ID GDF9_HUMAN Reviewed; 454 AA. AC O60383; Q4VAW5; DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot. DT 01-AUG-1998, sequence version 1. DT 27-MAR-2024, entry version 177. DE RecName: Full=Growth/differentiation factor 9; DE Short=GDF-9; DE Flags: Precursor; GN Name=GDF9; 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 [LARGE SCALE GENOMIC DNA]. RX PubMed=15372022; DOI=10.1038/nature02919; RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S., RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M., RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M., RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T., RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R., RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L., RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N., RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.; RT "The DNA sequence and comparative analysis of human chromosome 5."; RL Nature 431:268-274(2004). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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 [3] RP TISSUE SPECIFICITY. RX PubMed=10443672; DOI=10.1210/jcem.84.8.5921; RA Aaltonen J., Laitinen M.P., Vuojolainen K., Jaatinen R., RA Horelli-Kuitunen N., Seppae L., Louhio H., Tuuri T., Sjoeberg J., RA Buetzow R., Hovatta O., Dale L., Ritvos O.; RT "Human growth differentiation factor 9 (GDF-9) and its novel homolog GDF-9B RT are expressed in oocytes during early folliculogenesis."; RL J. Clin. Endocrinol. Metab. 84:2744-2750(1999). RN [4] RP FUNCTION AS REGULATOR OF PROGESTERONE RELEASE, AND TISSUE SPECIFICITY. RX PubMed=12050262; DOI=10.1210/jcem.87.6.8551; RA Yamamoto N., Christenson L.K., McAllister J.M., Strauss J.F. III; RT "Growth differentiation factor-9 inhibits 3'5'-adenosine monophosphate- RT stimulated steroidogenesis in human granulosa and theca cells."; RL J. Clin. Endocrinol. Metab. 87:2849-2856(2002). RN [5] RP ERRATUM OF PUBMED:12050262. RA Yamamoto N., Christenson L.K., McAllister J.M., Strauss J.F. III; RL J. Clin. Endocrinol. Metab. 87:4495-4495(2002). RN [6] RP PHOSPHORYLATION. RX PubMed=18006624; DOI=10.1210/en.2007-1439; RA McMahon H.E., Sharma S., Shimasaki S.; RT "Phosphorylation of bone morphogenetic protein-15 and growth and RT differentiation factor-9 plays a critical role in determining agonistic or RT antagonistic functions."; RL Endocrinology 149:812-817(2008). RN [7] RP FUNCTION IN GRANULOSA CELLS PROLIFERATION. RX PubMed=19366876; DOI=10.1152/ajpendo.90929.2008; RA Huang Q., Cheung A.P., Zhang Y., Huang H.F., Auersperg N., Leung P.C.; RT "Effects of growth differentiation factor 9 on cell cycle regulators and RT ERK42/44 in human granulosa cell proliferation."; RL Am. J. Physiol. 296:E1344-E1353(2009). RN [8] RP PHOSPHORYLATION AT SER-325 BY CK, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=20067794; DOI=10.1016/j.febslet.2009.12.052; RA Tibaldi E., Arrigoni G., Martinez H.M., Inagaki K., Shimasaki S., RA Pinna L.A.; RT "Golgi apparatus casein kinase phosphorylates bioactive Ser-6 of bone RT morphogenetic protein 15 and growth and differentiation factor 9."; RL FEBS Lett. 584:801-805(2010). RN [9] RP FUNCTION AS REGULATOR OF STAR EXPRESSION AND PROGESTERONE RELEASE. RX PubMed=20660033; DOI=10.1210/jc.2010-0477; RA Shi F.T., Cheung A.P., Klausen C., Huang H.F., Leung P.C.; RT "Growth differentiation factor 9 reverses activin A suppression of RT steroidogenic acute regulatory protein expression and progesterone RT production in human granulosa-lutein cells."; RL J. Clin. Endocrinol. Metab. 95:E172-E180(2010). RN [10] RP FUNCTION IN PRIMORDIAL FOLLICLE DEVELOPMENT. RX PubMed=21632818; DOI=10.1210/jc.2011-0410; RA Kedem A., Fisch B., Garor R., Ben-Zaken A., Gizunterman T., Felz C., RA Ben-Haroush A., Kravarusic D., Abir R.; RT "Growth differentiating factor 9 (GDF9) and bone morphogenetic protein 15 RT both activate development of human primordial follicles in vitro, with RT seemingly more beneficial effects of GDF9."; RL J. Clin. Endocrinol. Metab. 96:E1246-E1254(2011). RN [11] RP FUNCTION. RX PubMed=21829661; DOI=10.1371/journal.pone.0022866; RA Shi F.T., Cheung A.P., Huang H.F., Leung P.C.; RT "Growth differentiation factor 9 (GDF9) suppresses follistatin and RT follistatin-like 3 production in human granulosa-lutein cells."; RL PLoS ONE 6:E22866-E22866(2011). RN [12] RP SPECIES-SPECIFIC OVULATION RATE DETERMINATION. RX PubMed=21970812; DOI=10.1016/j.mce.2011.09.033; RA Crawford J.L., McNatty K.P.; RT "The ratio of growth differentiation factor 9: bone morphogenetic protein RT 15 mRNA expression is tightly co-regulated and differs between species over RT a wide range of ovulation rates."; RL Mol. Cell. Endocrinol. 348:339-343(2012). RN [13] RP INVOLVEMENT IN POF14. RX PubMed=29044499; DOI=10.1111/cge.13156; RA Franca M.M., Funari M.F.A., Nishi M.Y., Narcizo A.M., Domenice S., RA Costa E.M.F., Lerario A.M., Mendonca B.B.; RT "Identification of the first homozygous 1-bp deletion in GDF9 gene leading RT to primary ovarian insufficiency by using targeted massively parallel RT sequencing."; RL Clin. Genet. 93:408-411(2018). RN [14] RP VARIANTS POF14 GLU-67 AND MET-216, AND INVOLVEMENT IN POF14. RX PubMed=16278619; DOI=10.1097/01.gme.0000184424.96437.7a; RA Dixit H., Rao L.K., Padmalatha V., Kanakavalli M., Deenadayal M., Gupta N., RA Chakravarty B., Singh L.; RT "Mutational screening of the coding region of growth differentiation factor RT 9 gene in Indian women with ovarian failure."; RL Menopause 12:749-754(2005). RN [15] RP VARIANT POF14 TYR-186, AND INVOLVEMENT IN POF14. RX PubMed=16645022; DOI=10.1530/eje.1.02135; RA Laissue P., Christin-Maitre S., Touraine P., Kuttenn F., Ritvos O., RA Aittomaki K., Bourcigaux N., Jacquesson L., Bouchard P., Frydman R., RA Dewailly D., Reyss A.-C., Jeffery L., Bachelot A., Massin N., Fellous M., RA Veitia R.A.; RT "Mutations and sequence variants in GDF9 and BMP15 in patients with RT premature ovarian failure."; RL Eur. J. Endocrinol. 154:739-744(2006). RN [16] RP VARIANT POF14 SER-103, VARIANTS ILE-121; LEU-374 AND CYS-454, AND POSSIBLE RP INVOLVEMENT IN DIZYGOTIC TWINNING. RX PubMed=16954162; DOI=10.1210/jc.2006-0970; RA Palmer J.S., Zhao Z.Z., Hoekstra C., Hayward N.K., Webb P.M., RA Whiteman D.C., Martin N.G., Boomsma D.I., Duffy D.L., Montgomery G.W.; RT "Novel variants in growth differentiation factor 9 in mothers of dizygotic RT twins."; RL J. Clin. Endocrinol. Metab. 91:4713-4716(2006). RN [17] RP VARIANT POF14 SER-103. RX PubMed=17156781; DOI=10.1016/j.fertnstert.2006.05.079; RA Kovanci E., Rohozinski J., Simpson J.L., Heard M.J., Bishop C.E., RA Carson S.A.; RT "Growth differentiating factor-9 mutations may be associated with premature RT ovarian failure."; RL Fertil. Steril. 87:143-146(2007). RN [18] RP VARIANTS POF14 CYS-146; ALA-238 AND THR-428. RX PubMed=17482612; DOI=10.1016/j.fertnstert.2007.01.021; RA Zhao H., Qin Y., Kovanci E., Simpson J.L., Chen Z.J., Rajkovic A.; RT "Analyses of GDF9 mutation in 100 Chinese women with premature ovarian RT failure."; RL Fertil. Steril. 88:1474-1476(2007). RN [19] RP VARIANT POF14 TYR-57. RX PubMed=19438907; DOI=10.1111/j.1365-2265.2009.03613.x; RA Wang B., Wen Q., Ni F., Zhou S., Wang J., Cao Y., Ma X.; RT "Analyses of growth differentiation factor 9 (GDF9) and bone morphogenetic RT protein 15 (BMP15) mutation in Chinese women with premature ovarian RT failure."; RL Clin. Endocrinol. (Oxf.) 72:135-136(2010). CC -!- FUNCTION: Required for ovarian folliculogenesis. Promotes primordial CC follicle development. Stimulates granulosa cell proliferation. Promotes CC cell transition from G0/G1 to S and G2/M phases, through an increase of CC CCND1 and CCNE1 expression, and RB1 phosphorylation. It regulates STAR CC expression and cAMP-dependent progesterone release in granulosa and CC thecal cells. Attenuates the suppressive effects of activin A on STAR CC expression and progesterone production by increasing the expression of CC inhibin B. It suppresses FST and FSTL3 production in granulosa-lutein CC cells. {ECO:0000269|PubMed:12050262, ECO:0000269|PubMed:19366876, CC ECO:0000269|PubMed:20660033, ECO:0000269|PubMed:21632818, CC ECO:0000269|PubMed:21829661}. CC -!- SUBUNIT: Homodimer or heterodimer (Potential). But, in contrast to CC other members of this family, cannot be disulfide-linked (By CC similarity). {ECO:0000250, ECO:0000305}. CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250}. CC -!- TISSUE SPECIFICITY: Expressed in ovarian granulosa cells. Present in CC oocytes of primary follicles (at protein level). CC {ECO:0000269|PubMed:10443672, ECO:0000269|PubMed:12050262}. CC -!- PTM: Phosphorylated; phosphorylation is critical for GDF9 function. In CC vitro, can be phosphorylated by CK at Ser-325. CC {ECO:0000269|PubMed:18006624, ECO:0000269|PubMed:20067794}. CC -!- DISEASE: Note=Altered GDF9 function may be involved in ovarian CC disorders and contribute to the likelihood of dizygotic twinning. CC {ECO:0000269|PubMed:16954162}. CC -!- DISEASE: Premature ovarian failure 14 (POF14) [MIM:618014]: An ovarian CC disorder defined as the cessation of ovarian function under the age of CC 40 years. It is characterized by oligomenorrhea or amenorrhea, in the CC presence of elevated levels of serum gonadotropins and low estradiol. CC {ECO:0000269|PubMed:16278619, ECO:0000269|PubMed:16645022, CC ECO:0000269|PubMed:16954162, ECO:0000269|PubMed:17156781, CC ECO:0000269|PubMed:17482612, ECO:0000269|PubMed:19438907, CC ECO:0000269|PubMed:29044499}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- MISCELLANEOUS: Ovarian physiology and fertility are controlled by CC endocrine and paracrine signals. These act in a species-dependent CC manner and determine the ovulation quota in different mammalian CC species. While humans, and mammals such as the cow or red deer, CC normally ovulate only one egg per cycle, other mammals such as mouse CC and pig can ovulate in excess of ten per cycle. The mechanisms that CC regulate the species-specific differences in the number of follicles CC that go onto ovulate during each reproductive cycle are poorly CC understood. According to PubMed:21970812, mRNA expression levels of CC GDF9 and BMP15 are tightly coregulated within each species and CC influence species-specific ovulation-rates. CC -!- SIMILARITY: Belongs to the TGF-beta family. {ECO:0000305}. 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; AC004500; AAC08450.1; -; Genomic_DNA. DR EMBL; BC096228; AAH96228.1; -; mRNA. DR EMBL; BC096229; AAH96229.1; -; mRNA. DR EMBL; BC096230; AAH96230.1; -; mRNA. DR EMBL; BC096231; AAH96231.1; -; mRNA. DR CCDS; CCDS4162.1; -. DR RefSeq; NP_001275753.1; NM_001288824.2. DR RefSeq; NP_005251.1; NM_005260.5. DR RefSeq; XP_011541610.1; XM_011543308.2. DR AlphaFoldDB; O60383; -. DR BioGRID; 108930; 58. DR IntAct; O60383; 50. DR MINT; O60383; -. DR STRING; 9606.ENSP00000367942; -. DR GlyCosmos; O60383; 6 sites, No reported glycans. DR GlyGen; O60383; 6 sites. DR iPTMnet; O60383; -. DR PhosphoSitePlus; O60383; -. DR BioMuta; GDF9; -. DR MassIVE; O60383; -. DR PaxDb; 9606-ENSP00000367942; -. DR PeptideAtlas; O60383; -. DR ProteomicsDB; 49386; -. DR Antibodypedia; 26178; 633 antibodies from 32 providers. DR DNASU; 2661; -. DR Ensembl; ENST00000378673.2; ENSP00000367942.2; ENSG00000164404.9. DR Ensembl; ENST00000464378.2; ENSP00000509893.1; ENSG00000164404.9. DR Ensembl; ENST00000687138.1; ENSP00000510441.1; ENSG00000164404.9. DR GeneID; 2661; -. DR KEGG; hsa:2661; -. DR MANE-Select; ENST00000687138.1; ENSP00000510441.1; NM_005260.7; NP_005251.1. DR UCSC; uc003kxz.3; human. DR AGR; HGNC:4224; -. DR CTD; 2661; -. DR DisGeNET; 2661; -. DR GeneCards; GDF9; -. DR HGNC; HGNC:4224; GDF9. DR HPA; ENSG00000164404; Tissue enhanced (testis). DR MalaCards; GDF9; -. DR MIM; 601918; gene. DR MIM; 618014; phenotype. DR neXtProt; NX_O60383; -. DR OpenTargets; ENSG00000164404; -. DR Orphanet; 619; NON RARE IN EUROPE: Primary ovarian failure. DR PharmGKB; PA28639; -. DR VEuPathDB; HostDB:ENSG00000164404; -. DR eggNOG; KOG3900; Eukaryota. DR GeneTree; ENSGT00940000159784; -. DR InParanoid; O60383; -. DR OMA; TWRICVC; -. DR OrthoDB; 5301288at2759; -. DR PhylomeDB; O60383; -. DR TreeFam; TF351788; -. DR PathwayCommons; O60383; -. DR SignaLink; O60383; -. DR BioGRID-ORCS; 2661; 7 hits in 1145 CRISPR screens. DR ChiTaRS; GDF9; human. DR GeneWiki; Growth_differentiation_factor-9; -. DR GenomeRNAi; 2661; -. DR Pharos; O60383; Tbio. DR PRO; PR:O60383; -. DR Proteomes; UP000005640; Chromosome 5. DR RNAct; O60383; Protein. DR Bgee; ENSG00000164404; Expressed in oocyte and 102 other cell types or tissues. DR ExpressionAtlas; O60383; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IEA:Ensembl. DR GO; GO:0005615; C:extracellular space; IBA:GO_Central. DR GO; GO:0005125; F:cytokine activity; IBA:GO_Central. DR GO; GO:0008083; F:growth factor activity; TAS:ProtInc. DR GO; GO:0007292; P:female gamete generation; TAS:ProtInc. DR GO; GO:0030308; P:negative regulation of cell growth; IEA:Ensembl. DR GO; GO:0001555; P:oocyte growth; IEA:Ensembl. DR GO; GO:0008284; P:positive regulation of cell population proliferation; IDA:UniProtKB. DR GO; GO:2000870; P:regulation of progesterone secretion; IDA:UniProtKB. DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; TAS:ProtInc. DR CDD; cd19403; TGF_beta_GDF9; 1. DR Gene3D; 2.10.90.10; Cystine-knot cytokines; 1. DR InterPro; IPR029034; Cystine-knot_cytokine. DR InterPro; IPR015617; Growth_differentiation_fac-9_C. DR InterPro; IPR001839; TGF-b_C. DR InterPro; IPR015615; TGF-beta-rel. DR InterPro; IPR017948; TGFb_CS. DR PANTHER; PTHR11848:SF19; GROWTH_DIFFERENTIATION FACTOR 9; 1. DR PANTHER; PTHR11848; TGF-BETA FAMILY; 1. DR Pfam; PF00019; TGF_beta; 1. DR SMART; SM00204; TGFB; 1. DR SUPFAM; SSF57501; Cystine-knot cytokines; 1. DR PROSITE; PS00250; TGF_BETA_1; 1. DR PROSITE; PS51362; TGF_BETA_2; 1. DR Genevisible; O60383; HS. PE 1: Evidence at protein level; KW Cleavage on pair of basic residues; Cytokine; Disulfide bond; Glycoprotein; KW Growth factor; Phosphoprotein; Premature ovarian failure; KW Reference proteome; Secreted; Signal. FT SIGNAL 1..24 FT /evidence="ECO:0000255" FT PROPEP 25..319 FT /evidence="ECO:0000255" FT /id="PRO_0000033980" FT CHAIN 320..454 FT /note="Growth/differentiation factor 9" FT /id="PRO_0000033981" FT REGION 303..330 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 307..325 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 325 FT /note="Phosphoserine; by CK" FT /evidence="ECO:0000305|PubMed:20067794" FT CARBOHYD 106 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 163 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 236 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 255 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 268 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 338 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 353..419 FT /evidence="ECO:0000250" FT DISULFID 382..451 FT /evidence="ECO:0000250" FT DISULFID 386..453 FT /evidence="ECO:0000250" FT VARIANT 57 FT /note="D -> Y (in POF14; uncertain significance; FT dbSNP:rs138136756)" FT /evidence="ECO:0000269|PubMed:19438907" FT /id="VAR_066934" FT VARIANT 67 FT /note="K -> E (in POF14; uncertain significance)" FT /evidence="ECO:0000269|PubMed:16278619" FT /id="VAR_058945" FT VARIANT 103 FT /note="P -> S (in POF14; uncertain significance; also found FT at higher frequency in mothers of dizygotic twins than in FT controls; dbSNP:rs61754583)" FT /evidence="ECO:0000269|PubMed:16954162, FT ECO:0000269|PubMed:17156781" FT /id="VAR_066935" FT VARIANT 121 FT /note="T -> I (found at higher frequency in mothers of FT dizygotic twins than in controls; dbSNP:rs149821575)" FT /evidence="ECO:0000269|PubMed:16954162" FT /id="VAR_066936" FT VARIANT 146 FT /note="R -> C (in POF14; uncertain significance; FT dbSNP:rs76349024)" FT /evidence="ECO:0000269|PubMed:17482612" FT /id="VAR_066937" FT VARIANT 186 FT /note="S -> Y (in POF14; uncertain significance)" FT /evidence="ECO:0000269|PubMed:16645022" FT /id="VAR_058946" FT VARIANT 216 FT /note="V -> M (in POF14; uncertain significance; FT dbSNP:rs1205723048)" FT /evidence="ECO:0000269|PubMed:16278619" FT /id="VAR_058947" FT VARIANT 238 FT /note="T -> A (in POF14; uncertain significance)" FT /evidence="ECO:0000269|PubMed:17482612" FT /id="VAR_066938" FT VARIANT 374 FT /note="P -> L (found at higher frequency in mothers of FT dizygotic twins than in controls; dbSNP:rs373477788)" FT /evidence="ECO:0000269|PubMed:16954162" FT /id="VAR_066939" FT VARIANT 428 FT /note="S -> T (in POF14; uncertain significance; FT dbSNP:rs118080183)" FT /evidence="ECO:0000269|PubMed:17482612" FT /id="VAR_066940" FT VARIANT 454 FT /note="R -> C (found at higher frequency in mothers of FT dizygotic twins than in controls; dbSNP:rs61754582)" FT /evidence="ECO:0000269|PubMed:16954162" FT /id="VAR_066941" SQ SEQUENCE 454 AA; 51444 MW; 94EA366E90CDBC27 CRC64; MARPNKFLLW FCCFAWLCFP ISLGSQASGG EAQIAASAEL ESGAMPWSLL QHIDERDRAG LLPALFKVLS VGRGGSPRLQ PDSRALHYMK KLYKTYATKE GIPKSNRSHL YNTVRLFTPC TRHKQAPGDQ VTGILPSVEL LFNLDRITTV EHLLKSVLLY NINNSVSFSS AVKCVCNLMI KEPKSSSRTL GRAPYSFTFN SQFEFGKKHK WIQIDVTSLL QPLVASNKRS IHMSINFTCM KDQLEHPSAQ NGLFNMTLVS PSLILYLNDT SAQAYHSWYS LHYKRRPSQG PDQERSLSAY PVGEEAAEDG RSSHHRHRRG QETVSSELKK PLGPASFNLS EYFRQFLLPQ NECELHDFRL SFSQLKWDNW IVAPHRYNPR YCKGDCPRAV GHRYGSPVHT MVQNIIYEKL DSSVPRPSCV PAKYSPLSVL TIEPDGSIAY KEYEDMIATK CTCR //