GDF9

Summary

GDF9 (growth differentiation factor 9, HGNC:4224) is a protein-coding gene on chromosome 5q31.1, encoding Growth/differentiation factor 9 (O60383). Required for ovarian folliculogenesis.

This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. This protein regulates ovarian function. Reduced expression of this gene may be associated with polycystic ovary syndrome and mutations in this gene may be more common in mothers of dizygotic twins.

Source: NCBI Gene 2661 — RefSeq curated summary.

At a glance

• Gene–disease (curated): premature ovarian failure 14 (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 105 total — 2 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 6
• MANE Select transcript: NM_005260

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4224
Approved symbol	GDF9
Name	growth differentiation factor 9
Location	5q31.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000164404
Ensembl biotype	protein_coding
OMIM	601918
Entrez	2661

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 8 protein_coding

ENST00000296875, ENST00000378673, ENST00000464378, ENST00000621295, ENST00000624492, ENST00000624495, ENST00000687138, ENST00000687214

RefSeq mRNA: 6 — MANE Select: NM_005260 NM_001288824, NM_001288825, NM_001288826, NM_001288827, NM_001288828, NM_005260

CCDS: CCDS4162, CCDS75299

Canonical transcript exons

ENST00000687138 — 2 exons

Exon	Start	End
ENSE00001084102	132861185	132862556
ENSE00003932799	132864137	132866469

Expression profiles

Bgee: expression breadth ubiquitous, 168 present calls, max score 99.82.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0197 / max 6.7689, expressed in 8 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
63373	0.0197	8

Top tissues by expression

275 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	99.82	gold quality
secondary oocyte	CL:0000655	99.79	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.43	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.06	gold quality
right testis	UBERON:0004534	78.62	gold quality
left testis	UBERON:0004533	77.86	gold quality
testis	UBERON:0000473	75.41	gold quality
right uterine tube	UBERON:0001302	71.98	gold quality
cortical plate	UBERON:0005343	70.46	gold quality
ganglionic eminence	UBERON:0004023	68.60	gold quality
ileal mucosa	UBERON:0000331	67.23	silver quality
tibialis anterior	UBERON:0001385	66.90	silver quality
islet of Langerhans	UBERON:0000006	66.33	gold quality
pancreatic ductal cell	CL:0002079	65.90	silver quality
ventricular zone	UBERON:0003053	65.88	gold quality
prefrontal cortex	UBERON:0000451	64.02	gold quality
hindlimb stylopod muscle	UBERON:0004252	63.54	gold quality
body of pancreas	UBERON:0001150	62.82	gold quality
nucleus accumbens	UBERON:0001882	62.47	gold quality
pancreas	UBERON:0001264	62.46	gold quality
muscle of leg	UBERON:0001383	62.36	gold quality
gastrocnemius	UBERON:0001388	62.28	gold quality
adenohypophysis	UBERON:0002196	61.41	gold quality
pituitary gland	UBERON:0000007	61.35	gold quality
caudate nucleus	UBERON:0001873	61.06	gold quality
embryo	UBERON:0000922	60.53	gold quality
right adrenal gland	UBERON:0001233	60.35	gold quality
Brodmann (1909) area 9	UBERON:0013540	60.32	gold quality
right frontal lobe	UBERON:0002810	60.26	gold quality
hypothalamus	UBERON:0001898	60.14	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-3929	yes	1953.58
E-ANND-3	no	3.16

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NOBOX, NR6A1

miRNA regulators (miRDB)

30 targeting GDF9, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-202-5P	99.78	67.65	991
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-3120-3P	99.54	70.28	2669
HSA-MIR-7849-3P	99.47	68.17	1224
HSA-MIR-410-3P	99.27	69.98	2457
HSA-MIR-5582-5P	99.27	71.42	1879
HSA-MIR-329-5P	99.27	68.11	1597
HSA-MIR-3978	99.24	68.39	2201
HSA-MIR-6830-5P	99.01	68.73	1884
HSA-MIR-4680-3P	98.64	68.60	2093
HSA-MIR-9903	98.47	66.70	748
HSA-MIR-561-5P	98.25	68.13	1365
HSA-MIR-4423-3P	97.98	69.66	912
HSA-MIR-6883-3P	97.97	67.35	643
HSA-MIR-188-5P	97.89	67.01	756
HSA-MIR-4432	97.80	67.87	705
HSA-MIR-6866-3P	97.38	66.94	748
HSA-MIR-219B-3P	97.31	66.96	672
HSA-MIR-3137	97.26	66.78	761
HSA-MIR-454-5P	96.51	68.35	263

Literature-anchored findings (GeneRIF, showing 40)

• Bone morphogenetic protein receptor type II is a receptor for growth differentiation factor-9 (PMID:12135884)
• interaction with bone morphogenetic protein-15 (PMID:12446716)
• BMP-15 and GDF-9 have roles in fertility; critical sequences are determined by mutagenesis (PMID:14970198)
• This case-control study revealed eight mutations in the GDF9 gene in women with premature ovarian failure (PMID:16278619)
• although mutations in BMP15 and GDF9 are not a major cause of ovarian insufficiency, they may be involved in premature ovarian failure (PMID:16645022)
• new variants in the GDF9 gene that are significantly more common in mothers of DZ twins than controls, suggesting that rare GDF9 variants contribute to the likelihood of DZ twinning. (PMID:16954162)
• Mutational screening of the bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9) genes in a population with premature ovarian failure (POF) identified no new mutations. (PMID:17027369)
• GDF9 mutations may be one explanation for POF, albeit uncommon. (PMID:17156781)
• GDF9 may act as a growth inhibitor in breast cancer.Losing GDF9 during cancer progression may increase its aggressiveness. (PMID:17453295)
• Substitution of hydrophobic amino acid residue alanine for hydrophilic threonine may disrupt growth differentiation factor 9 function in women with premature ovarian failure. (PMID:17482612)
• phosphorylation state of rhBMP-15 and rhGDF-9 is a determinant of their agonistic and antagonistic activities (PMID:18006624)
• This study is the first characterization of purified biologically active human GDF9 and as such is of importance for studies on human fertility. (PMID:18162287)
• The transition from resting to growing follicles leading to the development of secondary follicles showed the normal expression patterns of GDF-9 and AMH. (PMID:18854109)
• Human granulosa-lutein cell GDF-9 expression may play a role in folliculogenesis dependent on follicle-stimulating hormone in the in vitro fertilization cycle. (PMID:19111296)
• GDF-9 stimulates granulosa cell proliferation by stimulating cyclin D(1) and E and suppressing p15(INK4B) and p16(INK4A) via both Smad-dependent and Smad-independent pathways (PMID:19366876)
• Reduced GDF-9 expression in cumulus granulosa cells of patients with polycystic ovary syndrome (PCOS) appears to be associated with decreased long-term developmental potential of the oocytes of patients with PCOS. (PMID:19376510)
• 2 synonymous mutations (c.447C>T, c.546G>A) & a novel missense variant (c.169G>T) were found in both premature ovarian failure patients & control subjects in the coding region of GDF9, indicating them as a novel polymorphism (PMID:19438907)
• GDF9 regulates the expression of R-SMAD2/3-responsive reporter genes through ALK4, 5 or 7 in extra-ovarian (adrenocortical and Sertoli) cells with similar potency and signalling pathway to its actions on granulosa cells (PMID:19505950)
• We report here for the first time autocrine roles for endogenous GDF9 in human granulosa-lutein cells in enhancing activin A-induced beta(B)-subunit mRNA and inhibin B levels (PMID:19846738)
• GDF-9 concentration in women with severe endometriosis was lower than in those without (PMID:19931079)
• Data show that Golgi apparatus casein kinase (G-CK) catalyzes the phosphorylation of rhBMP-15 and rhGDF-9. (PMID:20067794)
• data demonstrate that polymorphisms in major folliculogenesis genes, GDF9, BMP15, AMH, and AMHR2, are not associated with polycystic ovary syndrome susceptibility. (PMID:20236105)
• The detection of GDF9 and TGFbetaR1 at both at the protein and mRNA levels suggests that GDF9 may have functions in human preantral follicles. (PMID:20427239)
• GDF-9 c.G546A, but not c.G169A or c.C447T, is correlated with the poor ovarian stimulation and in vitro fertilization outcomes in women with diminished ovarian reserve. (PMID:20451184)
• Cell growth was significantly increased in the GDF9 over-expressing cells compared to the two controls; apoptosis was decreased in the presence of GDF9. (PMID:20458753)
• Impaired production of BMP15 and GDF9 mature proteins derived from proproteins with mutation in the proregion. (PMID:20547206)
• GDF9 attenuates the suppressive effects of activin A on StAR expression and progesterone production by increasing the expression of inhibin B, which acts as an activin A competitor. (PMID:20660033)
• Mutational analysis of the coding region of GDF9 among 216 Chinese polycystic ovary syndrome patients. Five novel missense mutations were discovered namely c.15C>G, c.118T>G, c.133A>G, c.1025A>T and c.1275C>A. (PMID:20705511)
• GDF-9 signaling via ALK-5, can promote cell invasiveness (PMID:21116689)
• Integral role of GDF-9 and BMP-15 in ovarian function. (PMID:21226076)
• Higher mature GDF9 levels in the follicular fluid were significantly correlated with oocyte nuclear maturation and embryo quality. (PMID:21496799)
• In the samples from girls/women, the number of developing follicles was greater with GDF9 or BMP15 alone than with no BMP15 or GDF9. (PMID:21632818)
• The expression of GDF9 and BMP15 in oocytes from patients with polycystic ovary syndrome cannot reach the normal level even after ovarian stimulation. (PMID:21669410)
• GDF9 decreases basal and activin A-induced FST and FSTL3 expression, and this explains, in part, its enhancing effects on activin A-induced inhibin beta(B)-subunit mRNA expression and inhibin B production in hGL cells (PMID:21829661)
• GDF-9 levels are inversely correlated with the growth, adhesion and migration of bladder cancer cells in vitro. (PMID:22159313)
• GDF9 may contribute to the variation observed in follicular development, ovulation rate, and fecundity between mammals (PMID:22234469)
• BMP15 and GDF9 transcript levels increase in mature oocytes from women with polycystic ovary syndrome after ovarian stimulation, and might inhibit the progesterone secretion by follicular cells (PMID:22825968)
• CDC6 and GDF-9 might be closely related to the carcinogenesis, clinical biological behaviors, and prognosis of gallbladder adenocarcinoma. (PMID:23011157)
• It was shown that human kidney tumours have a reduced or loss of expression of GDF9. In vitro, GDF9 overexpression suppresses the invasiveness, growth and migration of kidney cancer cells. (PMID:23060562)
• findings that GDF9:BMP15 heterodimers are the most bioactive ligands in mice and humans compared with homodimers explain many puzzling genetic and physiological data and have important implications for improving female fertility in mammals (PMID:23382188)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gdf9	ENSDARG00000003229
mus_musculus	Gdf9	ENSMUSG00000018238
rattus_norvegicus	Gdf9	ENSRNOG00000007301

Paralogs (31): TGFB2 (ENSG00000092969), BMP7 (ENSG00000101144), TGFB1 (ENSG00000105329), BMP5 (ENSG00000112175), BMP8B (ENSG00000116985), TGFB3 (ENSG00000119699), INHBA (ENSG00000122641), INHA (ENSG00000123999), BMP4 (ENSG00000125378), BMP2 (ENSG00000125845), GDF5 (ENSG00000125965), GDF1 (ENSG00000130283), BMP15 (ENSG00000130385), GDF15 (ENSG00000130513), GDF11 (ENSG00000135414), MSTN (ENSG00000138379), INHBE (ENSG00000139269), LEFTY2 (ENSG00000143768), GDF7 (ENSG00000143869), BMP3 (ENSG00000152785), BMP6 (ENSG00000153162), GDF6 (ENSG00000156466), NODAL (ENSG00000156574), INHBB (ENSG00000163083), BMP10 (ENSG00000163217), INHBC (ENSG00000175189), BMP8A (ENSG00000183682), GDF3 (ENSG00000184344), LEFTY1 (ENSG00000243709), GDF2 (ENSG00000263761), GDF10 (ENSG00000266524)

Protein

Protein identifiers

Growth/differentiation factor 9 — O60383 (reviewed: O60383)

All UniProt accessions (3): A0A8I5KUL2, B4DXG3, O60383

UniProt curated annotations — full annotation on UniProt →

Function. Required for ovarian folliculogenesis. Promotes primordial follicle development. Stimulates granulosa cell proliferation. Promotes cell transition from G0/G1 to S and G2/M phases, through an increase of CCND1 and CCNE1 expression, and RB1 phosphorylation. It regulates STAR expression and cAMP-dependent progesterone release in granulosa and thecal cells. Attenuates the suppressive effects of activin A on STAR expression and progesterone production by increasing the expression of inhibin B. It suppresses FST and FSTL3 production in granulosa-lutein cells.

Subunit / interactions. Homodimer or heterodimer (Potential). But, in contrast to other members of this family, cannot be disulfide-linked.

Subcellular location. Secreted.

Tissue specificity. Expressed in ovarian granulosa cells. Present in oocytes of primary follicles (at protein level).

Post-translational modifications. Phosphorylated; phosphorylation is critical for GDF9 function. In vitro, can be phosphorylated by CK at Ser-325.

Disease relevance. Altered GDF9 function may be involved in ovarian disorders and contribute to the likelihood of dizygotic twinning. Premature ovarian failure 14 (POF14) [MIM:618014] An ovarian disorder defined as the cessation of ovarian function under the age of 40 years. It is characterized by oligomenorrhea or amenorrhea, in the presence of elevated levels of serum gonadotropins and low estradiol. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Ovarian physiology and fertility are controlled by endocrine and paracrine signals. These act in a species-dependent manner and determine the ovulation quota in different mammalian species. While humans, and mammals such as the cow or red deer, normally ovulate only one egg per cycle, other mammals such as mouse and pig can ovulate in excess of ten per cycle. The mechanisms that regulate the species-specific differences in the number of follicles that go onto ovulate during each reproductive cycle are poorly understood. According to PubMed:21970812, mRNA expression levels of GDF9 and BMP15 are tightly coregulated within each species and influence species-specific ovulation-rates.

Similarity. Belongs to the TGF-beta family.

RefSeq proteins (6): NP_001275753, NP_001275754, NP_001275755, NP_001275756, NP_001275757, NP_005251* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001839	TGF-b_C	Domain
IPR015615	TGF-beta-like	Family
IPR015617	Growth_differentiation_fac-9_C	Domain
IPR017948	TGFb_CS	Conserved_site
IPR029034	Cystine-knot_cytokine	Homologous_superfamily

Pfam: PF00019

UniProt features (25 total): sequence variant 11, glycosylation site 6, disulfide bond 3, signal peptide 1, propeptide 1, chain 1, region of interest 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60383-F1	66.81	0.28

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 325

Disulfide bonds (3): 353–419, 382–451, 386–453

Glycosylation sites (6): 338, 106, 163, 236, 255, 268

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 154 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, GOBP_GROWTH, GOBP_OOGENESIS, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_HORMONE_TRANSPORT, GOMF_GROWTH_FACTOR_ACTIVITY, GOBP_CELL_CELL_SIGNALING, MUELLER_PLURINET, GOBP_REGULATION_OF_FEMALE_GONAD_DEVELOPMENT, GOBP_REPRODUCTIVE_SYSTEM_DEVELOPMENT, GOBP_OVULATION_CYCLE_PROCESS, GOBP_REGULATION_OF_ENDOCRINE_PROCESS, GOBP_RESPONSE_TO_TRANSFORMING_GROWTH_FACTOR_BETA, BLALOCK_ALZHEIMERS_DISEASE_UP

GO Biological Process (8): oocyte growth (GO:0001555), cell surface receptor protein serine/threonine kinase signaling pathway (GO:0007178), transforming growth factor beta receptor signaling pathway (GO:0007179), female gamete generation (GO:0007292), positive regulation of cell population proliferation (GO:0008284), negative regulation of cell growth (GO:0030308), regulation of progesterone secretion (GO:2000870), signal transduction (GO:0007165)

GO Molecular Function (2): cytokine activity (GO:0005125), growth factor activity (GO:0008083)

GO Cellular Component (3): obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
receptor ligand activity	2
cellular anatomical structure	2
developmental process involved in reproduction	1
developmental cell growth	1
oocyte development	1
enzyme-linked receptor protein signaling pathway	1
cellular response to transforming growth factor beta stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
gamete generation	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
regulation of cell growth	1
cell growth	1
negative regulation of growth	1
negative regulation of cellular process	1
progesterone secretion	1
regulation of female gonad development	1
regulation of steroid hormone secretion	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1228 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GDF9	BMPR2	Q13873	977
GDF9	BMP15	O95972	968
GDF9	ZAR1	Q86SH2	965
GDF9	NOBOX	O60393	930
GDF9	FSHR	P23945	906
GDF9	RFPL4A	A6NLU0	884
GDF9	BMPR1B	P78366	867
GDF9	FIGLA	Q6QHK4	821
GDF9	AMH	P03971	818
GDF9	TGFBR1	P36897	814
GDF9	FST	P19883	806
GDF9	GREM2	Q9H772	805
GDF9	ZP3	P21754	789
GDF9	BMPR1A	P36894	777
GDF9	IGF1	P01343	776

IntAct

48 interactions, top by confidence:

A	B	Type	Score
SMN1	GDF9	psi-mi:“MI:0915”(physical association)	0.550
TK1	GDF9	psi-mi:“MI:0915”(physical association)	0.550
GDF9	MYH11	psi-mi:“MI:0914”(association)	0.530
GDF9	H1-5	psi-mi:“MI:0915”(physical association)	0.400
GDF9	GADD45G	psi-mi:“MI:0915”(physical association)	0.370
ANXA7	GDF9	psi-mi:“MI:0915”(physical association)	0.370
GDF9	CDKN1A	psi-mi:“MI:0915”(physical association)	0.370
GDF9	DNM2	psi-mi:“MI:0915”(physical association)	0.370
GDF9	PCYT2	psi-mi:“MI:0915”(physical association)	0.370
GDF9	APBB1	psi-mi:“MI:0914”(association)	0.350
PCDHGA6	GDF9	psi-mi:“MI:0914”(association)	0.350
ZNF691	GDF9	psi-mi:“MI:0914”(association)	0.350
GDF9	HSPG2	psi-mi:“MI:0914”(association)	0.350
LSM3	GDF9	psi-mi:“MI:0915”(physical association)	0.000
RSRC1	GDF9	psi-mi:“MI:0915”(physical association)	0.000
KDM1A	GDF9	psi-mi:“MI:0915”(physical association)	0.000
TRIB3	GDF9	psi-mi:“MI:0915”(physical association)	0.000
CRELD1	GDF9	psi-mi:“MI:0915”(physical association)	0.000
PRKRA	GDF9	psi-mi:“MI:0915”(physical association)	0.000
BTBD2	GDF9	psi-mi:“MI:0915”(physical association)	0.000
ORAI2	GDF9	psi-mi:“MI:0915”(physical association)	0.000
CDKN2C	GDF9	psi-mi:“MI:0915”(physical association)	0.000
WASHC3	GDF9	psi-mi:“MI:0915”(physical association)	0.000
SMPD3	GDF9	psi-mi:“MI:0915”(physical association)	0.000
FOXG1	GDF9	psi-mi:“MI:0915”(physical association)	0.000
FXYD6	GDF9	psi-mi:“MI:0915”(physical association)	0.000
ILF3	GDF9	psi-mi:“MI:0915”(physical association)	0.000
KIF22	GDF9	psi-mi:“MI:0915”(physical association)	0.000
MPHOSPH6	GDF9	psi-mi:“MI:0915”(physical association)	0.000
MYCBP	GDF9	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (64): MYH11 (Affinity Capture-MS), AP5B1 (Affinity Capture-MS), TUBA4A (Affinity Capture-MS), ACTBL2 (Affinity Capture-MS), TUBB8 (Affinity Capture-MS), TUBB3 (Affinity Capture-MS), MED20 (Affinity Capture-MS), FBXO2 (Affinity Capture-MS), VWA1 (Affinity Capture-MS), GNB2 (Affinity Capture-MS), GDF9 (Two-hybrid), GDF9 (Two-hybrid), GDF9 (Two-hybrid), GDF9 (Two-hybrid), GDF9 (Two-hybrid)

ESM2 similar proteins: A2VDJ0, A5D791, A9CB18, D3YYM4, D5K8A9, E7FKV8, F1LW30, M0R2J8, O60383, O70173, O75747, Q07105, Q08DV9, Q2F7Z7, Q3MJ13, Q3SXY7, Q3T0Q2, Q3U3D7, Q3U3S3, Q4R8C8, Q5F479, Q5R800, Q5RFQ4, Q5SUS0, Q5XX13, Q6IRU7, Q6P4T1, Q6UXZ4, Q7TP65, Q8BLA1, Q8K1S2, Q8NDB2, Q8NEM2, Q8QHJ9, Q8R526, Q8TDX9, Q920I9, Q96KN7, Q9BXS4, Q9D0L6

Diamond homologs: A9CB18, G5EEL5, O08717, O13048, O46576, O60383, O61643, O77681, O88959, O95972, P03970, P07713, P07995, P08476, P09529, P09534, P12643, P12644, P17491, P18075, P18331, P21274, P21275, P25703, P27093, P27539, P30884, P30885, P35621, P42917, P43021, P43026, P43027, P43028, P43029, P43032, P48970, P49001, P55102, P55104

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

105 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	4
Uncertain significance	82
Likely benign	6
Benign	7

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
3255469	NM_005260.7(GDF9):c.1121C>T (p.Pro374Leu)	Pathogenic
3255470	NM_005260.7(GDF9):c.794T>G (p.Leu265Ter)	Pathogenic
1256006	NM_005260.7(GDF9):c.946C>T (p.Arg316Cys)	Likely pathogenic
1299519	NM_005260.7(GDF9):c.1364A>C (p.Ter455Ser)	Likely pathogenic
3068062	NM_005260.7(GDF9):c.759_762del (p.Phe254fs)	Likely pathogenic
545504	NM_005260.7(GDF9):c.783del (p.Ser262fs)	Likely pathogenic

SpliceAI

828 predictions. Top by Δscore:

Variant	Effect	Δscore
5:132866679:C:G	donor_gain	1.0000
5:132866683:GCCCT:G	donor_gain	1.0000
5:132866688:GTGC:G	donor_gain	1.0000
5:132866690:GC:G	donor_gain	1.0000
5:132866692:G:GG	donor_gain	1.0000
5:132863123:AG:A	donor_gain	0.9900
5:132866513:CGGG:C	donor_gain	0.9900
5:132866675:C:T	donor_gain	0.9900
5:132866689:TGC:T	donor_gain	0.9900
5:132866690:GCG:G	donor_gain	0.9900
5:132866535:T:TA	donor_gain	0.9800
5:132866558:C:A	donor_gain	0.9800
5:132866670:G:GT	donor_gain	0.9800
5:132866673:G:GT	donor_gain	0.9800
5:132866858:C:CA	acceptor_gain	0.9800
5:132866859:G:A	acceptor_gain	0.9800
5:132866864:TGCAG:T	acceptor_loss	0.9800
5:132866865:GCAGG:G	acceptor_loss	0.9800
5:132866866:CAGGG:C	acceptor_loss	0.9800
5:132866868:G:GC	acceptor_loss	0.9800
5:132862553:ATTC:A	acceptor_loss	0.9700
5:132862554:TTC:T	acceptor_gain	0.9700
5:132862556:CCTAA:C	acceptor_loss	0.9700
5:132862557:C:CG	acceptor_loss	0.9700
5:132862558:T:A	acceptor_loss	0.9700
5:132866587:C:CA	donor_gain	0.9700
5:132866597:ACC:A	donor_loss	0.9700
5:132866863:CTGCA:C	acceptor_loss	0.9700
5:132866867:AG:A	acceptor_gain	0.9700
5:132866868:GG:G	acceptor_gain	0.9700

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000073220 (5:132863807 G>A,C), RS1000389665 (5:132865068 A>G,T), RS1000616233 (5:132866477 C>T), RS1001228203 (5:132862979 C>T), RS1002188417 (5:132861753 T>C), RS1002240660 (5:132861485 G>A,C), RS1002290601 (5:132867363 T>C), RS1002475617 (5:132867144 C>A,G,T), RS1002622665 (5:132868633 C>T), RS1002638736 (5:132862718 C>A,T), RS1002846245 (5:132864775 CCT>C), RS1003017149 (5:132863034 C>T), RS1004094815 (5:132868563 T>C), RS1004288651 (5:132864471 A>G), RS1004319268 (5:132864277 A>C,G)

Disease associations

OMIM: gene MIM:601918 | disease phenotypes: MIM:618014

GenCC curated gene-disease

Disease	Classification	Inheritance
premature ovarian failure 14	Strong	Autosomal recessive

Mondo (2): premature ovarian failure 14 (MONDO:0044777), primary ovarian failure (MONDO:0005387)

Orphanet (2): Rare genetic premature ovarian failure (Orphanet:485382), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

6 total (6 of 6 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000786	Primary amenorrhea
HP:0008214	Decreased serum estradiol
HP:0008232	Elevated circulating follicle stimulating hormone level
HP:0011462	Young adult onset
HP:0011969	Elevated circulating luteinizing hormone level

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008916_34	Asthma	2.000000e-09

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
diethyl maleate	increases expression	1
sodium arsenite	decreases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
brevetoxin 2	increases expression	1
theaflavin-3,3’-digallate	affects expression	1
Estradiol	increases abundance, increases reaction, affects cotreatment, decreases reaction	1
Lipopolysaccharides	decreases reaction, increases expression	1
Progesterone	decreases reaction, increases secretion, decreases secretion	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Triclosan	decreases reaction, increases expression	1
Valproic Acid	decreases methylation	1
Cadmium Chloride	increases expression	1
Acrylamide	increases expression	1

Clinical trials (associated diseases)

75 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT04009473	PHASE1/PHASE2	UNKNOWN	Stem Cell Therapy and Growth Factor Ovarian in Vitro Activation
NCT00948857	PHASE2/PHASE3	TERMINATED	Dehydroepiandrosterone (DHEA) Treatment and Premature Ovarian Failure (POF)
NCT04031456	PHASE2/PHASE3	RECRUITING	Autologous PRP Infusion May Restore Ovarian Function and May Promote Folliculogenesis in POI Patients
NCT02043743	PHASE1/PHASE2	UNKNOWN	Autologous Stem Cells Transplantation in Patients With Idiopathic and Drug Induced Premature Ovarian Failure
NCT02062931	PHASE1/PHASE2	UNKNOWN	Autologous Mesenchymal Stem Cells Transplantation In Women With Premature Ovarian Failure
NCT02151890	PHASE1/PHASE2	COMPLETED	Pregnancy After Stem Cell Transplantation in Premature Ovarian Failure
NCT02372474	PHASE1/PHASE2	COMPLETED	It is a Real The First Baby Of Autologous Stem Cell Therapy in Premature Ovarian Failure
NCT02603744	PHASE1/PHASE2	UNKNOWN	Autologous Adipose Derived Mesenchymal Stromal Cells Transplantation in Women With Premature Ovarian Failure (POF)
NCT02644447	PHASE1/PHASE2	COMPLETED	Transplantation of HUC-MSCs With Injectable Collagen Scaffold for POF
NCT03069209	PHASE1/PHASE2	UNKNOWN	Autologous Bone Marrow-Derived Stem Cell Transplantation in Patients With Premature Ovarian Failure (POF)
NCT03985462	PHASE1/PHASE2	WITHDRAWN	Very Small Embryonic-like Stem Cells for Ovary
NCT04071574	PHASE1/PHASE2	COMPLETED	Comparative Study on the Efficacy of Ovarian Stimulation Protocols on the Success Rate of ICSI in Female Infertility
NCT04922398	PHASE1/PHASE2	UNKNOWN	Ovarian Injection of PRP (Platelet -Rich Plasma) Vs Normal Saline in Premature Ovarian Insufficiency
NCT05462379	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Autologous Heterotopic Fresh Ovarian Graft in Woman With LACC Eligible for Pelvic Radiotherapy Treatment.
NCT06202547	PHASE1/PHASE2	UNKNOWN	Intra-ovarian Injection of MSC-EVs in Idiopathic Premature Ovarian Failure
NCT01129947	EARLY_PHASE1	WITHDRAWN	The Use of DHEA in Women With Premature Ovarian Failure
NCT05522634	EARLY_PHASE1	UNKNOWN	A Clinical Study of Chinese Herbal Compound TJAOA101 in the Treatment of Premature Ovarian Insufficiency
NCT07308327	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	The Influence of Gut Microbiota on Ovarian Function: A Single-center, Randomized,Double Blind, Parallel-controlled, Exploratory Clinical Trial
NCT00001275	Not specified	COMPLETED	Ovarian Follicle Function in Patients With Primary Ovarian Failure
NCT00001306	Not specified	COMPLETED	Steroid Therapy in Autoimmune Premature Ovarian Failure
NCT00006156	Not specified	COMPLETED	Feasibility Study for Development of an Early Test for Ovarian Failure
NCT00119925	Not specified	UNKNOWN	‘SPRING’-Study: Subfertility Guidelines: Patient Related Implementation in the Netherlands Among Gynaecologists