal transduction, and RT identification of multiple ovarian messenger ribonucleic acid RT transcripts."; RL Endocrinology 131:799-806(1992). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG), AND VARIANT THR-307. RC TISSUE=Testis; RX PubMed=1301382; DOI=10.1016/0303-7207(92)90220-Z; RA Kelton C.A., Cheng S.V., Nugent N.P., Schweickhardt R.L., RA Rosenthal J.L., Overton S.A., Wands G.D., Kuzeja J.B., Luchette C.A., RA Chappel S.C.; RT "The cloning of the human follicle stimulating hormone receptor and RT its expression in COS-7, CHO, and Y-1 cells."; RL Mol. Cell. Endocrinol. 89:141-151(1992). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG). RC TISSUE=Adipose tissue; RA Liu X., Huang H., Sheng J.; RT "FSHR expression in adipose tissue."; RL Submitted (MAY-2011) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM LONG), AND VARIANT RP THR-307. RC TISSUE=Testis; 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 [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM LONG), AND VARIANT RP THR-307. RC TISSUE=Testis; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT SER-680. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J., RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., RA Waterston R.H., Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 RT and 4."; RL Nature 434:724-731(2005). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT SER-680. RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R., RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., RA Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS LONG AND 3), AND RP VARIANTS THR-307 AND SER-680. 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 NUCLEOTIDE SEQUENCE [MRNA] OF 1-342 (ISOFORM SHORT), AND VARIANT RP THR-307. RC TISSUE=Testis; RX PubMed=1359889; DOI=10.1016/0006-291X(92)91341-M; RA Gromoll J., Gudermann T., Nieschlag E.; RT "Molecular cloning of a truncated isoform of the human follicle RT stimulating hormone receptor."; RL Biochem. Biophys. Res. Commun. 188:1077-1083(1992). RN [11] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-51. RX PubMed=7926278; DOI=10.1016/0303-7207(94)90102-3; RA Gromoll J., Dankbar B., Gudermann T.; RT "Characterization of the 5' flanking region of the human follicle- RT stimulating hormone receptor gene."; RL Mol. Cell. Endocrinol. 102:93-102(1994). RN [12] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 286-695, AND VARIANTS THR-307 AND RP SER-680. RX PubMed=7916967; DOI=10.1677/jme.0.0120265; RA Gromoll J., Ried T., Holtgreve-Grez H., Nieschlag E., Gudermann T.; RT "Localization of the human FSH receptor to chromosome 2p21 using a RT genomic probe comprising exon 10."; RL J. Mol. Endocrinol. 12:265-271(1994). RN [13] RP ALTERNATIVE SPLICING (ISOFORM 4). RX PubMed=11872202; DOI=10.1016/S0015-0282(01)03221-6; RA Song G.J., Park Y.S., Lee Y.S., Lee C.C., Kang I.S.; RT "Alternatively spliced variants of the follicle-stimulating hormone RT receptor gene in the testis of infertile men."; RL Fertil. Steril. 77:499-504(2002). RN [14] RP 3D-STRUCTURE MODELING OF 49-228. RX PubMed=8747461; DOI=10.1016/S0969-2126(01)00272-6; RA Jiang X., Dreano M., Buckler D.R., Cheng S., Ythier A., Wu H., RA Hendrickson W.A., el Tayar N.; RT "Structural predictions for the ligand-binding region of glycoprotein RT hormone receptors and the nature of hormone-receptor interactions."; RL Structure 3:1341-1353(1995). RN [15] RP X-RAY CRYSTALLOGRAPHY (2.92 ANGSTROMS) OF 17-268 IN COMPLEX WITH FSHA RP AND FSHB, DISULFIDE BONDS, AND GLYCOSYLATION AT ASN-191. RX PubMed=15662415; DOI=10.1038/nature03206; RA Fan Q.R., Hendrickson W.A.; RT "Structure of human follicle-stimulating hormone in complex with its RT receptor."; RL Nature 433:269-277(2005). RN [16] RP VARIANT ODG1 VAL-189. RX PubMed=7553856; DOI=10.1016/0092-8674(95)90275-9; RA Aittomaeki K., Lucena J.L.D., Pakarinen P., Sistonen P., RA Tapanainen J., Gromoll J., Kaskikari R., Sankila E.-M., RA Lehvaslaiho H., Engel A.R., Nieschlag E., Huhtaniemi I., RA de la Chapelle A.; RT "Mutation in the follicle-stimulating hormone receptor gene causes RT hereditary hypergonadotropic ovarian failure."; RL Cell 82:959-968(1995). RN [17] RP VARIANT OVARIAN SEX CORD TUMOR SER-591. RX PubMed=9100567; DOI=10.1210/jcem.82.4.3870; RA Kotlar T.J., Young R.H., Albanese C., Crowley W.F. Jr., Scully R.E., RA Jameson J.L.; RT "A mutation in the follicle-stimulating hormone receptor occurs RT frequently in human ovarian sex cord tumors."; RL J. Clin. Endocrinol. Metab. 82:1020-1026(1997). RN [18] RP VARIANT FSHR ACTIVATION GLY-567, AND CHARACTERIZATION OF VARIANT FSHR RP ACTIVATION GLY-567. RX PubMed=8636335; DOI=10.1210/jc.81.4.1367; RA Gromoll J., Simoni M., Nieschlag E.; RT "An activating mutation of the follicle-stimulating hormone receptor RT autonomously sustains spermatogenesis in a hypophysectomized man."; RL J. Clin. Endocrinol. Metab. 81:1367-1370(1996). RN [19] RP VARIANT ODG1 VAL-189. RX PubMed=9851774; DOI=10.1210/jc.83.12.4338; RA Jiang M., Aittomaeki K., Nilsson C., Pakarinen P., Iitia A., RA Torresani T., Simonsen H., Goh V., Pettersson K., de la Chapelle A., RA Huhtaniemi I.; RT "The frequency of an inactivating point mutation (566C-->T) of the RT human follicle-stimulating hormone receptor gene in four populations RT using allele-specific hybridization and time-resolved fluorometry."; RL J. Clin. Endocrinol. Metab. 83:4338-4343(1998). RN [20] RP VARIANTS ODG1 THR-160 AND CYS-573. RX PubMed=9769327; DOI=10.1172/JCI3795; RA Beau I., Touraine P., Meduri G., Gougeon A., Desroches A., RA Matuchansky C., Milgrom E., Kuttenn F., Misrahi M.; RT "A novel phenotype related to partial loss of function mutations of RT the follicle stimulating hormone receptor."; RL J. Clin. Invest. 102:1352-1359(1998). RN [21] RP VARIANTS ODG1 VAL-224 AND VAL-601, AND CHARACTERIZATION OF VARIANTS RP ODG1 VAL-224; CYS-573 AND VAL-601. RX PubMed=10551778; DOI=10.1210/me.13.11.1844; RA Touraine P., Beau I., Gougeon A., Meduri G., Desroches A., Pichard C., RA Detoeuf M., Paniel B., Prieur M., Zorn J.-R., Milgrom E., Kuttenn F., RA Misrahi M.; RT "New natural inactivating mutations of the follicle-stimulating RT hormone receptor: correlations between receptor function and RT phenotype."; RL Mol. Endocrinol. 13:1844-1854(1999). RN [22] RP VARIANTS THR-307; ARG-524 AND SER-680. RX PubMed=10391209; DOI=10.1038/10290; RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L., RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q., RA Lander E.S.; RT "Characterization of single-nucleotide polymorphisms in coding regions RT of human genes."; RL Nat. Genet. 22:231-238(1999). RN [23] RP ERRATUM. RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L., RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q., RA Lander E.S.; RL Nat. Genet. 23:373-373(1999). RN [24] RP VARIANTS THR-307 AND SER-680. RX PubMed=12059813; DOI=10.1046/j.1439-0272.2002.00493.x; RA Asatiani K., Gromoll J., Eckardstein S.V., Zitzmann M., Nieschlag E., RA Simoni M.; RT "Distribution and function of FSH receptor genetic variants in normal RT men."; RL Andrologia 34:172-176(2002). RN [25] RP VARIANT ODG1 THR-419, AND CHARACTERIZATION OF VARIANT ODG1 THR-419. RX PubMed=11889179; DOI=10.1210/jc.87.3.1151; RA Doherty E., Pakarinen P., Tiitinen A., Kiilavuori A., Huhtaniemi I., RA Forrest S., Aittomaeki K.; RT "A novel mutation in the FSH receptor inhibiting signal transduction RT and causing primary ovarian failure."; RL J. Clin. Endocrinol. Metab. 87:1151-1155(2002). RN [26] RP VARIANT ODG1 ARG-348. RX PubMed=12571157; DOI=10.1093/humrep/deg046; RA Allen L.A., Achermann J.C., Pakarinen P., Kotlar T.J., RA Huhtaniemi I.T., Jameson J.L., Cheetham T.D., Ball S.G.; RT "A novel loss of function mutation in exon 10 of the FSH receptor gene RT causing hypergonadotrophic hypogonadism: clinical and molecular RT characteristics."; RL Hum. Reprod. 18:251-256(2003). RN [27] RP VARIANT ODG1 THR-519, AND CHARACTERIZATION OF VARIANT ODG1 THR-519. RX PubMed=12915623; DOI=10.1210/jc.2003-030217; RA Meduri G., Touraine P., Beau I., Lahuna O., Desroches A., RA Vacher-Lavenu M.C., Kuttenn F., Misrahi M.; RT "Delayed puberty and primary amenorrhea associated with a novel RT mutation of the human follicle-stimulating hormone receptor: clinical, RT histological, and molecular studies."; RL J. Clin. Endocrinol. Metab. 88:3491-3498(2003). RN [28] RP VARIANT OHSS ILE-449. RX PubMed=12930927; DOI=10.1056/NEJMoa030065; RA Vasseur C., Rodien P., Beau I., Desroches A., Gerard C., RA de Poncheville L., Chaplot S., Savagner F., Croue A., Mathieu E., RA Lahlou N., Descamps P., Misrahi M.; RT "A chorionic gonadotropin-sensitive mutation in the follicle- RT stimulating hormone receptor as a cause of familial gestational RT spontaneous ovarian hyperstimulation syndrome."; RL N. Engl. J. Med. 349:753-759(2003). RN [29] RP VARIANT OHSS ASN-567. RX PubMed=12930928; DOI=10.1056/NEJMoa030064; RA Smits G., Olatunbosun O., Delbaere A., Pierson R., Vassart G., RA Costagliola S.; RT "Ovarian hyperstimulation syndrome due to a mutation in the follicle- RT stimulating hormone receptor."; RL N. Engl. J. Med. 349:760-766(2003). RN [30] RP VARIANT OHSS ALA-449, AND CHARACTERIZATION OF VARIANT OHSS ALA-449. RX PubMed=15080154; DOI=10.1210/jc.2003-031910; RA Montanelli L., Delbaere A., Di Carlo C., Nappi C., Smits G., RA Vassart G., Costagliola S.; RT "A mutation in the follicle-stimulating hormone receptor as a cause of RT familial spontaneous ovarian hyperstimulation syndrome."; RL J. Clin. Endocrinol. Metab. 89:1255-1258(2004). RN [31] RP VARIANT OHSS THR-545, AND CHARACTERIZATION OF VARIANT OHSS THR-545. RX PubMed=16278261; DOI=10.1210/jc.2005-1580; RA De Leener A., Montanelli L., Van Durme J., Chae H., Smits G., RA Vassart G., Costagliola S.; RT "Presence and absence of follicle-stimulating hormone receptor RT mutations provide some insights into spontaneous ovarian RT hyperstimulation syndrome physiopathology."; RL J. Clin. Endocrinol. Metab. 91:555-562(2006). RN [32] RP VARIANT OHSS TYR-128, AND CHARACTERIZATION OF VARIANT OHSS TYR-128. RX PubMed=17721928; DOI=10.1002/humu.20604; RA De Leener A., Caltabiano G., Erkan S., Idil M., Vassart G., Pardo L., RA Costagliola S.; RT "Identification of the first germline mutation in the extracellular RT domain of the follitropin receptor responsible for spontaneous ovarian RT hyperstimulation syndrome."; RL Hum. Mutat. 29:91-98(2008). RN [33] RP VARIANT OHSS ILE-512, CHARACTERIZATION OF VARIANT OHSS ILE-512, AND RP FUNCTION. RX PubMed=24058690; DOI=10.1371/journal.pone.0075478; RA Uchida S., Uchida H., Maruyama T., Kajitani T., Oda H., Miyazaki K., RA Kagami M., Yoshimura Y.; RT "Molecular analysis of a mutated FSH receptor detected in a patient RT with spontaneous ovarian hyperstimulation syndrome."; RL PLoS ONE 8:E75478-E75478(2013). RN [34] RP VARIANTS OHSS ALA-514 AND VAL-575, AND CHARACTERIZATION OF VARIANTS RP OHSS ALA-514 AND VAL-575. RX PubMed=25581598; DOI=10.1210/jc.2014-3662; RA Desai S.S., Achrekar S.K., Sahasrabuddhe K.A., Meharji P.K., RA Desai S.K., Mangoli V.S., Mahale S.D.; RT "Functional characterization of two naturally occurring mutations RT (Val514Ala and Ala575Val) in follicle-stimulating hormone receptor."; RL J. Clin. Endocrinol. Metab. 100:E638-E645(2015). CC -!- FUNCTION: Receptor for follicle-stimulating hormone. The activity CC of this receptor is mediated by G proteins which activate CC adenylate cyclase. Induces cAMP production through the activation CC of PI3K-AKT and SRC-ERK1/2 signaling pathways. CC {ECO:0000269|PubMed:24058690}. CC -!- SUBUNIT: Interacts with ARRB2. {ECO:0000250}. CC -!- INTERACTION: CC P27348:YWHAQ; NbExp=4; IntAct=EBI-848239, EBI-359854; CC -!- SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=Long; Synonyms=R1; CC IsoId=P23945-1; Sequence=Displayed; CC Name=Short; Synonyms=E9Del; CC IsoId=P23945-2; Sequence=VSP_001953; CC Name=3; Synonyms=E6Del; CC IsoId=P23945-3; Sequence=VSP_043181; CC Name=4; Synonyms=E8'Inc; CC IsoId=P23945-4; Sequence=VSP_053411; CC -!- TISSUE SPECIFICITY: Sertoli cells and ovarian granulosa cells. CC -!- PTM: N-glycosylated; indirectly required for FSH-binding, possibly CC via a conformational change that allows high affinity binding of CC hormone. {ECO:0000250}. CC -!- DISEASE: Ovarian dysgenesis 1 (ODG1) [MIM:233300]: An autosomal CC recessive disease characterized by primary amenorrhea, variable CC development of secondary sex characteristics, poorly developed CC streak ovaries, and high serum levels of follicle-stimulating CC hormone (FSH) and luteinizing hormone (LH). CC {ECO:0000269|PubMed:10551778, ECO:0000269|PubMed:11889179, CC ECO:0000269|PubMed:12571157, ECO:0000269|PubMed:12915623, CC ECO:0000269|PubMed:7553856, ECO:0000269|PubMed:9769327, CC ECO:0000269|PubMed:9851774}. Note=The disease is caused by CC mutations affecting the gene represented in this entry. CC -!- DISEASE: Ovarian hyperstimulation syndrome (OHSS) [MIM:608115]: CC Disorder which occurs either spontaneously or most often as an CC iatrogenic complication of ovarian stimulation treatments for in CC vitro fertilization. The clinical manifestations vary from CC abdominal distention and discomfort to potentially life- CC threatening, massive ovarian enlargement and capillary leak with CC fluid sequestration. Pathologic features of this syndrome include CC the presence of multiple serous and hemorrhagic follicular cysts CC lined by luteinized cells, a condition called hyperreactio CC luteinalis. {ECO:0000269|PubMed:12930927, CC ECO:0000269|PubMed:12930928, ECO:0000269|PubMed:15080154, CC ECO:0000269|PubMed:16278261, ECO:0000269|PubMed:17721928, CC ECO:0000269|PubMed:24058690, ECO:0000269|PubMed:25581598}. CC Note=The disease is caused by mutations affecting the gene CC represented in this entry. CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family. CC FSH/LSH/TSH subfamily. {ECO:0000255|PROSITE-ProRule:PRU00521}. CC -!- SIMILARITY: Contains 9 LRR (leucine-rich) repeats. {ECO:0000305}. CC -!- SIMILARITY: Contains 1 LRRNT domain. {ECO:0000305}. CC -!- WEB RESOURCE: Name=GRIS; Note=Glycoprotein-hormone Receptors CC Information System; CC URL="http://gris.ulb.ac.be/"; 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=FSHR"; CC -!- WEB RESOURCE: Name=Sequence-structure-function-analysis of CC glycoprotein hormone receptors; CC URL="http://www.ssfa-gphr.de/"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M65085; AAA52477.1; -; mRNA. DR EMBL; M95489; AAA52478.1; -; mRNA. DR EMBL; S59900; AAB26480.1; -; mRNA. DR EMBL; JN003607; AEI86722.1; -; mRNA. DR EMBL; AY429104; AAR07899.1; -; mRNA. DR EMBL; AK292562; BAF85251.1; -; mRNA. DR EMBL; AC007189; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC079394; AAX93229.1; -; Genomic_DNA. DR EMBL; AC092533; AAX88895.1; -; Genomic_DNA. DR EMBL; CH471053; EAX00188.1; -; Genomic_DNA. DR EMBL; CH471053; EAX00189.1; -; Genomic_DNA. DR EMBL; BC096831; AAH96831.1; -; mRNA. DR EMBL; BC118548; AAI18549.1; -; mRNA. DR EMBL; BC125270; AAI25271.1; -; mRNA. DR EMBL; X68044; CAA48179.1; -; mRNA. DR EMBL; S73199; AAB32071.1; -; Genomic_DNA. DR EMBL; S73526; AAB32225.1; -; Genomic_DNA. DR CCDS; CCDS1843.1; -. [P23945-1] DR CCDS; CCDS1844.2; -. [P23945-3] DR PIR; I57661; QRHUFT. DR RefSeq; NP_000136.2; NM_000145.3. DR RefSeq; NP_852111.2; NM_181446.2. DR UniGene; Hs.1428; -. DR PDB; 1XUN; Model; -; A=49-228. DR PDB; 1XWD; X-ray; 2.92 A; C/F=17-268. DR PDB; 4AY9; X-ray; 2.50 A; X/Y/Z=17-366. DR PDB; 4MQW; X-ray; 2.90 A; X/Y/Z=16-366. DR PDBsum; 1XUN; -. DR PDBsum; 1XWD; -. DR PDBsum; 4AY9; -. DR PDBsum; 4MQW; -. DR ProteinModelPortal; P23945; -. DR SMR; P23945; 18-359, 368-637. DR BioGrid; 108770; 32. DR DIP; DIP-35605N; -. DR IntAct; P23945; 2. DR MINT; MINT-1177926; -. DR STRING; 9606.ENSP00000384708; -. DR BindingDB; P23945; -. DR ChEMBL; CHEMBL2024; -. DR DrugBank; DB00097; Choriogonadotropin alfa. DR DrugBank; DB00066; Follitropin beta. DR DrugBank; DB00032; Menotropins. DR DrugBank; DB04786; Suramin. DR DrugBank; DB00094; Urofollitropin. DR GuidetoPHARMACOLOGY; 253; -. DR TCDB; 9.A.14.1.5; the g-protein-coupled receptor (gpcr) family. DR PhosphoSite; P23945; -. DR BioMuta; FSHR; -. DR DMDM; 311033420; -. DR PaxDb; P23945; -. DR PRIDE; P23945; -. DR Ensembl; ENST00000304421; ENSP00000306780; ENSG00000170820. DR GeneID; 2492; -. DR KEGG; hsa:2492; -. DR UCSC; uc002rww.3; human. DR UCSC; uc002rwx.3; human. DR UCSC; uc010fbn.3; human. [P23945-3] DR CTD; 2492; -. DR GeneCards; FSHR; -. DR H-InvDB; HIX0029905; -. DR HGNC; HGNC:3969; FSHR. DR MalaCards; FSHR; -. DR MIM; 136435; gene. DR MIM; 233300; phenotype. DR MIM; 608115; phenotype. DR neXtProt; NX_P23945; -. DR Orphanet; 243; 46,XX gonadal dysgenesis. DR Orphanet; 64739; Ovarian hyperstimulation syndrome. DR Orphanet; 619; Primary ovarian failure. DR PharmGKB; PA28386; -. DR eggNOG; KOG2087; Eukaryota. DR eggNOG; ENOG410XR1T; LUCA. DR HOGENOM; HOG000045902; -. DR HOVERGEN; HBG003521; -. DR InParanoid; P23945; -. DR KO; K04247; -. DR OrthoDB; EOG73BVCG; -. DR PhylomeDB; P23945; -. DR TreeFam; TF316814; -. DR Reactome; R-HSA-375281; Hormone ligand-binding receptors. DR Reactome; R-HSA-418555; G alpha (s) signalling events. DR SignaLink; P23945; -. DR ChiTaRS; FSHR; human. DR EvolutionaryTrace; P23945; -. DR GeneWiki; Follicle-stimulating_hormone_receptor; -. DR GenomeRNAi; 2492; -. DR NextBio; 35518027; -. DR PRO; PR:P23945; -. DR Proteomes; UP000005640; Chromosome 2. DR Bgee; P23945; -. DR CleanEx; HS_FSHR; -. DR ExpressionAtlas; P23945; baseline and differential. DR Genevisible; P23945; HS. DR GO; GO:0016021; C:integral component of membrane; TAS:ProtInc. DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0004963; F:follicle-stimulating hormone receptor activity; TAS:ProtInc. DR GO; GO:0008528; F:G-protein coupled peptide receptor activity; IBA:GO_Central. DR GO; GO:0007190; P:activation of adenylate cyclase activity; IBA:GO_Central. DR GO; GO:0007189; P:adenylate cyclase-activating G-protein coupled receptor signaling pathway; IBA:GO_Central. DR GO; GO:0007292; P:female gamete generation; TAS:ProtInc. DR GO; GO:0008585; P:female gonad development; TAS:ProtInc. DR GO; GO:0042699; P:follicle-stimulating hormone signaling pathway; TAS:GOC. DR GO; GO:0007186; P:G-protein coupled receptor signaling pathway; TAS:ProtInc. DR GO; GO:0008406; P:gonad development; TAS:ProtInc. DR GO; GO:0009755; P:hormone-mediated signaling pathway; IBA:GO_Central. DR GO; GO:0008584; P:male gonad development; IEP:UniProtKB. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:UniProtKB. DR GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase signaling; IMP:UniProtKB. DR GO; GO:0001545; P:primary ovarian follicle growth; IBA:GO_Central. DR GO; GO:0045670; P:regulation of osteoclast differentiation; IBA:GO_Central. DR GO; GO:0010738; P:regulation of protein kinase A signaling; IMP:UniProtKB. DR GO; GO:0007283; P:spermatogenesis; TAS:ProtInc. DR GO; GO:0060065; P:uterus development; IBA:GO_Central. DR InterPro; IPR002272; FSH_rcpt. DR InterPro; IPR024635; GnHR_TM. DR InterPro; IPR000276; GPCR_Rhodpsn. DR InterPro; IPR017452; GPCR_Rhodpsn_7TM. DR InterPro; IPR002131; Gphrmn_rcpt_fam. DR InterPro; IPR026906; LRR_5. DR InterPro; IPR000372; LRRNT. DR PANTHER; PTHR24372; PTHR24372; 1. DR PANTHER; PTHR24372:SF5; PTHR24372:SF5; 1. DR Pfam; PF00001; 7tm_1; 1. DR Pfam; PF12369; GnHR_trans; 1. DR Pfam; PF13306; LRR_5; 2. DR Pfam; PF01462; LRRNT; 1. DR PRINTS; PR01143; FSHRECEPTOR. DR PRINTS; PR00373; GLYCHORMONER. DR PRINTS; PR00237; GPCRRHODOPSN. DR SMART; SM00013; LRRNT; 1. 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 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 17 {ECO:0000255}. FT CHAIN 18 695 Follicle-stimulating hormone receptor. FT /FTId=PRO_0000012771. FT TOPO_DOM 18 366 Extracellular. {ECO:0000255}. FT TRANSMEM 367 387 Helical; Name=1. {ECO:0000255}. FT TOPO_DOM 388 398 Cytoplasmic. {ECO:0000255}. FT TRANSMEM 399 421 Helical; Name=2. {ECO:0000255}. FT TOPO_DOM 422 443 Extracellular. {ECO:0000255}. FT TRANSMEM 444 465 Helical; Name=3. {ECO:0000255}. FT TOPO_DOM 466 485 Cytoplasmic. {ECO:0000255}. FT TRANSMEM 486 508 Helical; Name=4. {ECO:0000255}. FT TOPO_DOM 509 528 Extracellular. {ECO:0000255}. FT TRANSMEM 529 550 Helical; Name=5. {ECO:0000255}. FT TOPO_DOM 551 573 Cytoplasmic. {ECO:0000255}. FT TRANSMEM 574 597 Helical; Name=6. {ECO:0000255}. FT TOPO_DOM 598 608 Extracellular. {ECO:0000255}. FT TRANSMEM 609 630 Helical; Name=7. {ECO:0000255}. FT TOPO_DOM 631 695 Cytoplasmic. {ECO:0000255}. FT DOMAIN 18 46 LRRNT. FT REPEAT 49 72 LRR 1. FT REPEAT 73 97 LRR 2. FT REPEAT 98 118 LRR 3. FT REPEAT 119 143 LRR 4. FT REPEAT 144 169 LRR 5. FT REPEAT 170 192 LRR 6. FT REPEAT 193 216 LRR 7. FT REPEAT 217 240 LRR 8. FT REPEAT 241 259 LRR 9. FT CARBOHYD 191 191 N-linked (GlcNAc...). FT {ECO:0000269|PubMed:15662415}. FT CARBOHYD 199 199 N-linked (GlcNAc...). {ECO:0000255}. FT CARBOHYD 293 293 N-linked (GlcNAc...). {ECO:0000250}. FT CARBOHYD 318 318 N-linked (GlcNAc...). {ECO:0000255}. FT DISULFID 18 25 {ECO:0000255|PROSITE-ProRule:PRU00521, FT ECO:0000269|PubMed:15662415}. FT DISULFID 23 32 {ECO:0000255|PROSITE-ProRule:PRU00521, FT ECO:0000269|PubMed:15662415}. FT DISULFID 442 517 {ECO:0000255|PROSITE-ProRule:PRU00521}. FT VAR_SEQ 149 174 Missing (in isoform 3). FT {ECO:0000303|PubMed:15489334}. FT /FTId=VSP_043181. FT VAR_SEQ 223 223 L -> LNRRTRTPTEPNVLLAKYPSGQGVLEEPESLSSSI FT (in isoform 4). {ECO:0000305}. FT /FTId=VSP_053411. FT VAR_SEQ 224 285 Missing (in isoform Short). FT {ECO:0000303|PubMed:1359889}. FT /FTId=VSP_001953. FT VARIANT 128 128 S -> Y (in OHSS; displays increase in FT affinity and sensitivity toward hCG and FT does not show any constitutive activity FT nor promiscuous activation by TSH). FT {ECO:0000269|PubMed:17721928}. FT /FTId=VAR_039279. FT VARIANT 160 160 I -> T (in ODG1; impairs cell surface FT expression). FT {ECO:0000269|PubMed:9769327}. FT /FTId=VAR_018045. FT VARIANT 189 189 A -> V (in ODG1; very frequent in the FT Finnish population). FT {ECO:0000269|PubMed:7553856, FT ECO:0000269|PubMed:9851774}. FT /FTId=VAR_018046. FT VARIANT 224 224 D -> V (in ODG1; FSH binding is barely FT detectable; impaired targeting to the FT cell membrane; adenylate cyclase FT stimulation by FSH is 4 +-2% residual FT activity). {ECO:0000269|PubMed:10551778}. FT /FTId=VAR_039280. FT VARIANT 307 307 A -> T (in dbSNP:rs6165). FT {ECO:0000269|PubMed:10391209, FT ECO:0000269|PubMed:12059813, FT ECO:0000269|PubMed:1301382, FT ECO:0000269|PubMed:1322283, FT ECO:0000269|PubMed:1359889, FT ECO:0000269|PubMed:14702039, FT ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:7916967, FT ECO:0000269|Ref.5}. FT /FTId=VAR_013903. FT VARIANT 348 348 P -> R (in ODG1). FT {ECO:0000269|PubMed:12571157}. FT /FTId=VAR_039281. FT VARIANT 419 419 A -> T (in ODG1). FT {ECO:0000269|PubMed:11889179}. FT /FTId=VAR_018047. FT VARIANT 449 449 T -> A (in OHSS; increase of receptor FT sensitivity to both hCG and TSH together FT with an increase in basal activity). FT {ECO:0000269|PubMed:15080154}. FT /FTId=VAR_039282. FT VARIANT 449 449 T -> I (in OHSS; dbSNP:rs28928870). FT {ECO:0000269|PubMed:12930927}. FT /FTId=VAR_017244. FT VARIANT 512 512 M -> I (in OHSS; inhibits activation of FT PI3K/AKT signaling pathway; reduces cAMP FT production; no effect on ERK1/2 signaling FT pathway activation). FT {ECO:0000269|PubMed:24058690}. FT /FTId=VAR_074535. FT VARIANT 514 514 V -> A (in OHSS; increases cell surface FT expression; no effect on hormone binding; FT increases signaling activity). FT {ECO:0000269|PubMed:25581598}. FT /FTId=VAR_074536. FT VARIANT 519 519 P -> T (in ODG1; totally impairs FT adenylate cyclase stimulation in vitro; FT alters the cell surface targeting of the FT receptor which remains trapped FT intracellularly). FT {ECO:0000269|PubMed:12915623}. FT /FTId=VAR_039283. FT VARIANT 524 524 S -> R (in dbSNP:rs6167). FT {ECO:0000269|PubMed:10391209}. FT /FTId=VAR_013904. FT VARIANT 545 545 I -> T (in OHSS; displays promiscuous FT activation by both hCG and TSH together FT with detectable constitutive activity). FT {ECO:0000269|PubMed:16278261}. FT /FTId=VAR_039284. FT VARIANT 567 567 D -> G (activating mutation resulting in FT 1.5-fold increase in basal cAMP FT production compared to the wild-type FT receptor). {ECO:0000269|PubMed:8636335}. FT /FTId=VAR_039285. FT VARIANT 567 567 D -> N (in OHSS; dbSNP:rs28928871). FT {ECO:0000269|PubMed:12930928}. FT /FTId=VAR_017245. FT VARIANT 573 573 R -> C (in ODG1; alters signal FT transduction of the receptor; adenylate FT cyclase stimulation by FSH is 24 +-4% FT residual activity). FT {ECO:0000269|PubMed:10551778, FT ECO:0000269|PubMed:9769327}. FT /FTId=VAR_018048. FT VARIANT 575 575 A -> V (in OHSS; decreases cell surface FT expression; no effect on hormone binding; FT increases levels of internalized hormone FT receptor complex; cAMP levels are similar FT to basal levels even at high doses of FSH FT stimulation indicating reduced FT signaling). FT {ECO:0000269|PubMed:25581598}. FT /FTId=VAR_074537. FT VARIANT 591 591 F -> S (in ovarian sex cord tumor; loss FT of function). FT {ECO:0000269|PubMed:9100567}. FT /FTId=VAR_018049. FT VARIANT 601 601 L -> V (in ODG1; binds FSH with a similar FT affinity than the wild-type receptor; FT adenylate cyclase stimulation by FSH is FT 12 +-3% residual activity). FT {ECO:0000269|PubMed:10551778}. FT /FTId=VAR_039286. FT VARIANT 680 680 N -> S (associated with longer menstrual FT cycles; dbSNP:rs6166). FT {ECO:0000269|PubMed:10391209, FT ECO:0000269|PubMed:12059813, FT ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:15815621, FT ECO:0000269|PubMed:1709010, FT ECO:0000269|PubMed:7916967, FT ECO:0000269|Ref.8}. FT /FTId=VAR_013905. FT CONFLICT 13 13 S -> R (in Ref. 10; CAA48179). FT {ECO:0000305}. FT CONFLICT 112 112 N -> T (in Ref. 1; AAA52477). FT {ECO:0000305}. FT CONFLICT 197 198 EL -> AV (in Ref. 1; AAA52477). FT {ECO:0000305}. FT CONFLICT 295 295 S -> P (in Ref. 10; CAA48179). FT {ECO:0000305}. FT STRAND 21 26 {ECO:0000244|PDB:4AY9}. FT STRAND 29 34 {ECO:0000244|PDB:4AY9}. FT STRAND 49 55 {ECO:0000244|PDB:4AY9}. FT STRAND 59 61 {ECO:0000244|PDB:4AY9}. FT TURN 63 68 {ECO:0000244|PDB:1XWD}. FT STRAND 74 78 {ECO:0000244|PDB:4AY9}. FT TURN 88 90 {ECO:0000244|PDB:4MQW}. FT STRAND 99 105 {ECO:0000244|PDB:4AY9}. FT STRAND 115 117 {ECO:0000244|PDB:1XWD}. FT STRAND 124 130 {ECO:0000244|PDB:4AY9}. FT STRAND 143 145 {ECO:0000244|PDB:4AY9}. FT STRAND 147 153 {ECO:0000244|PDB:4AY9}. FT STRAND 168 171 {ECO:0000244|PDB:4AY9}. FT STRAND 173 176 {ECO:0000244|PDB:4AY9}. FT TURN 187 192 {ECO:0000244|PDB:4MQW}. FT STRAND 193 199 {ECO:0000244|PDB:4AY9}. FT TURN 211 216 {ECO:0000244|PDB:4AY9}. FT STRAND 221 224 {ECO:0000244|PDB:4AY9}. FT STRAND 235 237 {ECO:0000244|PDB:4AY9}. FT STRAND 243 245 {ECO:0000244|PDB:4AY9}. FT TURN 258 260 {ECO:0000244|PDB:4AY9}. FT STRAND 266 268 {ECO:0000244|PDB:4AY9}. FT HELIX 272 280 {ECO:0000244|PDB:4AY9}. FT STRAND 345 348 {ECO:0000244|PDB:4AY9}. FT STRAND 351 353 {ECO:0000244|PDB:4MQW}. SQ SEQUENCE 695 AA; 78265 MW; 766BC421014CD5A4 CRC64; MALLLVSLLA FLSLGSGCHH RICHCSNRVF LCQESKVTEI PSDLPRNAIE LRFVLTKLRV IQKGAFSGFG DLEKIEISQN DVLEVIEADV FSNLPKLHEI RIEKANNLLY INPEAFQNLP NLQYLLISNT GIKHLPDVHK IHSLQKVLLD IQDNINIHTI ERNSFVGLSF ESVILWLNKN GIQEIHNCAF NGTQLDELNL SDNNNLEELP NDVFHGASGP VILDISRTRI HSLPSYGLEN LKKLRARSTY NLKKLPTLEK LVALMEASLT YPSHCCAFAN WRRQISELHP ICNKSILRQE VDYMTQARGQ RSSLAEDNES SYSRGFDMTY TEFDYDLCNE VVDVTCSPKP DAFNPCEDIM GYNILRVLIW FISILAITGN IIVLVILTTS QYKLTVPRFL MCNLAFADLC IGIYLLLIAS VDIHTKSQYH NYAIDWQTGA GCDAAGFFTV FASELSVYTL TAITLERWHT ITHAMQLDCK VQLRHAASVM VMGWIFAFAA ALFPIFGISS YMKVSICLPM DIDSPLSQLY VMSLLVLNVL AFVVICGCYI HIYLTVRNPN IVSSSSDTRI AKRMAMLIFT DFLCMAPISF FAISASLKVP LITVSKAKIL LVLFHPINSC ANPFLYAIFT KNFRRDFFIL LSKCGCYEMQ AQIYRTETSS TVHNTHPRNG HCSSAPRVTN GSTYILVPLS HLAQN //