GON1_HUMAN
ID GON1_HUMAN Reviewed; 92 AA.
AC P01148; A0AVP0;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 01-APR-1988, sequence version 1.
DT 03-AUG-2022, entry version 189.
DE RecName: Full=Progonadoliberin-1;
DE AltName: Full=Progonadoliberin I;
DE Contains:
DE RecName: Full=Gonadoliberin-1;
DE AltName: Full=Gonadoliberin I;
DE AltName: Full=Gonadorelin;
DE AltName: Full=Gonadotropin-releasing hormone I;
DE Short=GnRH-I;
DE AltName: Full=Luliberin I;
DE AltName: Full=Luteinizing hormone-releasing hormone I;
DE Short=LH-RH I;
DE Contains:
DE RecName: Full=GnRH-associated peptide 1;
DE AltName: Full=GnRH-associated peptide I;
DE Flags: Precursor;
GN Name=GNRH1; Synonyms=GNRH, GRH, LHRH;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2671939; DOI=10.1093/nar/17.15.6403;
RA Hayflick J.S., Adelman J.P., Seeburg P.H.;
RT "The complete nucleotide sequence of the human gonadotropin-releasing
RT hormone gene.";
RL Nucleic Acids Res. 17:6403-6403(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2867548; DOI=10.1073/pnas.83.1.179;
RA Adelman J.P., Mason A.J., Hayflick J.S., Seeburg P.H.;
RT "Isolation of the gene and hypothalamic cDNA for the common precursor of
RT gonadotropin-releasing hormone and prolactin release-inhibiting factor in
RT human and rat.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:179-183(1986).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT SER-16.
RX PubMed=6090951; DOI=10.1038/311666a0;
RA Seeburg P.H., Adelman J.P.;
RT "Characterization of cDNA for precursor of human luteinizing hormone
RT releasing hormone.";
RL Nature 311:666-668(1984).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP PROTEIN SEQUENCE OF 24-33, PYROGLUTAMATE FORMATION AT GLN-24, AND AMIDATION
RP AT GLY-33.
RX PubMed=6760865; DOI=10.1016/0006-291x(82)92047-2;
RA Tan L., Rousseau P.;
RT "The chemical identity of the immunoreactive LHRH-like peptide
RT biosynthesized in the human placenta.";
RL Biochem. Biophys. Res. Commun. 109:1061-1071(1982).
RN [6]
RP PROTEOLYTIC CLEAVAGE (GONADOLIBERIN-1).
RX PubMed=2983326; DOI=10.1073/pnas.82.4.1025;
RA Skidgel R.A., Erdoes E.G.;
RT "Novel activity of human angiotensin I converting enzyme: release of the
RT NH2- and COOH-terminal tripeptides from the luteinizing hormone-releasing
RT hormone.";
RL Proc. Natl. Acad. Sci. U.S.A. 82:1025-1029(1985).
RN [7]
RP PROTEOLYTIC CLEAVAGE (GONADOLIBERIN-1).
RX PubMed=10336644; DOI=10.1046/j.1432-1327.1999.00419.x;
RA Isaac R.E., Michaud A., Keen J.N., Williams T.A., Coates D., Wetsel W.C.,
RA Corvol P.;
RT "Hydrolysis by somatic angiotensin-I converting enzyme of basic dipeptides
RT from a cholecystokinin/gastrin and a LH-RH peptide extended at the C-
RT terminus with gly-Arg/Lys-arg, but not from diarginyl insulin.";
RL Eur. J. Biochem. 262:569-574(1999).
RN [8]
RP PROTEOLYTIC CLEAVAGE (GONADOLIBERIN-1).
RX PubMed=7683654; DOI=10.1016/s0021-9258(18)98378-x;
RA Jaspard E., Wei L., Alhenc-Gelas F.;
RT "Differences in the properties and enzymatic specificities of the two
RT active sites of angiotensin I-converting enzyme (kininase II). Studies with
RT bradykinin and other natural peptides.";
RL J. Biol. Chem. 268:9496-9503(1993).
RN [9]
RP INVOLVEMENT IN HH12.
RX PubMed=19535795; DOI=10.1056/nejmoa0900136;
RA Bouligand J., Ghervan C., Tello J.A., Brailly-Tabard S., Salenave S.,
RA Chanson P., Lombes M., Millar R.P., Guiochon-Mantel A., Young J.;
RT "Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation.";
RL N. Engl. J. Med. 360:2742-2748(2009).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (0.85 ANGSTROMS) OF 24-33.
RX PubMed=26190377; DOI=10.1038/ncomms8771;
RA Valery C., Deville-Foillard S., Lefebvre C., Taberner N., Legrand P.,
RA Meneau F., Meriadec C., Delvaux C., Bizien T., Kasotakis E.,
RA Lopez-Iglesias C., Gall A., Bressanelli S., Le Du M.H., Paternostre M.,
RA Artzner F.;
RT "Atomic view of the histidine environment stabilizing higher-pH
RT conformations of pH-dependent proteins.";
RL Nat. Commun. 6:7771-7771(2015).
RN [11]
RP VARIANT SER-16.
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 of
RT human genes.";
RL Nat. Genet. 22:231-238(1999).
RN [12]
RP ERRATUM OF PUBMED:10391209.
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 [13]
RP VARIANT HH12 CYS-31.
RX PubMed=23643382; DOI=10.1016/j.ajhg.2013.04.008;
RA Miraoui H., Dwyer A.A., Sykiotis G.P., Plummer L., Chung W., Feng B.,
RA Beenken A., Clarke J., Pers T.H., Dworzynski P., Keefe K., Niedziela M.,
RA Raivio T., Crowley W.F. Jr., Seminara S.B., Quinton R., Hughes V.A.,
RA Kumanov P., Young J., Yialamas M.A., Hall J.E., Van Vliet G.,
RA Chanoine J.P., Rubenstein J., Mohammadi M., Tsai P.S., Sidis Y., Lage K.,
RA Pitteloud N.;
RT "Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in
RT individuals with congenital hypogonadotropic hypogonadism.";
RL Am. J. Hum. Genet. 92:725-743(2013).
CC -!- FUNCTION: Stimulates the secretion of gonadotropins; it stimulates the
CC secretion of both luteinizing and follicle-stimulating hormones.
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- PTM: [Gonadoliberin-1]: The precursor is cleaved by ACE, which removes
CC the Gly-Lys-Arg peptide at the C-terminus, leading to mature hormone
CC (PubMed:10336644, PubMed:7683654). The mature form of Gonadoliberin-1
CC is also cleaved and degraded by ACE (PubMed:2983326, PubMed:7683654).
CC {ECO:0000269|PubMed:10336644, ECO:0000269|PubMed:2983326,
CC ECO:0000269|PubMed:7683654}.
CC -!- DISEASE: Hypogonadotropic hypogonadism 12 with or without anosmia
CC (HH12) [MIM:614841]: A disorder characterized by absent or incomplete
CC sexual maturation by the age of 18 years, in conjunction with low
CC levels of circulating gonadotropins and testosterone and no other
CC abnormalities of the hypothalamic-pituitary axis. In some cases, it is
CC associated with non-reproductive phenotypes, such as anosmia, cleft
CC palate, and sensorineural hearing loss. Anosmia or hyposmia is related
CC to the absence or hypoplasia of the olfactory bulbs and tracts.
CC Hypogonadism is due to deficiency in gonadotropin-releasing hormone and
CC probably results from a failure of embryonic migration of gonadotropin-
CC releasing hormone-synthesizing neurons. In the presence of anosmia,
CC idiopathic hypogonadotropic hypogonadism is referred to as Kallmann
CC syndrome, whereas in the presence of a normal sense of smell, it has
CC been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH).
CC {ECO:0000269|PubMed:19535795, ECO:0000269|PubMed:23643382}. Note=The
CC disease is caused by variants affecting distinct genetic loci,
CC including the gene represented in this entry. The genetics of
CC hypogonadotropic hypogonadism involves various modes of transmission.
CC Oligogenic inheritance has been reported in some patients carrying
CC mutations in GNRH1 as well as in other HH-associated genes including
CC PROKR2 and FGFR1 (PubMed:23643382). {ECO:0000269|PubMed:23643382}.
CC -!- PHARMACEUTICAL: Available under the names Factrel (Ayerst Labs),
CC Lutrepulse or Lutrelef (Ferring Pharmaceuticals) and Relisorm (Serono).
CC Used in evaluating hypothalamic-pituitary gonadotropic function.
CC -!- MISCELLANEOUS: The 3D-structure was determined for the synthetic analog
CC Triptorelin. {ECO:0000269|PubMed:26190377}.
CC -!- SIMILARITY: Belongs to the GnRH family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Gonadotropin-releasing hormone
CC entry;
CC URL="https://en.wikipedia.org/wiki/Gonadotropin-releasing_hormone";
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DR EMBL; X01059; CAA25526.1; -; mRNA.
DR EMBL; M12578; AAA35916.1; -; mRNA.
DR EMBL; X15215; CAA33285.1; -; Genomic_DNA.
DR EMBL; BC126437; AAI26438.1; -; mRNA.
DR EMBL; BC126463; AAI26464.1; -; mRNA.
DR CCDS; CCDS43725.1; -.
DR PIR; S05308; RHHUG.
DR RefSeq; NP_001076580.1; NM_001083111.1.
DR PDB; 4D5M; X-ray; 0.85 A; A/B/C/D=24-33.
DR PDBsum; 4D5M; -.
DR AlphaFoldDB; P01148; -.
DR SMR; P01148; -.
DR BioGRID; 109058; 10.
DR IntAct; P01148; 7.
DR STRING; 9606.ENSP00000276414; -.
DR BioMuta; GNRH1; -.
DR DMDM; 121522; -.
DR MassIVE; P01148; -.
DR PaxDb; P01148; -.
DR PeptideAtlas; P01148; -.
DR PRIDE; P01148; -.
DR Antibodypedia; 5376; 471 antibodies from 33 providers.
DR DNASU; 2796; -.
DR Ensembl; ENST00000276414.4; ENSP00000276414.4; ENSG00000147437.10.
DR Ensembl; ENST00000421054.7; ENSP00000391280.2; ENSG00000147437.10.
DR GeneID; 2796; -.
DR KEGG; hsa:2796; -.
DR MANE-Select; ENST00000421054.7; ENSP00000391280.2; NM_001083111.2; NP_001076580.1.
DR UCSC; uc003xem.5; human.
DR CTD; 2796; -.
DR DisGeNET; 2796; -.
DR GeneCards; GNRH1; -.
DR GeneReviews; GNRH1; -.
DR HGNC; HGNC:4419; GNRH1.
DR HPA; ENSG00000147437; Low tissue specificity.
DR MalaCards; GNRH1; -.
DR MIM; 152760; gene.
DR MIM; 614841; phenotype.
DR neXtProt; NX_P01148; -.
DR OpenTargets; ENSG00000147437; -.
DR Orphanet; 432; Normosmic congenital hypogonadotropic hypogonadism.
DR PharmGKB; PA28798; -.
DR VEuPathDB; HostDB:ENSG00000147437; -.
DR eggNOG; ENOG502S8C8; Eukaryota.
DR GeneTree; ENSGT00390000008225; -.
DR HOGENOM; CLU_2412553_0_0_1; -.
DR InParanoid; P01148; -.
DR OMA; ISSGQHW; -.
DR OrthoDB; 1556205at2759; -.
DR PhylomeDB; P01148; -.
DR TreeFam; TF330934; -.
DR PathwayCommons; P01148; -.
DR Reactome; R-HSA-375281; Hormone ligand-binding receptors.
DR Reactome; R-HSA-416476; G alpha (q) signalling events.
DR SignaLink; P01148; -.
DR SIGNOR; P01148; -.
DR BioGRID-ORCS; 2796; 16 hits in 1085 CRISPR screens.
DR GeneWiki; Gonadotropin-releasing_hormone; -.
DR GenomeRNAi; 2796; -.
DR Pharos; P01148; Tbio.
DR PRO; PR:P01148; -.
DR Proteomes; UP000005640; Chromosome 8.
DR RNAct; P01148; protein.
DR Bgee; ENSG00000147437; Expressed in tibial nerve and 105 other tissues.
DR Genevisible; P01148; HS.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:0005183; F:gonadotropin hormone-releasing hormone activity; IBA:GO_Central.
DR GO; GO:0031530; F:gonadotropin-releasing hormone receptor binding; IBA:GO_Central.
DR GO; GO:0005179; F:hormone activity; TAS:ProtInc.
DR GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc.
DR GO; GO:2001223; P:negative regulation of neuron migration; IEA:Ensembl.
DR GO; GO:0010468; P:regulation of gene expression; IEA:Ensembl.
DR GO; GO:2000354; P:regulation of ovarian follicle development; IEA:Ensembl.
DR GO; GO:0000003; P:reproduction; IBA:GO_Central.
DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl.
DR GO; GO:0048545; P:response to steroid hormone; IEA:Ensembl.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR InterPro; IPR002012; GnRH.
DR InterPro; IPR019792; Gonadoliberin.
DR InterPro; IPR004079; Gonadoliberin_I_precursor.
DR PANTHER; PTHR10522; PTHR10522; 1.
DR Pfam; PF00446; GnRH; 1.
DR PRINTS; PR01541; GONADOLIBRNI.
DR PROSITE; PS00473; GNRH; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Amidation; Cleavage on pair of basic residues;
KW Direct protein sequencing; Disease variant; Hormone;
KW Hypogonadotropic hypogonadism; Kallmann syndrome; Pharmaceutical;
KW Pyrrolidone carboxylic acid; Reference proteome; Secreted; Signal.
FT SIGNAL 1..23
FT /evidence="ECO:0000269|PubMed:6760865"
FT CHAIN 24..92
FT /note="Progonadoliberin-1"
FT /id="PRO_0000012395"
FT PEPTIDE 24..33
FT /note="Gonadoliberin-1"
FT /evidence="ECO:0000269|PubMed:6760865"
FT /id="PRO_0000012396"
FT PEPTIDE 37..92
FT /note="GnRH-associated peptide 1"
FT /id="PRO_0000012397"
FT SITE 26..27
FT /note="Cleavage; by ACE"
FT /evidence="ECO:0000269|PubMed:2983326"
FT SITE 26
FT /note="Appears to be essential for biological activity"
FT SITE 28..29
FT /note="Cleavage; by ACE"
FT /evidence="ECO:0000269|PubMed:2983326"
FT SITE 30..31
FT /note="Cleavage; by ACE"
FT /evidence="ECO:0000269|PubMed:2983326"
FT SITE 33..34
FT /note="Cleavage; by ACE"
FT /evidence="ECO:0000269|PubMed:10336644"
FT MOD_RES 24
FT /note="Pyrrolidone carboxylic acid"
FT /evidence="ECO:0000269|PubMed:6760865"
FT MOD_RES 33
FT /note="Glycine amide"
FT /evidence="ECO:0000269|PubMed:6760865"
FT VARIANT 16
FT /note="W -> S (in dbSNP:rs6185)"
FT /evidence="ECO:0000269|PubMed:10391209,
FT ECO:0000269|PubMed:6090951"
FT /id="VAR_013943"
FT VARIANT 31
FT /note="R -> C (in HH12; uncertain pathological
FT significance; the patient also carries mutations in PROKR2
FT and FGFR1)"
FT /evidence="ECO:0000269|PubMed:23643382"
FT /id="VAR_069966"
FT HELIX 26..28
FT /evidence="ECO:0007829|PDB:4D5M"
SQ SEQUENCE 92 AA; 10380 MW; 30A72221B076FA79 CRC64;
MKPIQKLLAG LILLTWCVEG CSSQHWSYGL RPGGKRDAEN LIDSFQEIVK EVGQLAETQR
FECTTHQPRS PLRDLKGALE SLIEEETGQK KI
