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P30968 (GNRHR_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 140. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Gonadotropin-releasing hormone receptor

Short name=GnRH receptor
Short name=GnRH-R
Gene names
Name:GNRHR
Synonyms:GRHR
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length328 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Receptor for gonadotropin releasing hormone (GnRH) that mediates the action of GnRH to stimulate the secretion of the gonadotropic hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This receptor mediates its action by association with G-proteins that activate a phosphatidylinositol-calcium second messenger system. Isoform 2 may act as an inhibitor of GnRH-R signaling.

Subcellular location

Cell membrane; Multi-pass membrane protein.

Tissue specificity

Pituitary, ovary, testis, breast and prostate but not in liver and spleen.

Involvement in disease

Hypogonadotropic hypogonadism 7 with or without anosmia (HH7) [MIM:146110]: A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. In some cases, it is associated with non-reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH).
Note: The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. The genetics of hypogonadotropic hypogonadism involves various modes of transmission. Oligogenic inheritance has been reported in some patients carrying mutations in GNRHR as well as in other HH-associated genes including FGFR1 (Ref.19). Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.15 Ref.16 Ref.17 Ref.18 Ref.19

Fertile eunuch syndrome (FEUNS) [MIM:228300]: Mild phenotypic form of HH going with the presence of normal testicular size and some degree of spermatogenesis.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.14

Sequence similarities

Belongs to the G-protein coupled receptor 1 family.

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: P30968-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: P30968-2)

Also known as: Truncated;

The sequence of this isoform differs from the canonical sequence as follows:
     176-328: YIFRMIHLAD...DPLIYGYFSL → PLHHPSFHHA...LLCPRNLVLV

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 328328Gonadotropin-releasing hormone receptor
PRO_0000069487

Regions

Topological domain1 – 3838Extracellular Potential
Transmembrane39 – 5820Helical; Name=1; Potential
Topological domain59 – 7719Cytoplasmic Potential
Transmembrane78 – 9720Helical; Name=2; Potential
Topological domain98 – 11518Extracellular Potential
Transmembrane116 – 13722Helical; Name=3; Potential
Topological domain138 – 16427Cytoplasmic Potential
Transmembrane165 – 18420Helical; Name=4; Potential
Topological domain185 – 21228Extracellular Potential
Transmembrane213 – 23220Helical; Name=5; Potential
Topological domain233 – 28149Cytoplasmic Potential
Transmembrane282 – 30019Helical; Name=6; Potential
Topological domain301 – 3066Extracellular Potential
Transmembrane307 – 32620Helical; Name=7; Potential
Topological domain327 – 3282Cytoplasmic Potential

Amino acid modifications

Glycosylation181N-linked (GlcNAc...) Potential
Glycosylation1021N-linked (GlcNAc...) Potential
Disulfide bond114 ↔ 196 By similarity

Natural variations

Alternative sequence176 – 328153YIFRM…GYFSL → PLHHPSFHHADLQCKNHLHP DTGPSSGPPRTTTESVQEQY TKSTAEDSKNDGCICHFIYC LLDSLLCPRNLVLV in isoform 2.
VSP_001914
Natural variant101N → K in HH7; is able to bind GnRH but with a reduced affinity in vitro. Ref.16
VAR_019311
Natural variant831L → V in HH7; the patient also carries a mutation in FGFR1. Ref.19
VAR_069960
Natural variant901E → K in HH7; virtual abolition of GnRH agonist binding and agonist-stimulated phosphoinositide turnover; impairs GnRHR-effector coupling. Ref.15 Ref.17
VAR_019312
Natural variant1061Q → R in HH7 and FEUNS; some patients also carry mutations in FGFR1; decreases but does not eliminate GnRH binding. Ref.9 Ref.11 Ref.14 Ref.16 Ref.19
Corresponds to variant rs104893836 [ dbSNP | Ensembl ].
VAR_019313
Natural variant1291A → D in HH7; complete loss of function. Ref.12
VAR_019314
Natural variant1391R → H in HH7; completely eliminates detectable GnRH-binding activity and prevents GnRH-induced stimulation of inositol phosphate accumulation in vitro. Ref.16
VAR_019315
Natural variant1681S → R in HH7; complete loss of the receptor-mediated signaling response. Ref.13
VAR_019316
Natural variant1711A → T in HH7; complete loss of ligand binding and receptor activation; specific receptor binding of radioisotope-labeled GnRH ligand is undetectable in transfected cells. Ref.18
VAR_019317
Natural variant2171S → R in HH7; altered hormone binding. Ref.11
VAR_019318
Natural variant2621R → Q in HH7; some patients also carry mutations in FGFR1; minimal effects upon receptor affinity but expression decreased; altered activation of phospholipase C. Ref.9 Ref.10 Ref.11 Ref.12 Ref.19
Corresponds to variant rs104893837 [ dbSNP | Ensembl ].
VAR_019319
Natural variant2841Y → C in HH7; minimal effects upon receptor affinity but receptor expression decreased. Ref.10
Corresponds to variant rs28933074 [ dbSNP | Ensembl ].
VAR_019320

Experimental info

Sequence conflict2471H → T in CAB17082. Ref.8

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified July 1, 1993. Version 1.
Checksum: D02B2EA2F4246D7B

FASTA32837,731
        10         20         30         40         50         60 
MANSASPEQN QNHCSAINNS IPLMQGNLPT LTLSGKIRVT VTFFLFLLSA TFNASFLLKL 

        70         80         90        100        110        120 
QKWTQKKEKG KKLSRMKLLL KHLTLANLLE TLIVMPLDGM WNITVQWYAG ELLCKVLSYL 

       130        140        150        160        170        180 
KLFSMYAPAF MMVVISLDRS LAITRPLALK SNSKVGQSMV GLAWILSSVF AGPQLYIFRM 

       190        200        210        220        230        240 
IHLADSSGQT KVFSQCVTHC SFSQWWHQAF YNFFTFSCLF IIPLFIMLIC NAKIIFTLTR 

       250        260        270        280        290        300 
VLHQDPHELQ LNQSKNNIPR ARLKTLKMTV AFATSFTVCW TPYYVLGIWY WFDPEMLNRL 

       310        320 
SDPVNHFFFL FAFLNPCFDP LIYGYFSL 

« Hide

Isoform 2 (Truncated) [UniParc].

Checksum: 5801B1C5E5FBA64A
Show »

FASTA24927,727

References

« Hide 'large scale' references
[1]"Cloning, sequencing, and expression of human gonadotropin releasing hormone (GnRH) receptor."
Kakar S.S., Musgrove L.C., Devor D.C., Sellers J.C., Neill J.D.
Biochem. Biophys. Res. Commun. 189:289-295(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Tissue: Pituitary.
[2]"Cloning and characterization of the human GnRH receptor."
Chi L., Zhou W., Prikhozhan A., Flanagan C.A., Davidson J.S., Golembo M., Illing N., Millar R.P., Sealfon S.C.
Mol. Cell. Endocrinol. 91:R1-R6(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Tissue: Pituitary.
[3]"The nucleotide sequences of human GnRH receptors in breast and ovarian tumors are identical with that found in pituitary."
Kakar S.S., Grizzle W.E., Neill J.D.
Mol. Cell. Endocrinol. 106:145-149(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[4]"Molecular structure of the human gonadotropin-releasing hormone receptor gene."
Kakar S.S.
Eur. J. Endocrinol. 137:183-192(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
[5]"Inhibition of gonadotropin-releasing hormone receptor signaling by expression of a splice variant of the human receptor."
Grosse R., Schoneberg T., Schultz G., Gudermann T.
Mol. Endocrinol. 11:1305-1318(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
Tissue: Pituitary.
[6]"cDNA clones of human proteins involved in signal transduction sequenced by the Guthrie cDNA resource center (www.cdna.org)."
Kopatz S.A., Aronstam R.S., Sharma S.V.
Submitted (SEP-2003) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Tissue: Testis.
[7]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[8]"Tissue-specific pattern of variant transcripts of the human gonadotropin-releasing hormone receptor gene."
Kottler M.L., Bergametti F., Carre M.C., Morice S., Decoret E., Lagarde J.P., Starzec A., Counis R.
Eur. J. Endocrinol. 140:561-569(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 247-328 (ISOFORM 1).
[9]"A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor."
de Roux N., Young J., Misrahi M., Genet R., Chanson P., Schaison G., Milgrom E.
N. Engl. J. Med. 337:1597-1602(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS HH7 ARG-106 AND GLN-262.
[10]"Mutations in gonadotropin-releasing hormone receptor gene cause hypogonadotropic hypogonadism."
Layman L.C., Cohen D.P., Jin M., Xie J., Li Z., Reindollar R.H., Bolbolan S., Bick D.P., Sherins R.R., Duck L.W., Musgrove L.C., Sellers J.C., Neill J.D.
Nat. Genet. 18:14-15(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS HH7 GLN-262 AND CYS-284, CHARACTERIZATION OF VARIANTS HH7 GLN-262 AND CYS-284.
[11]"The same molecular defects of the gonadotropin-releasing hormone receptor determine a variable degree of hypogonadism in affected kindred."
de Roux N., Young J., Brailly-Tabard S., Misrahi M., Milgrom E., Schaison G.
J. Clin. Endocrinol. Metab. 84:567-572(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS HH7 ARG-106; ARG-217 AND GLN-262, CHARACTERIZATION OF VARIANTS HH7 ARG-106; ARG-217 AND GLN-262.
[12]"Resistance of hypogonadic patients with mutated GnRH receptor genes to pulsatile GnRH administration."
Caron P., Chauvin S., Christin-Maitre S., Bennet A., Lahlou N., Counis R., Bouchard P., Kottler M.-L.
J. Clin. Endocrinol. Metab. 84:990-996(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS HH7 ASP-129 AND GLN-262, CHARACTERIZATION OF VARIANT HH7 ASP-129.
[13]"Complete hypogonadotropic hypogonadism associated with a novel inactivating mutation of the gonadotropin-releasing hormone receptor."
Pralong F.P., Gomez F., Castillo E., Cotecchia S., Abuin L., Aubert M.L., Portmann L., Gaillard R.C.
J. Clin. Endocrinol. Metab. 84:3811-3816(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT HH7 ARG-168, CHARACTERIZATION OF VARIANT HH7 ARG-168.
[14]"The fertile eunuch variant of idiopathic hypogonadotropic hypogonadism: spontaneous reversal associated with a homozygous mutation in the gonadotropin-releasing hormone receptor."
Pitteloud N., Boepple P.A., DeCruz S., Valkenburgh S.B., Crowley W.F. Jr., Hayes F.J.
J. Clin. Endocrinol. Metab. 86:2470-2475(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT FEUNS ARG-106.
[15]"A novel homozygous mutation in the second transmembrane domain of the gonadotrophin releasing hormone receptor gene."
Soederlund D., Canto P., de la Chesnaye E., Ulloa-Aguirre A., Mendez J.P.
Clin. Endocrinol. (Oxf.) 54:493-498(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT HH7 LYS-90.
[16]"Two novel mutations in the gonadotropin-releasing hormone receptor gene in Brazilian patients with hypogonadotropic hypogonadism and normal olfaction."
Costa E.M.F., Bedecarrats G.Y., Mendonca B.B., Arnhold I.J.P., Kaiser U.B., Latronico A.C.
J. Clin. Endocrinol. Metab. 86:2680-2686(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS HH7 LYS-10; ARG-106 AND HIS-139, CHARACTERIZATION OF VARIANTS HH7 LYS-10; ARG-106 AND HIS-139.
[17]"Molecular basis of hypogonadotropic hypogonadism: restoration of mutant (E(90)K) GnRH receptor function by a deletion at a distant site."
Maya-Nunez G., Janovick J.A., Ulloa-Aguirre A., Soederlund D., Conn P.M., Mendez J.P.
J. Clin. Endocrinol. Metab. 87:2144-2149(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: CHARACTERIZATION OF VARIANT HH7 LYS-90.
[18]"Mutation Ala(171)Thr stabilizes the gonadotropin-releasing hormone receptor in its inactive conformation, causing familial hypogonadotropic hypogonadism."
Karges B., Karges W., Mine M., Ludwig L., Kuehne R., Milgrom E., de Roux N.
J. Clin. Endocrinol. Metab. 88:1873-1879(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT HH7 THR-171, CHARACTERIZATION OF VARIANT HH7 THR-171.
[19]"Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism."
Miraoui H., Dwyer A.A., Sykiotis G.P., Plummer L., Chung W., Feng B., Beenken A., Clarke J., Pers T.H., Dworzynski P., Keefe K., Niedziela M., Raivio T., Crowley W.F. Jr., Seminara S.B., Quinton R., Hughes V.A., Kumanov P. expand/collapse author list , Young J., Yialamas M.A., Hall J.E., Van Vliet G., Chanoine J.P., Rubenstein J., Mohammadi M., Tsai P.S., Sidis Y., Lage K., Pitteloud N.
Am. J. Hum. Genet. 92:725-743(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS HH7 VAL-83; ARG-106 AND GLN-262.
+Additional computationally mapped references.

Web resources

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
L03380 mRNA. Translation: AAA35918.1.
L07949 mRNA. Translation: AAA35917.1.
S60587 mRNA. Translation: AAB26287.1.
S77472 mRNA. Translation: AAB33884.1.
AF001952, AF001950, AF001951 Genomic DNA. Translation: AAB71348.1.
Z81148 mRNA. Translation: CAB03541.1.
AY392011 mRNA. Translation: AAR92228.1.
BC113546 mRNA. Translation: AAI13547.1.
Z99995 Genomic DNA. Translation: CAB17082.1.
PIRJC1353.
RefSeqNP_000397.1. NM_000406.2.
NP_001012781.1. NM_001012763.1.
UniGeneHs.407587.

3D structure databases

ProteinModelPortalP30968.
SMRP30968. Positions 21-327.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid109060. 1 interaction.
STRING9606.ENSP00000226413.

Chemistry

BindingDBP30968.
ChEMBLCHEMBL1855.
DrugBankDB00106. Abarelix.
DB00050. Cetrorelix.
DB01406. Danazol.
DB00644. Gonadorelin.
DB00007. Leuprolide.
DB00666. Nafarelin.
GuidetoPHARMACOLOGY256.

Protein family/group databases

TCDB9.A.14.10.1. the g-protein-coupled receptor (gpcr) family.
GPCRDBSearch...

Polymorphism databases

DMDM399777.

Proteomic databases

PaxDbP30968.
PRIDEP30968.

Protocols and materials databases

DNASU2798.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000226413; ENSP00000226413; ENSG00000109163. [P30968-1]
ENST00000420975; ENSP00000397561; ENSG00000109163. [P30968-2]
GeneID2798.
KEGGhsa:2798.
UCSCuc003hdm.3. human. [P30968-2]
uc003hdn.3. human. [P30968-1]

Organism-specific databases

CTD2798.
GeneCardsGC04M068608.
HGNCHGNC:4421. GNRHR.
MIM138850. gene.
146110. phenotype.
228300. phenotype.
neXtProtNX_P30968.
Orphanet432. Normosmic congenital hypogonadotropic hypogonadism.
PharmGKBPA28800.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG277514.
HOGENOMHOG000251590.
HOVERGENHBG009082.
InParanoidP30968.
KOK04280.
OMAATSFTVC.
OrthoDBEOG71G9V8.
PhylomeDBP30968.
TreeFamTF106499.

Enzyme and pathway databases

ReactomeREACT_111102. Signal Transduction.

Gene expression databases

BgeeP30968.
CleanExHS_GNRHR.
GenevestigatorP30968.

Family and domain databases

Gene3D1.20.1070.10. 1 hit.
InterProIPR000276. GPCR_Rhodpsn.
IPR017452. GPCR_Rhodpsn_7TM.
IPR001658. GphnRH_fam_rcpt.
IPR027982. GphnRH_rcpt.
[Graphical view]
PANTHERPTHR24241:SF33. PTHR24241:SF33. 1 hit.
PfamPF00001. 7tm_1. 1 hit.
[Graphical view]
PRINTSPR00529. GNADOTRPHINR.
PR00237. GPCRRHODOPSN.
PROSITEPS00237. G_PROTEIN_RECEP_F1_1. 1 hit.
PS50262. G_PROTEIN_RECEP_F1_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GeneWikiGNRHR.
GenomeRNAi2798.
NextBio11027.
PROP30968.
SOURCESearch...

Entry information

Entry nameGNRHR_HUMAN
AccessionPrimary (citable) accession number: P30968
Secondary accession number(s): O75793, Q14D13, Q92644
Entry history
Integrated into UniProtKB/Swiss-Prot: July 1, 1993
Last sequence update: July 1, 1993
Last modified: April 16, 2014
This is version 140 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 4

Human chromosome 4: entries, gene names and cross-references to MIM

7-transmembrane G-linked receptors

List of 7-transmembrane G-linked receptor entries