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Follicle-stimulating hormone receptor (FSH-R) (Follitropin receptor)

 FSHR_HUMAN              Reviewed;         695 AA.
P23945; A0A0A0MSC5; A8K947; G5CBS7; G5E967; J3KQ00; Q05AH0; Q16225;
Q4QRJ3; Q4ZFZ2; Q53RW2;
01-MAR-1992, integrated into UniProtKB/Swiss-Prot.
02-NOV-2010, sequence version 3.
22-NOV-2017, entry version 202.
RecName: Full=Follicle-stimulating hormone receptor;
Short=FSH-R;
AltName: Full=Follitropin receptor;
Flags: Precursor;
Name=FSHR; Synonyms=LGR1;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG), AND VARIANT SER-680.
TISSUE=Ovary;
PubMed=1709010; DOI=10.1016/0006-291X(91)91682-3;
Minegish T., Nakamura K., Takakura Y., Ibuki Y., Igarashi M.;
"Cloning and sequencing of human FSH receptor cDNA.";
Biochem. Biophys. Res. Commun. 175:1125-1130(1991).
[2]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG), AND VARIANT THR-307.
PubMed=1322283; DOI=10.1210/endo.131.2.1322283;
Tilly J.L., Aihara T., Nishimori K., Jia X.-C., Billig H.,
Kowalski K.I., Perlas E.A., Hsueh A.J.;
"Expression of recombinant human follicle-stimulating hormone
receptor: species-specific ligand binding, signal transduction, and
identification of multiple ovarian messenger ribonucleic acid
transcripts.";
Endocrinology 131:799-806(1992).
[3]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG), AND VARIANT THR-307.
TISSUE=Testis;
PubMed=1301382; DOI=10.1016/0303-7207(92)90220-Z;
Kelton C.A., Cheng S.V., Nugent N.P., Schweickhardt R.L.,
Rosenthal J.L., Overton S.A., Wands G.D., Kuzeja J.B., Luchette C.A.,
Chappel S.C.;
"The cloning of the human follicle stimulating hormone receptor and
its expression in COS-7, CHO, and Y-1 cells.";
Mol. Cell. Endocrinol. 89:141-151(1992).
[4]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG).
TISSUE=Adipose tissue;
Liu X., Huang H., Sheng J.;
"FSHR expression in adipose tissue.";
Submitted (MAY-2011) to the EMBL/GenBank/DDBJ databases.
[5]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM LONG), AND VARIANT
THR-307.
TISSUE=Testis;
Kopatz S.A., Aronstam R.S., Sharma S.V.;
"cDNA clones of human proteins involved in signal transduction
sequenced by the Guthrie cDNA resource center (www.cdna.org).";
Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases.
[6]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM LONG), AND VARIANT
THR-307.
TISSUE=Testis;
PubMed=14702039; DOI=10.1038/ng1285;
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
"Complete sequencing and characterization of 21,243 full-length human
cDNAs.";
Nat. Genet. 36:40-45(2004).
[7]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT SER-680.
PubMed=15815621; DOI=10.1038/nature03466;
Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
Waterston R.H., Wilson R.K.;
"Generation and annotation of the DNA sequences of human chromosomes 2
and 4.";
Nature 434:724-731(2005).
[8]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT SER-680.
Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L.,
Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
Venter J.C.;
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
[9]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS LONG AND 3), AND
VARIANTS THR-307 AND SER-680.
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[10]
NUCLEOTIDE SEQUENCE [MRNA] OF 1-342 (ISOFORM SHORT), AND VARIANT
THR-307.
TISSUE=Testis;
PubMed=1359889; DOI=10.1016/0006-291X(92)91341-M;
Gromoll J., Gudermann T., Nieschlag E.;
"Molecular cloning of a truncated isoform of the human follicle
stimulating hormone receptor.";
Biochem. Biophys. Res. Commun. 188:1077-1083(1992).
[11]
NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-51.
PubMed=7926278; DOI=10.1016/0303-7207(94)90102-3;
Gromoll J., Dankbar B., Gudermann T.;
"Characterization of the 5' flanking region of the human follicle-
stimulating hormone receptor gene.";
Mol. Cell. Endocrinol. 102:93-102(1994).
[12]
NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 286-695, AND VARIANTS THR-307 AND
SER-680.
PubMed=7916967; DOI=10.1677/jme.0.0120265;
Gromoll J., Ried T., Holtgreve-Grez H., Nieschlag E., Gudermann T.;
"Localization of the human FSH receptor to chromosome 2p21 using a
genomic probe comprising exon 10.";
J. Mol. Endocrinol. 12:265-271(1994).
[13]
FUNCTION, SUBCELLULAR LOCATION, SULFATION AT TYR-335, AND MUTAGENESIS
OF TYR-330 AND TYR-335.
PubMed=11847099; DOI=10.1093/emboj/21.4.504;
Costagliola S., Panneels V., Bonomi M., Koch J., Many M.C., Smits G.,
Vassart G.;
"Tyrosine sulfation is required for agonist recognition by
glycoprotein hormone receptors.";
EMBO J. 21:504-513(2002).
[14]
ALTERNATIVE SPLICING (ISOFORM 4).
PubMed=11872202; DOI=10.1016/S0015-0282(01)03221-6;
Song G.J., Park Y.S., Lee Y.S., Lee C.C., Kang I.S.;
"Alternatively spliced variants of the follicle-stimulating hormone
receptor gene in the testis of infertile men.";
Fertil. Steril. 77:499-504(2002).
[15]
3D-STRUCTURE MODELING OF 49-228.
PubMed=8747461; DOI=10.1016/S0969-2126(01)00272-6;
Jiang X., Dreano M., Buckler D.R., Cheng S., Ythier A., Wu H.,
Hendrickson W.A., el Tayar N.;
"Structural predictions for the ligand-binding region of glycoprotein
hormone receptors and the nature of hormone-receptor interactions.";
Structure 3:1341-1353(1995).
[16]
X-RAY CRYSTALLOGRAPHY (2.92 ANGSTROMS) OF 17-268 IN COMPLEX WITH FSHA
AND FSHB, DISULFIDE BONDS, AND GLYCOSYLATION AT ASN-191.
PubMed=15662415; DOI=10.1038/nature03206;
Fan Q.R., Hendrickson W.A.;
"Structure of human follicle-stimulating hormone in complex with its
receptor.";
Nature 433:269-277(2005).
[17]
VARIANT ODG1 VAL-189.
PubMed=7553856; DOI=10.1016/0092-8674(95)90275-9;
Aittomaeki K., Lucena J.L.D., Pakarinen P., Sistonen P.,
Tapanainen J., Gromoll J., Kaskikari R., Sankila E.-M.,
Lehvaslaiho H., Engel A.R., Nieschlag E., Huhtaniemi I.,
de la Chapelle A.;
"Mutation in the follicle-stimulating hormone receptor gene causes
hereditary hypergonadotropic ovarian failure.";
Cell 82:959-968(1995).
[18]
VARIANT OVARIAN SEX CORD TUMOR SER-591.
PubMed=9100567; DOI=10.1210/jcem.82.4.3870;
Kotlar T.J., Young R.H., Albanese C., Crowley W.F. Jr., Scully R.E.,
Jameson J.L.;
"A mutation in the follicle-stimulating hormone receptor occurs
frequently in human ovarian sex cord tumors.";
J. Clin. Endocrinol. Metab. 82:1020-1026(1997).
[19]
VARIANT FSHR ACTIVATION GLY-567, AND CHARACTERIZATION OF VARIANT FSHR
ACTIVATION GLY-567.
PubMed=8636335; DOI=10.1210/jcem.81.4.8636335;
Gromoll J., Simoni M., Nieschlag E.;
"An activating mutation of the follicle-stimulating hormone receptor
autonomously sustains spermatogenesis in a hypophysectomized man.";
J. Clin. Endocrinol. Metab. 81:1367-1370(1996).
[20]
VARIANT ODG1 VAL-189.
PubMed=9851774; DOI=10.1210/jcem.83.12.5306;
Jiang M., Aittomaeki K., Nilsson C., Pakarinen P., Iitia A.,
Torresani T., Simonsen H., Goh V., Pettersson K., de la Chapelle A.,
Huhtaniemi I.;
"The frequency of an inactivating point mutation (566C-->T) of the
human follicle-stimulating hormone receptor gene in four populations
using allele-specific hybridization and time-resolved fluorometry.";
J. Clin. Endocrinol. Metab. 83:4338-4343(1998).
[21]
VARIANTS ODG1 THR-160 AND CYS-573.
PubMed=9769327; DOI=10.1172/JCI3795;
Beau I., Touraine P., Meduri G., Gougeon A., Desroches A.,
Matuchansky C., Milgrom E., Kuttenn F., Misrahi M.;
"A novel phenotype related to partial loss of function mutations of
the follicle stimulating hormone receptor.";
J. Clin. Invest. 102:1352-1359(1998).
[22]
VARIANTS ODG1 VAL-224 AND VAL-601, AND CHARACTERIZATION OF VARIANTS
ODG1 VAL-224; CYS-573 AND VAL-601.
PubMed=10551778; DOI=10.1210/mend.13.11.0370;
Touraine P., Beau I., Gougeon A., Meduri G., Desroches A., Pichard C.,
Detoeuf M., Paniel B., Prieur M., Zorn J.-R., Milgrom E., Kuttenn F.,
Misrahi M.;
"New natural inactivating mutations of the follicle-stimulating
hormone receptor: correlations between receptor function and
phenotype.";
Mol. Endocrinol. 13:1844-1854(1999).
[23]
VARIANTS THR-307; ARG-524 AND SER-680.
PubMed=10391209; DOI=10.1038/10290;
Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N.,
Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L.,
Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q.,
Lander E.S.;
"Characterization of single-nucleotide polymorphisms in coding regions
of human genes.";
Nat. Genet. 22:231-238(1999).
[24]
ERRATUM.
Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N.,
Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L.,
Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q.,
Lander E.S.;
Nat. Genet. 23:373-373(1999).
[25]
VARIANTS THR-307 AND SER-680.
PubMed=12059813; DOI=10.1046/j.1439-0272.2002.00493.x;
Asatiani K., Gromoll J., Eckardstein S.V., Zitzmann M., Nieschlag E.,
Simoni M.;
"Distribution and function of FSH receptor genetic variants in normal
men.";
Andrologia 34:172-176(2002).
[26]
VARIANT ODG1 THR-419, AND CHARACTERIZATION OF VARIANT ODG1 THR-419.
PubMed=11889179; DOI=10.1210/jcem.87.3.8319;
Doherty E., Pakarinen P., Tiitinen A., Kiilavuori A., Huhtaniemi I.,
Forrest S., Aittomaeki K.;
"A novel mutation in the FSH receptor inhibiting signal transduction
and causing primary ovarian failure.";
J. Clin. Endocrinol. Metab. 87:1151-1155(2002).
[27]
VARIANT ODG1 ARG-348.
PubMed=12571157; DOI=10.1093/humrep/deg046;
Allen L.A., Achermann J.C., Pakarinen P., Kotlar T.J.,
Huhtaniemi I.T., Jameson J.L., Cheetham T.D., Ball S.G.;
"A novel loss of function mutation in exon 10 of the FSH receptor gene
causing hypergonadotrophic hypogonadism: clinical and molecular
characteristics.";
Hum. Reprod. 18:251-256(2003).
[28]
VARIANT ODG1 THR-519, AND CHARACTERIZATION OF VARIANT ODG1 THR-519.
PubMed=12915623; DOI=10.1210/jc.2003-030217;
Meduri G., Touraine P., Beau I., Lahuna O., Desroches A.,
Vacher-Lavenu M.C., Kuttenn F., Misrahi M.;
"Delayed puberty and primary amenorrhea associated with a novel
mutation of the human follicle-stimulating hormone receptor: clinical,
histological, and molecular studies.";
J. Clin. Endocrinol. Metab. 88:3491-3498(2003).
[29]
VARIANT OHSS ILE-449.
PubMed=12930927; DOI=10.1056/NEJMoa030065;
Vasseur C., Rodien P., Beau I., Desroches A., Gerard C.,
de Poncheville L., Chaplot S., Savagner F., Croue A., Mathieu E.,
Lahlou N., Descamps P., Misrahi M.;
"A chorionic gonadotropin-sensitive mutation in the follicle-
stimulating hormone receptor as a cause of familial gestational
spontaneous ovarian hyperstimulation syndrome.";
N. Engl. J. Med. 349:753-759(2003).
[30]
VARIANT OHSS ASN-567.
PubMed=12930928; DOI=10.1056/NEJMoa030064;
Smits G., Olatunbosun O., Delbaere A., Pierson R., Vassart G.,
Costagliola S.;
"Ovarian hyperstimulation syndrome due to a mutation in the follicle-
stimulating hormone receptor.";
N. Engl. J. Med. 349:760-766(2003).
[31]
VARIANT OHSS ALA-449, AND CHARACTERIZATION OF VARIANT OHSS ALA-449.
PubMed=15080154; DOI=10.1210/jc.2003-031910;
Montanelli L., Delbaere A., Di Carlo C., Nappi C., Smits G.,
Vassart G., Costagliola S.;
"A mutation in the follicle-stimulating hormone receptor as a cause of
familial spontaneous ovarian hyperstimulation syndrome.";
J. Clin. Endocrinol. Metab. 89:1255-1258(2004).
[32]
VARIANT OHSS THR-545, AND CHARACTERIZATION OF VARIANT OHSS THR-545.
PubMed=16278261; DOI=10.1210/jc.2005-1580;
De Leener A., Montanelli L., Van Durme J., Chae H., Smits G.,
Vassart G., Costagliola S.;
"Presence and absence of follicle-stimulating hormone receptor
mutations provide some insights into spontaneous ovarian
hyperstimulation syndrome physiopathology.";
J. Clin. Endocrinol. Metab. 91:555-562(2006).
[33]
VARIANT OHSS TYR-128, AND CHARACTERIZATION OF VARIANT OHSS TYR-128.
PubMed=17721928; DOI=10.1002/humu.20604;
De Leener A., Caltabiano G., Erkan S., Idil M., Vassart G., Pardo L.,
Costagliola S.;
"Identification of the first germline mutation in the extracellular
domain of the follitropin receptor responsible for spontaneous ovarian
hyperstimulation syndrome.";
Hum. Mutat. 29:91-98(2008).
[34]
VARIANT OHSS ILE-512, CHARACTERIZATION OF VARIANT OHSS ILE-512, AND
FUNCTION.
PubMed=24058690; DOI=10.1371/journal.pone.0075478;
Uchida S., Uchida H., Maruyama T., Kajitani T., Oda H., Miyazaki K.,
Kagami M., Yoshimura Y.;
"Molecular analysis of a mutated FSH receptor detected in a patient
with spontaneous ovarian hyperstimulation syndrome.";
PLoS ONE 8:E75478-E75478(2013).
[35]
VARIANTS OHSS ALA-514 AND VAL-575, AND CHARACTERIZATION OF VARIANTS
OHSS ALA-514 AND VAL-575.
PubMed=25581598; DOI=10.1210/jc.2014-3662;
Desai S.S., Achrekar S.K., Sahasrabuddhe K.A., Meharji P.K.,
Desai S.K., Mangoli V.S., Mahale S.D.;
"Functional characterization of two naturally occurring mutations
(Val514Ala and Ala575Val) in follicle-stimulating hormone receptor.";
J. Clin. Endocrinol. Metab. 100:E638-E645(2015).
-!- FUNCTION: Receptor for follicle-stimulating hormone or follitropin
(PubMed:11847099, PubMed:24058690). The activity of this receptor
is mediated by G proteins which activate adenylate cyclase
(PubMed:11847099). Induces cAMP production through the activation
of PI3K-AKT and SRC-ERK1/2 signaling pathways (PubMed:24058690).
{ECO:0000269|PubMed:11847099, ECO:0000269|PubMed:24058690}.
-!- SUBUNIT: Interacts with ARRB2. {ECO:0000250|UniProtKB:P20395}.
-!- INTERACTION:
P27348:YWHAQ; NbExp=4; IntAct=EBI-848239, EBI-359854;
-!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:11847099};
Multi-pass membrane protein {ECO:0000305}.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=4;
Name=Long; Synonyms=R1;
IsoId=P23945-1; Sequence=Displayed;
Name=Short; Synonyms=E9Del;
IsoId=P23945-2; Sequence=VSP_001953;
Name=3; Synonyms=E6Del;
IsoId=P23945-3; Sequence=VSP_043181;
Name=4; Synonyms=E8'Inc;
IsoId=P23945-4; Sequence=VSP_053411;
-!- TISSUE SPECIFICITY: Sertoli cells and ovarian granulosa cells.
-!- PTM: Sulfated. {ECO:0000269|PubMed:11847099}.
-!- PTM: N-glycosylated; indirectly required for FSH-binding, possibly
via a conformational change that allows high affinity binding of
hormone. {ECO:0000250|UniProtKB:P20395}.
-!- DISEASE: Ovarian dysgenesis 1 (ODG1) [MIM:233300]: An autosomal
recessive disease characterized by primary amenorrhea, variable
development of secondary sex characteristics, poorly developed
streak ovaries, and high serum levels of follicle-stimulating
hormone (FSH) and luteinizing hormone (LH).
{ECO:0000269|PubMed:10551778, ECO:0000269|PubMed:11889179,
ECO:0000269|PubMed:12571157, ECO:0000269|PubMed:12915623,
ECO:0000269|PubMed:7553856, ECO:0000269|PubMed:9769327,
ECO:0000269|PubMed:9851774}. Note=The disease is caused by
mutations affecting the gene represented in this entry.
-!- DISEASE: Ovarian hyperstimulation syndrome (OHSS) [MIM:608115]:
Disorder which occurs either spontaneously or most often as an
iatrogenic complication of ovarian stimulation treatments for in
vitro fertilization. The clinical manifestations vary from
abdominal distention and discomfort to potentially life-
threatening, massive ovarian enlargement and capillary leak with
fluid sequestration. Pathologic features of this syndrome include
the presence of multiple serous and hemorrhagic follicular cysts
lined by luteinized cells, a condition called hyperreactio
luteinalis. {ECO:0000269|PubMed:12930927,
ECO:0000269|PubMed:12930928, ECO:0000269|PubMed:15080154,
ECO:0000269|PubMed:16278261, ECO:0000269|PubMed:17721928,
ECO:0000269|PubMed:24058690, ECO:0000269|PubMed:25581598}.
Note=The disease is caused by mutations affecting the gene
represented in this entry.
-!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family.
FSH/LSH/TSH subfamily. {ECO:0000255|PROSITE-ProRule:PRU00521}.
-!- WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and
polymorphism database;
URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename=FSHR";
-!- WEB RESOURCE: Name=Sequence-structure-function-analysis of
glycoprotein hormone receptors;
URL="http://www.ssfa-gphr.de/";
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EMBL; M65085; AAA52477.1; -; mRNA.
EMBL; M95489; AAA52478.1; -; mRNA.
EMBL; S59900; AAB26480.1; -; mRNA.
EMBL; JN003607; AEI86722.1; -; mRNA.
EMBL; AY429104; AAR07899.1; -; mRNA.
EMBL; AK292562; BAF85251.1; -; mRNA.
EMBL; AC007189; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; AC079394; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; AC092533; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; CH471053; EAX00188.1; -; Genomic_DNA.
EMBL; CH471053; EAX00189.1; -; Genomic_DNA.
EMBL; BC096831; AAH96831.1; -; mRNA.
EMBL; BC118548; AAI18549.1; -; mRNA.
EMBL; BC125270; AAI25271.1; -; mRNA.
EMBL; X68044; CAA48179.1; -; mRNA.
EMBL; S73199; AAB32071.1; -; Genomic_DNA.
EMBL; S73526; AAB32225.1; -; Genomic_DNA.
CCDS; CCDS1843.1; -. [P23945-1]
CCDS; CCDS1844.2; -. [P23945-3]
PIR; I57661; QRHUFT.
RefSeq; NP_000136.2; NM_000145.3.
RefSeq; NP_852111.2; NM_181446.2.
UniGene; Hs.1428; -.
PDB; 1XUN; Model; -; A=49-228.
PDB; 1XWD; X-ray; 2.92 A; C/F=17-268.
PDB; 4AY9; X-ray; 2.50 A; X/Y/Z=17-366.
PDB; 4MQW; X-ray; 2.90 A; X/Y/Z=16-366.
PDBsum; 1XUN; -.
PDBsum; 1XWD; -.
PDBsum; 4AY9; -.
PDBsum; 4MQW; -.
ProteinModelPortal; P23945; -.
SMR; P23945; -.
BioGrid; 108770; 34.
DIP; DIP-35605N; -.
IntAct; P23945; 2.
MINT; MINT-1177926; -.
STRING; 9606.ENSP00000384708; -.
BindingDB; P23945; -.
ChEMBL; CHEMBL2024; -.
DrugBank; DB00097; Chorionic Gonadotropin (Recombinant).
DrugBank; DB00066; Follitropin beta.
DrugBank; DB00032; Menotropins.
DrugBank; DB04786; Suramin.
DrugBank; DB00094; Urofollitropin.
GuidetoPHARMACOLOGY; 253; -.
TCDB; 9.A.14.1.5; the g-protein-coupled receptor (gpcr) family.
iPTMnet; P23945; -.
PhosphoSitePlus; P23945; -.
BioMuta; FSHR; -.
DMDM; 311033420; -.
PaxDb; P23945; -.
PeptideAtlas; P23945; -.
PRIDE; P23945; -.
Ensembl; ENST00000304421; ENSP00000306780; ENSG00000170820.
GeneID; 2492; -.
KEGG; hsa:2492; -.
UCSC; uc002rww.4; human.
UCSC; uc010fbn.4; human. [P23945-1]
CTD; 2492; -.
DisGeNET; 2492; -.
EuPathDB; HostDB:ENSG00000170820.11; -.
GeneCards; FSHR; -.
H-InvDB; HIX0029905; -.
HGNC; HGNC:3969; FSHR.
MalaCards; FSHR; -.
MIM; 136435; gene.
MIM; 233300; phenotype.
MIM; 608115; phenotype.
neXtProt; NX_P23945; -.
Orphanet; 243; 46,XX gonadal dysgenesis.
Orphanet; 64739; Ovarian hyperstimulation syndrome.
Orphanet; 619; Primary ovarian failure.
PharmGKB; PA28386; -.
eggNOG; KOG2087; Eukaryota.
eggNOG; ENOG410XR1T; LUCA.
HOGENOM; HOG000045902; -.
HOVERGEN; HBG003521; -.
InParanoid; P23945; -.
KO; K04247; -.
OrthoDB; EOG091G02BV; -.
PhylomeDB; P23945; -.
TreeFam; TF316814; -.
Reactome; R-HSA-375281; Hormone ligand-binding receptors.
Reactome; R-HSA-418555; G alpha (s) signalling events.
SignaLink; P23945; -.
SIGNOR; P23945; -.
ChiTaRS; FSHR; human.
EvolutionaryTrace; P23945; -.
GeneWiki; Follicle-stimulating_hormone_receptor; -.
GenomeRNAi; 2492; -.
PRO; PR:P23945; -.
Proteomes; UP000005640; Chromosome 2.
Bgee; ENSG00000170820; -.
CleanEx; HS_FSHR; -.
ExpressionAtlas; P23945; baseline and differential.
Genevisible; P23945; HS.
GO; GO:0016021; C:integral component of membrane; TAS:ProtInc.
GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
GO; GO:0005622; C:intracellular; IEA:GOC.
GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
GO; GO:0004963; F:follicle-stimulating hormone receptor activity; IMP:UniProtKB.
GO; GO:0008528; F:G-protein coupled peptide receptor activity; IBA:GO_Central.
GO; GO:0007190; P:activation of adenylate cyclase activity; IBA:GO_Central.
GO; GO:0007189; P:adenylate cyclase-activating G-protein coupled receptor signaling pathway; IBA:GO_Central.
GO; GO:0071372; P:cellular response to follicle-stimulating hormone stimulus; IMP:UniProtKB.
GO; GO:0007292; P:female gamete generation; TAS:ProtInc.
GO; GO:0008585; P:female gonad development; TAS:ProtInc.
GO; GO:0042699; P:follicle-stimulating hormone signaling pathway; IMP:UniProtKB.
GO; GO:0007186; P:G-protein coupled receptor signaling pathway; TAS:ProtInc.
GO; GO:0008406; P:gonad development; TAS:ProtInc.
GO; GO:0009755; P:hormone-mediated signaling pathway; IBA:GO_Central.
GO; GO:0008584; P:male gonad development; IEP:UniProtKB.
GO; GO:0045762; P:positive regulation of adenylate cyclase activity; IMP:UniProtKB.
GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:UniProtKB.
GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase signaling; IMP:UniProtKB.
GO; GO:0001545; P:primary ovarian follicle growth; IBA:GO_Central.
GO; GO:0045670; P:regulation of osteoclast differentiation; IBA:GO_Central.
GO; GO:0010738; P:regulation of protein kinase A signaling; IMP:UniProtKB.
GO; GO:0007283; P:spermatogenesis; TAS:ProtInc.
Gene3D; 3.80.10.10; -; 1.
InterPro; IPR002272; FSH_rcpt.
InterPro; IPR024635; GnHR_TM.
InterPro; IPR000276; GPCR_Rhodpsn.
InterPro; IPR017452; GPCR_Rhodpsn_7TM.
InterPro; IPR002131; Gphrmn_rcpt_fam.
InterPro; IPR026906; LRR_5.
InterPro; IPR032675; LRR_dom_sf.
InterPro; IPR000372; LRRNT.
InterPro; IPR034298; TSHR/LHCGR/FSHR.
PANTHER; PTHR24372; PTHR24372; 1.
PANTHER; PTHR24372:SF5; PTHR24372:SF5; 1.
Pfam; PF00001; 7tm_1; 1.
Pfam; PF12369; GnHR_trans; 1.
Pfam; PF13306; LRR_5; 2.
Pfam; PF01462; LRRNT; 1.
PRINTS; PR01143; FSHRECEPTOR.
PRINTS; PR00373; GLYCHORMONER.
PRINTS; PR00237; GPCRRHODOPSN.
SMART; SM00013; LRRNT; 1.
SUPFAM; SSF52058; SSF52058; 1.
PROSITE; PS00237; G_PROTEIN_RECEP_F1_1; 1.
PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1.
1: Evidence at protein level;
3D-structure; Alternative splicing; Cell membrane; Complete proteome;
Disease mutation; Disulfide bond; G-protein coupled receptor;
Glycoprotein; Leucine-rich repeat; Membrane; Polymorphism; Receptor;
Reference proteome; Repeat; Signal; Sulfation; Transducer;
Transmembrane; Transmembrane helix.
SIGNAL 1 17 {ECO:0000255}.
CHAIN 18 695 Follicle-stimulating hormone receptor.
/FTId=PRO_0000012771.
TOPO_DOM 18 366 Extracellular. {ECO:0000255}.
TRANSMEM 367 387 Helical; Name=1. {ECO:0000255}.
TOPO_DOM 388 398 Cytoplasmic. {ECO:0000255}.
TRANSMEM 399 421 Helical; Name=2. {ECO:0000255}.
TOPO_DOM 422 443 Extracellular. {ECO:0000255}.
TRANSMEM 444 465 Helical; Name=3. {ECO:0000255}.
TOPO_DOM 466 485 Cytoplasmic. {ECO:0000255}.
TRANSMEM 486 508 Helical; Name=4. {ECO:0000255}.
TOPO_DOM 509 528 Extracellular. {ECO:0000255}.
TRANSMEM 529 550 Helical; Name=5. {ECO:0000255}.
TOPO_DOM 551 573 Cytoplasmic. {ECO:0000255}.
TRANSMEM 574 597 Helical; Name=6. {ECO:0000255}.
TOPO_DOM 598 608 Extracellular. {ECO:0000255}.
TRANSMEM 609 630 Helical; Name=7. {ECO:0000255}.
TOPO_DOM 631 695 Cytoplasmic. {ECO:0000255}.
DOMAIN 18 46 LRRNT.
REPEAT 49 72 LRR 1.
REPEAT 73 97 LRR 2.
REPEAT 98 118 LRR 3.
REPEAT 119 143 LRR 4.
REPEAT 144 169 LRR 5.
REPEAT 170 192 LRR 6.
REPEAT 193 216 LRR 7.
REPEAT 217 240 LRR 8.
REPEAT 241 259 LRR 9.
MOD_RES 335 335 Sulfotyrosine.
{ECO:0000305|PubMed:11847099}.
CARBOHYD 191 191 N-linked (GlcNAc...) asparagine.
{ECO:0000269|PubMed:15662415}.
CARBOHYD 199 199 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
CARBOHYD 293 293 N-linked (GlcNAc...) asparagine.
{ECO:0000250}.
CARBOHYD 318 318 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
DISULFID 18 25 {ECO:0000255|PROSITE-ProRule:PRU00521,
ECO:0000269|PubMed:15662415}.
DISULFID 23 32 {ECO:0000255|PROSITE-ProRule:PRU00521,
ECO:0000269|PubMed:15662415}.
DISULFID 442 517 {ECO:0000255|PROSITE-ProRule:PRU00521}.
VAR_SEQ 149 174 Missing (in isoform 3).
{ECO:0000303|PubMed:15489334}.
/FTId=VSP_043181.
VAR_SEQ 223 223 L -> LNRRTRTPTEPNVLLAKYPSGQGVLEEPESLSSSI
(in isoform 4). {ECO:0000305}.
/FTId=VSP_053411.
VAR_SEQ 224 285 Missing (in isoform Short).
{ECO:0000303|PubMed:1359889}.
/FTId=VSP_001953.
VARIANT 128 128 S -> Y (in OHSS; displays increase in
affinity and sensitivity toward hCG and
does not show any constitutive activity
nor promiscuous activation by TSH).
{ECO:0000269|PubMed:17721928}.
/FTId=VAR_039279.
VARIANT 160 160 I -> T (in ODG1; impairs cell surface
expression).
{ECO:0000269|PubMed:9769327}.
/FTId=VAR_018045.
VARIANT 189 189 A -> V (in ODG1; very frequent in the
Finnish population).
{ECO:0000269|PubMed:7553856,
ECO:0000269|PubMed:9851774}.
/FTId=VAR_018046.
VARIANT 224 224 D -> V (in ODG1; FSH binding is barely
detectable; impaired targeting to the
cell membrane; adenylate cyclase
stimulation by FSH is 4 +-2% residual
activity). {ECO:0000269|PubMed:10551778}.
/FTId=VAR_039280.
VARIANT 307 307 A -> T (in dbSNP:rs6165).
{ECO:0000269|PubMed:10391209,
ECO:0000269|PubMed:12059813,
ECO:0000269|PubMed:1301382,
ECO:0000269|PubMed:1322283,
ECO:0000269|PubMed:1359889,
ECO:0000269|PubMed:14702039,
ECO:0000269|PubMed:15489334,
ECO:0000269|PubMed:7916967,
ECO:0000269|Ref.5}.
/FTId=VAR_013903.
VARIANT 348 348 P -> R (in ODG1).
{ECO:0000269|PubMed:12571157}.
/FTId=VAR_039281.
VARIANT 419 419 A -> T (in ODG1).
{ECO:0000269|PubMed:11889179}.
/FTId=VAR_018047.
VARIANT 449 449 T -> A (in OHSS; increase of receptor
sensitivity to both hCG and TSH together
with an increase in basal activity).
{ECO:0000269|PubMed:15080154}.
/FTId=VAR_039282.
VARIANT 449 449 T -> I (in OHSS; dbSNP:rs28928870).
{ECO:0000269|PubMed:12930927}.
/FTId=VAR_017244.
VARIANT 512 512 M -> I (in OHSS; inhibits activation of
PI3K/AKT signaling pathway; reduces cAMP
production; no effect on ERK1/2 signaling
pathway activation).
{ECO:0000269|PubMed:24058690}.
/FTId=VAR_074535.
VARIANT 514 514 V -> A (in OHSS; increases cell surface
expression; no effect on hormone binding;
increases signaling activity).
{ECO:0000269|PubMed:25581598}.
/FTId=VAR_074536.
VARIANT 519 519 P -> T (in ODG1; totally impairs
adenylate cyclase stimulation in vitro;
alters the cell surface targeting of the
receptor which remains trapped
intracellularly).
{ECO:0000269|PubMed:12915623}.
/FTId=VAR_039283.
VARIANT 524 524 S -> R (in dbSNP:rs6167).
{ECO:0000269|PubMed:10391209}.
/FTId=VAR_013904.
VARIANT 545 545 I -> T (in OHSS; displays promiscuous
activation by both hCG and TSH together
with detectable constitutive activity).
{ECO:0000269|PubMed:16278261}.
/FTId=VAR_039284.
VARIANT 567 567 D -> G (activating mutation resulting in
1.5-fold increase in basal cAMP
production compared to the wild-type
receptor). {ECO:0000269|PubMed:8636335}.
/FTId=VAR_039285.
VARIANT 567 567 D -> N (in OHSS; dbSNP:rs28928871).
{ECO:0000269|PubMed:12930928}.
/FTId=VAR_017245.
VARIANT 573 573 R -> C (in ODG1; alters signal
transduction of the receptor; adenylate
cyclase stimulation by FSH is 24 +-4%
residual activity).
{ECO:0000269|PubMed:10551778,
ECO:0000269|PubMed:9769327}.
/FTId=VAR_018048.
VARIANT 575 575 A -> V (in OHSS; decreases cell surface
expression; no effect on hormone binding;
increases levels of internalized hormone
receptor complex; cAMP levels are similar
to basal levels even at high doses of FSH
stimulation indicating reduced
signaling).
{ECO:0000269|PubMed:25581598}.
/FTId=VAR_074537.
VARIANT 591 591 F -> S (in ovarian sex cord tumor; loss
of function).
{ECO:0000269|PubMed:9100567}.
/FTId=VAR_018049.
VARIANT 601 601 L -> V (in ODG1; binds FSH with a similar
affinity than the wild-type receptor;
adenylate cyclase stimulation by FSH is
12 +-3% residual activity).
{ECO:0000269|PubMed:10551778}.
/FTId=VAR_039286.
VARIANT 680 680 N -> S (associated with longer menstrual
cycles; dbSNP:rs6166).
{ECO:0000269|PubMed:10391209,
ECO:0000269|PubMed:12059813,
ECO:0000269|PubMed:15489334,
ECO:0000269|PubMed:15815621,
ECO:0000269|PubMed:1709010,
ECO:0000269|PubMed:7916967,
ECO:0000269|Ref.8}.
/FTId=VAR_013905.
MUTAGEN 330 330 Y->F: No change in intracellular cAMP
accumulation.
{ECO:0000269|PubMed:11847099}.
MUTAGEN 335 335 Y->F: Reduces intracellular cAMP
accumulation.
{ECO:0000269|PubMed:11847099}.
CONFLICT 13 13 S -> R (in Ref. 10; CAA48179).
{ECO:0000305}.
CONFLICT 112 112 N -> T (in Ref. 1; AAA52477).
{ECO:0000305}.
CONFLICT 197 198 EL -> AV (in Ref. 1; AAA52477).
{ECO:0000305}.
CONFLICT 295 295 S -> P (in Ref. 10; CAA48179).
{ECO:0000305}.
STRAND 21 26 {ECO:0000244|PDB:4AY9}.
STRAND 29 34 {ECO:0000244|PDB:4AY9}.
STRAND 49 55 {ECO:0000244|PDB:4AY9}.
STRAND 59 61 {ECO:0000244|PDB:4AY9}.
TURN 63 68 {ECO:0000244|PDB:1XWD}.
STRAND 74 78 {ECO:0000244|PDB:4AY9}.
TURN 88 90 {ECO:0000244|PDB:4MQW}.
STRAND 99 105 {ECO:0000244|PDB:4AY9}.
STRAND 115 117 {ECO:0000244|PDB:1XWD}.
STRAND 124 130 {ECO:0000244|PDB:4AY9}.
STRAND 143 145 {ECO:0000244|PDB:4AY9}.
STRAND 147 153 {ECO:0000244|PDB:4AY9}.
STRAND 168 171 {ECO:0000244|PDB:4AY9}.
STRAND 173 176 {ECO:0000244|PDB:4AY9}.
TURN 187 192 {ECO:0000244|PDB:4MQW}.
STRAND 193 199 {ECO:0000244|PDB:4AY9}.
TURN 211 216 {ECO:0000244|PDB:4AY9}.
STRAND 221 224 {ECO:0000244|PDB:4AY9}.
STRAND 235 237 {ECO:0000244|PDB:4AY9}.
STRAND 243 245 {ECO:0000244|PDB:4AY9}.
TURN 258 260 {ECO:0000244|PDB:4AY9}.
STRAND 266 268 {ECO:0000244|PDB:4AY9}.
HELIX 272 280 {ECO:0000244|PDB:4AY9}.
STRAND 345 348 {ECO:0000244|PDB:4AY9}.
STRAND 351 353 {ECO:0000244|PDB:4MQW}.
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


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