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 13-FEB-2019, entry version 150. 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; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; 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., RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M., RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K., RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C., RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M., RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A., RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M., RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M., RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S., RA 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 RT project: 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 RT GDF-9B 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 RT monophosphate-stimulated steroidogenesis in human granulosa and theca RT cells."; RL J. Clin. Endocrinol. Metab. 87:2849-2856(2002). RN [5] RP ERRATUM. 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 RT agonistic or 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 RT and 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 RP 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 RT 15 both activate development of human primordial follicles in vitro, RT with 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 RT protein 15 mRNA expression is tightly co-regulated and differs between RT species over 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 RT leading to primary ovarian insufficiency by using targeted massively RT parallel 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., RA Gupta N., Chakravarty B., Singh L.; RT "Mutational screening of the coding region of growth differentiation RT factor 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., RA Fellous M., 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 RP POSSIBLE 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 RT dizygotic 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 RT premature 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 RT morphogenetic protein 15 (BMP15) mutation in Chinese women with RT premature ovarian failure."; RL Clin. Endocrinol. (Oxf.) 72:135-136(2010). CC -!- FUNCTION: Required for ovarian folliculogenesis. Promotes CC primordial follicle development. Stimulates granulosa cell CC proliferation. Promotes cell transition from G0/G1 to S and G2/M CC phases, through an increase of CCND1 and CCNE1 expression, and RB1 CC phosphorylation. It regulates STAR expression and cAMP-dependent CC progesterone release in granulosa and thecal cells. Attenuates the CC suppressive effects of activin A on STAR expression and CC progesterone production by increasing the expression of inhibin B. CC It suppresses FST and FSTL3 production in granulosa-lutein cells. CC {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 CC in oocytes of primary follicles (at protein level). CC {ECO:0000269|PubMed:10443672, ECO:0000269|PubMed:12050262}. CC -!- PTM: Phosphorylated; phosphorylation is critical for GDF9 CC function. In 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 CC ovarian disorder defined as the cessation of ovarian function CC under the age of 40 years. It is characterized by oligomenorrhea CC or amenorrhea, in the presence of elevated levels of serum CC gonadotropins and low estradiol. {ECO:0000269|PubMed:16278619, CC ECO:0000269|PubMed:16645022, ECO:0000269|PubMed:16954162, CC ECO:0000269|PubMed:17156781, ECO:0000269|PubMed:17482612, CC ECO:0000269|PubMed:19438907, ECO:0000269|PubMed:29044499}. CC Note=The disease is caused by mutations affecting the gene CC 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 CC mouse and pig can ovulate in excess of ten per cycle. The CC mechanisms that regulate the species-specific differences in the CC number of follicles that go onto ovulate during each reproductive CC cycle are poorly understood. According to PubMed:21970812, mRNA CC expression levels of GDF9 and BMP15 are tightly coregulated within CC each species and 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 UniGene; Hs.25022; -. DR UniGene; Hs.739230; -. DR UniGene; Hs.742490; -. DR ProteinModelPortal; O60383; -. DR BioGrid; 108930; 51. DR IntAct; O60383; 40. DR MINT; O60383; -. DR STRING; 9606.ENSP00000296875; -. DR iPTMnet; O60383; -. DR PhosphoSitePlus; O60383; -. DR BioMuta; GDF9; -. DR PaxDb; O60383; -. DR PeptideAtlas; O60383; -. DR PRIDE; O60383; -. DR ProteomicsDB; 49386; -. DR Ensembl; ENST00000378673; ENSP00000367942; ENSG00000164404. DR GeneID; 2661; -. DR KEGG; hsa:2661; -. DR UCSC; uc003kxz.3; human. DR CTD; 2661; -. DR DisGeNET; 2661; -. DR EuPathDB; HostDB:ENSG00000164404.8; -. DR GeneCards; GDF9; -. DR HGNC; HGNC:4224; GDF9. DR HPA; HPA069146; -. 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 eggNOG; KOG3900; Eukaryota. DR eggNOG; ENOG410XT8Z; LUCA. DR GeneTree; ENSGT00940000159784; -. DR HOGENOM; HOG000073526; -. DR HOVERGEN; HBG004660; -. DR InParanoid; O60383; -. DR KO; K22673; -. DR OMA; HMSVNFT; -. DR OrthoDB; 724783at2759; -. DR PhylomeDB; O60383; -. DR TreeFam; TF351788; -. DR ChiTaRS; GDF9; human. DR GeneWiki; Growth_differentiation_factor-9; -. DR GenomeRNAi; 2661; -. DR PRO; PR:O60383; -. DR Proteomes; UP000005640; Chromosome 5. DR Bgee; ENSG00000164404; Expressed in 96 organ(s), highest expression level in oocyte. DR ExpressionAtlas; O60383; baseline and differential. DR Genevisible; O60383; HS. 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:0005160; F:transforming growth factor beta receptor binding; IBA:GO_Central. DR GO; GO:0030509; P:BMP signaling pathway; IBA:GO_Central. DR GO; GO:0048468; P:cell development; IBA:GO_Central. 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:0010862; P:positive regulation of pathway-restricted SMAD protein phosphorylation; IBA:GO_Central. DR GO; GO:0042981; P:regulation of apoptotic process; IBA:GO_Central. DR GO; GO:0043408; P:regulation of MAPK cascade; IBA:GO_Central. DR GO; GO:2000870; P:regulation of progesterone secretion; IDA:UniProtKB. DR GO; GO:0060395; P:SMAD protein signal transduction; IBA:GO_Central. DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; TAS:ProtInc. DR Gene3D; 2.10.90.10; -; 1. DR InterPro; IPR029034; Cystine-knot_cytokine. DR InterPro; IPR015617; Growth_differentiation_fac-9. DR InterPro; IPR001839; TGF-b_C. DR InterPro; IPR015615; TGF-beta-rel. DR InterPro; IPR017948; TGFb_CS. DR PANTHER; PTHR11848; PTHR11848; 1. DR PANTHER; PTHR11848:SF19; PTHR11848:SF19; 1. DR Pfam; PF00019; TGF_beta; 1. DR SMART; SM00204; TGFB; 1. DR SUPFAM; SSF57501; SSF57501; 1. DR PROSITE; PS00250; TGF_BETA_1; 1. DR PROSITE; PS51362; TGF_BETA_2; 1. PE 1: Evidence at protein level; KW Cleavage on pair of basic residues; Complete proteome; Cytokine; KW Disulfide bond; Glycoprotein; Growth factor; Phosphoprotein; KW Polymorphism; Premature ovarian failure; Reference proteome; Secreted; KW Signal. FT SIGNAL 1 24 {ECO:0000255}. FT PROPEP 25 319 {ECO:0000255}. FT /FTId=PRO_0000033980. FT CHAIN 320 454 Growth/differentiation factor 9. FT /FTId=PRO_0000033981. FT MOD_RES 325 325 Phosphoserine; by CK. FT {ECO:0000305|PubMed:20067794}. FT CARBOHYD 106 106 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT CARBOHYD 163 163 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT CARBOHYD 236 236 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT CARBOHYD 255 255 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT CARBOHYD 268 268 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT CARBOHYD 338 338 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT DISULFID 353 419 {ECO:0000250}. FT DISULFID 382 451 {ECO:0000250}. FT DISULFID 386 453 {ECO:0000250}. FT VARIANT 57 57 D -> Y (in POF14; unknown pathological FT significance; dbSNP:rs138136756). FT {ECO:0000269|PubMed:19438907}. FT /FTId=VAR_066934. FT VARIANT 67 67 K -> E (in POF14; unknown pathological FT significance). FT {ECO:0000269|PubMed:16278619}. FT /FTId=VAR_058945. FT VARIANT 103 103 P -> S (in POF14; unknown pathological FT significance; also found at higher FT frequency in mothers of dizygotic twins FT than in controls; dbSNP:rs61754583). FT {ECO:0000269|PubMed:16954162, FT ECO:0000269|PubMed:17156781}. FT /FTId=VAR_066935. FT VARIANT 121 121 T -> I (rare polymorphism; found at FT higher frequency in mothers of dizygotic FT twins than in controls; FT dbSNP:rs149821575). FT {ECO:0000269|PubMed:16954162}. FT /FTId=VAR_066936. FT VARIANT 146 146 R -> C (in POF14; unknown pathological FT significance; dbSNP:rs76349024). FT {ECO:0000269|PubMed:17482612}. FT /FTId=VAR_066937. FT VARIANT 186 186 S -> Y (in POF14; unknown pathological FT significance). FT {ECO:0000269|PubMed:16645022}. FT /FTId=VAR_058946. FT VARIANT 216 216 V -> M (in POF14; unknown pathological FT significance; dbSNP:rs1205723048). FT {ECO:0000269|PubMed:16278619}. FT /FTId=VAR_058947. FT VARIANT 238 238 T -> A (in POF14; unknown pathological FT significance). FT {ECO:0000269|PubMed:17482612}. FT /FTId=VAR_066938. FT VARIANT 374 374 P -> L (rare polymorphism; found at FT higher frequency in mothers of dizygotic FT twins than in controls; FT dbSNP:rs373477788). FT {ECO:0000269|PubMed:16954162}. FT /FTId=VAR_066939. FT VARIANT 428 428 S -> T (in POF14; unknown pathological FT significance; dbSNP:rs118080183). FT {ECO:0000269|PubMed:17482612}. FT /FTId=VAR_066940. FT VARIANT 454 454 R -> C (rare polymorphism; found at FT higher frequency in mothers of dizygotic FT twins than in controls; FT dbSNP:rs61754582). FT {ECO:0000269|PubMed:16954162}. FT /FTId=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 //