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 13-FEB-2019, entry version 174. 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; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; 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 RT of gonadotropin-releasing hormone and prolactin release-inhibiting RT factor in 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 RT project: 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 RP AMIDATION 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 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 RT mutation."; RL N. Engl. J. Med. 360:2742-2748(2009). RN [7] 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., RA Paternostre M., 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 [8] 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 RT of human genes."; RL Nat. Genet. 22:231-238(1999). RN [9] 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 [10] 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., RA Niedziela M., Raivio T., Crowley W.F. Jr., Seminara S.B., Quinton R., RA Hughes V.A., Kumanov P., Young J., Yialamas M.A., Hall J.E., RA Van Vliet G., Chanoine J.P., Rubenstein J., Mohammadi M., Tsai P.S., RA Sidis Y., Lage K., 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 CC the secretion of both luteinizing and follicle-stimulating CC hormones. CC -!- SUBCELLULAR LOCATION: Secreted. CC -!- DISEASE: Hypogonadotropic hypogonadism 12 with or without anosmia CC (HH12) [MIM:614841]: A disorder characterized by absent or CC incomplete sexual maturation by the age of 18 years, in CC conjunction with low levels of circulating gonadotropins and CC testosterone and no other abnormalities of the hypothalamic- CC pituitary axis. In some cases, it is associated with non- CC reproductive phenotypes, such as anosmia, cleft palate, and CC sensorineural hearing loss. Anosmia or hyposmia is related to the CC absence or hypoplasia of the olfactory bulbs and tracts. CC Hypogonadism is due to deficiency in gonadotropin-releasing CC hormone and probably results from a failure of embryonic migration CC of gonadotropin-releasing hormone-synthesizing neurons. In the CC presence of anosmia, idiopathic hypogonadotropic hypogonadism is CC referred to as Kallmann syndrome, whereas in the presence of a CC normal sense of smell, it has been termed normosmic idiopathic CC hypogonadotropic hypogonadism (nIHH). CC {ECO:0000269|PubMed:19535795, ECO:0000269|PubMed:23643382}. CC Note=The disease is caused by mutations affecting distinct genetic CC loci, including the gene represented in this entry. The genetics CC of hypogonadotropic hypogonadism involves various modes of CC transmission. Oligogenic inheritance has been reported in some CC patients carrying mutations in GNRH1 as well as in other HH- CC associated genes including PROKR2 and FGFR1 (PubMed:23643382). CC {ECO:0000269|PubMed:23643382}. CC -!- PHARMACEUTICAL: Available under the names Factrel (Ayerst Labs), CC Lutrepulse or Lutrelef (Ferring Pharmaceuticals) and Relisorm CC (Serono). Used in evaluating hypothalamic-pituitary gonadotropic CC function. CC -!- MISCELLANEOUS: The 3D-structure was determined for the synthetic CC analog 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"; 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; 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 UniGene; Hs.82963; -. DR PDB; 4D5M; X-ray; 0.85 A; A/B/C/D=24-33. DR PDBsum; 4D5M; -. DR ProteinModelPortal; P01148; -. DR SMR; P01148; -. DR BioGrid; 109058; 8. DR STRING; 9606.ENSP00000276414; -. DR BioMuta; GNRH1; -. DR DMDM; 121522; -. DR PaxDb; P01148; -. DR PeptideAtlas; P01148; -. DR PRIDE; P01148; -. DR ProteomicsDB; 51339; -. DR DNASU; 2796; -. DR Ensembl; ENST00000276414; ENSP00000276414; ENSG00000147437. DR Ensembl; ENST00000421054; ENSP00000391280; ENSG00000147437. DR GeneID; 2796; -. DR KEGG; hsa:2796; -. DR UCSC; uc003xem.5; human. DR CTD; 2796; -. DR DisGeNET; 2796; -. DR EuPathDB; HostDB:ENSG00000147437.9; -. DR GeneCards; GNRH1; -. DR GeneReviews; GNRH1; -. DR HGNC; HGNC:4419; GNRH1. DR HPA; HPA027532; -. 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 eggNOG; ENOG410J18B; Eukaryota. DR eggNOG; ENOG410ZDKS; LUCA. DR GeneTree; ENSGT00390000008225; -. DR HOGENOM; HOG000033698; -. DR HOVERGEN; HBG014746; -. DR InParanoid; P01148; -. DR KO; K05252; -. DR OMA; SGQHWSY; -. DR OrthoDB; 1247924at2759; -. DR PhylomeDB; P01148; -. DR TreeFam; TF330934; -. DR Reactome; R-HSA-375281; Hormone ligand-binding receptors. DR Reactome; R-HSA-416476; G alpha (q) signalling events. DR SIGNOR; P01148; -. DR GeneWiki; Gonadotropin-releasing_hormone; -. DR GenomeRNAi; 2796; -. DR PMAP-CutDB; P01148; -. DR PRO; PR:P01148; -. DR Proteomes; UP000005640; Chromosome 8. DR Bgee; ENSG00000147437; Expressed in 127 organ(s), highest expression level in tibial nerve. DR Genevisible; P01148; HS. DR GO; GO:0043679; C:axon terminus; IEA:Ensembl. DR GO; GO:0098556; C:cytoplasmic side of rough endoplasmic reticulum membrane; IEA:Ensembl. DR GO; GO:0030425; C:dendrite; IEA:Ensembl. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:0005615; C:extracellular space; IBA:GO_Central. DR GO; GO:0005798; C:Golgi-associated vesicle; IEA:Ensembl. DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl. DR GO; GO:1990008; C:neurosecretory vesicle; IEA:Ensembl. DR GO; GO:0043204; C:perikaryon; IEA:Ensembl. 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:0007568; P:aging; IEA:Ensembl. DR GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc. DR GO; GO:0044849; P:estrous cycle; IEA:Ensembl. DR GO; GO:0007565; P:female pregnancy; IEA:Ensembl. DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; TAS:Reactome. DR GO; GO:0030238; P:male sex determination; IEA:Ensembl. DR GO; GO:0007275; P:multicellular organism development; TAS:ProtInc. DR GO; GO:0043066; P:negative regulation of apoptotic process; IEA:Ensembl. DR GO; GO:0008285; P:negative regulation of cell population proliferation; TAS:ProtInc. DR GO; GO:0033087; P:negative regulation of immature T cell proliferation; IEA:Ensembl. 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:0031960; P:response to corticosteroid; IEA:Ensembl. DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl. DR GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl. DR GO; GO:0035864; P:response to potassium ion; IEA:Ensembl. DR GO; GO:1990637; P:response to prolactin; IEA:Ensembl. DR GO; GO:0034695; P:response to prostaglandin E; IEA:Ensembl. DR GO; GO:0033574; P:response to testosterone; IEA:Ensembl. DR GO; GO:0007165; P:signal transduction; TAS:ProtInc. DR InterPro; IPR002012; GnRH. DR InterPro; IPR019792; Gonadoliberin_I. DR InterPro; IPR004079; Gonadoliberin_I_precursor. DR PANTHER; PTHR10522; PTHR10522; 1. DR PANTHER; PTHR10522:SF0; PTHR10522:SF0; 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 Complete proteome; Direct protein sequencing; Disease mutation; KW Hormone; Hypogonadotropic hypogonadism; Kallmann syndrome; KW Pharmaceutical; Polymorphism; Pyrrolidone carboxylic acid; KW Reference proteome; Secreted; Signal. FT SIGNAL 1 23 {ECO:0000269|PubMed:6760865}. FT CHAIN 24 92 Progonadoliberin-1. FT /FTId=PRO_0000012395. FT PEPTIDE 24 33 Gonadoliberin-1. FT {ECO:0000269|PubMed:6760865}. FT /FTId=PRO_0000012396. FT PEPTIDE 37 92 GnRH-associated peptide 1. FT /FTId=PRO_0000012397. FT SITE 26 26 Appears to be essential for biological FT activity. FT MOD_RES 24 24 Pyrrolidone carboxylic acid. FT {ECO:0000269|PubMed:6760865}. FT MOD_RES 33 33 Glycine amide. FT {ECO:0000269|PubMed:6760865}. FT VARIANT 16 16 W -> S (in dbSNP:rs6185). FT {ECO:0000269|PubMed:10391209, FT ECO:0000269|PubMed:6090951}. FT /FTId=VAR_013943. FT VARIANT 31 31 R -> C (in HH12; uncertain pathological FT significance; the patient also carries FT mutations in PROKR2 and FGFR1). FT {ECO:0000269|PubMed:23643382}. FT /FTId=VAR_069966. FT HELIX 26 28 {ECO:0000244|PDB:4D5M}. SQ SEQUENCE 92 AA; 10380 MW; 30A72221B076FA79 CRC64; MKPIQKLLAG LILLTWCVEG CSSQHWSYGL RPGGKRDAEN LIDSFQEIVK EVGQLAETQR FECTTHQPRS PLRDLKGALE SLIEEETGQK KI //