FGF9

Summary

FGF9 (fibroblast growth factor 9, HGNC:3687) is a protein-coding gene on chromosome 13q12.11, encoding Fibroblast growth factor 9 (P31371). Plays an important role in the regulation of embryonic development, cell proliferation, cell differentiation and cell migration.

The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This protein was isolated as a secreted factor that exhibits a growth-stimulating effect on cultured glial cells. In nervous system, this protein is produced mainly by neurons and may be important for glial cell development. Expression of the mouse homolog of this gene was found to be dependent on Sonic hedgehog (Shh) signaling. Mice lacking the homolog gene displayed a male-to-female sex reversal phenotype, which suggested a role in testicular embryogenesis.

Source: NCBI Gene 2254 — RefSeq curated summary.

At a glance

• Gene–disease (curated): multiple synostoses syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 12
• Clinical variants (ClinVar): 161 total — 3 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 21
• MANE Select transcript: NM_002010

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3687
Approved symbol	FGF9
Name	fibroblast growth factor 9
Location	13q12.11
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000102678
Ensembl biotype	protein_coding
OMIM	600921
Entrez	2254

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding_CDS_not_defined, 1 protein_coding

ENST00000382353, ENST00000461657, ENST00000478546

RefSeq mRNA: 1 — MANE Select: NM_002010 NM_002010

CCDS: CCDS9298

Canonical transcript exons

ENST00000382353 — 3 exons

Exon	Start	End
ENSE00001491824	21701190	21704498
ENSE00001491832	21671073	21672189
ENSE00003571832	21681042	21681145

Expression profiles

Bgee: expression breadth ubiquitous, 237 present calls, max score 99.26.

FANTOM5 (CAGE): breadth broad, TPM avg 1.5834 / max 172.0743, expressed in 378 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
134345	0.8548	285
134347	0.2577	127
134346	0.2034	112
134350	0.1616	71
134348	0.0592	30
206972	0.0327	13
134349	0.0142	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.26	gold quality
renal medulla	UBERON:0000362	96.67	gold quality
oocyte	CL:0000023	95.48	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.94	gold quality
pons	UBERON:0000988	94.50	gold quality
buccal mucosa cell	CL:0002336	94.15	gold quality
cerebellar vermis	UBERON:0004720	94.00	gold quality
middle temporal gyrus	UBERON:0002771	93.96	gold quality
parietal pleura	UBERON:0002400	92.05	gold quality
germinal epithelium of ovary	UBERON:0001304	91.91	gold quality
paraflocculus	UBERON:0005351	91.48	gold quality
adrenal tissue	UBERON:0018303	91.09	gold quality
primary visual cortex	UBERON:0002436	89.81	gold quality
tendon of biceps brachii	UBERON:0008188	89.49	gold quality
cerebellum	UBERON:0002037	88.86	gold quality
occipital lobe	UBERON:0002021	88.51	gold quality
cerebellar cortex	UBERON:0002129	88.19	gold quality
cerebellar hemisphere	UBERON:0002245	88.07	gold quality
right hemisphere of cerebellum	UBERON:0014890	87.81	gold quality
pleura	UBERON:0000977	87.79	gold quality
renal glomerulus	UBERON:0000074	87.16	gold quality
nephron tubule	UBERON:0001231	86.65	gold quality
kidney epithelium	UBERON:0004819	86.06	gold quality
metanephric glomerulus	UBERON:0004736	85.96	gold quality
sperm	CL:0000019	85.71	gold quality
lateral nuclear group of thalamus	UBERON:0002736	85.40	gold quality
dorsal root ganglion	UBERON:0000044	85.33	gold quality
parietal lobe	UBERON:0001872	84.38	gold quality
postcentral gyrus	UBERON:0002581	83.91	gold quality
kidney	UBERON:0002113	82.91	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.85

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
BMP2	Unknown
PDGFRB	Activation
TGFB1	Unknown

Upstream regulators (CollecTRI, top): AHR, CTNNB1, FUBP3, MYC, SOX9

miRNA regulators (miRDB)

173 targeting FGF9, 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-8485	100.00	77.57	4731
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-12133	99.92	71.82	2006

Literature-anchored findings (GeneRIF, showing 40)

• FGF9 is an autocrine estromedin endometrial stromal growth factor that plays roles in cyclic proliferation of uterine endometrial stroma (PMID:12072406)
• The capability of proliferation possessed by endometriotic stromal cell during menstruation when ovarian 17 beta-estradiol is in the nadir may be mediated, at least in part, by autocrined estrogen-stimulated expression of FGF-9 and its receptors. (PMID:14602803)
• Recombinant human FGF-9 signaling enhances the intrinsic osteogenic potential by selectively expanding committed chick embryo osteogenic cell populations as well as inversely regulating bone morphogenetic protein 2 (BMP-2) and noggin gene expression. (PMID:15780951)
• Mesothelial and epithelial transgenic FGF9 directs lung development by regulating mesenchymal growth, and the pattern and expression levels of mesenchymal growth factors that signal back to the epithelium. (PMID:16540513)
• Our findings may also provide a molecular framework for considering roles for PGE2 in FGF-9-related embryonic development and/or human diseases. (PMID:16982695)
• Polymorphic microsatellite in the 3’-UTR of FGF9 in patients with Gonadal dysgenesis. (PMID:17154280)
• FGF9 mutant tumors showed normal membranous beta-catenin expression and the absence of mutation in the beta-catenin gene (PMID:18165946)
• Inhibition of fibroblast growth factor 19 reduces tumor growth by modulating beta-catenin signaling. (PMID:18593907)
• Androgen receptor-negative human prostate cancer cells induce osteogenesis in mice through FGF9-mediated mechanisms. (PMID:18618013)
• the study ruled out microdeletions on the critical region as a common cause of Moebius syndrome and excluded FGF9 gene (PMID:19460469)
• Data demonstrate that homodimerization autoregulates FGF9 and FGF20’s receptor binding and concentration gradients in the extracellular matrix. (PMID:19564416)
• Data demonstrate a previously uncharacterized mutation in FGF9 as one of the causes of Multiple synostoses syndrome, implicating an important role of FGF9 in normal joint development. (PMID:19589401)
• Microvessels formed in the presence of FGF9 had enhanced capacity to receive flow and were vasoreactive. (PMID:21499246)
• Fibroblast growth factor 9 was also overexpressed in all serous ovarian tumors with greater than 1000-fold increase in gene expression in 4 tumors. (PMID:21666490)
• These results indicate that FGF9 can stimulate proliferation and invasion in prostate cancer cells, thus FGF9 could be a candidate of a predictive factor for recurrence after radical prostatectomy. (PMID:22006051)
• the FGF9(S99N) monomer is preferred to bind with the FGFR3c receptor to form an inactive complex, leading to impaired FGF signaling; the impaired FGF signaling is believed to be a potential cause of synostoses syndrome, implicating an important role for FGF9 in normal joint development (PMID:22920789)
• neither DMRT1 nor FGF9 abnormalities are frequently involved in dysgenetic male gonad development in patients with non-syndromic 46,XY disorder of sex development. (PMID:22939835)
• The importance of Fgf9 in hair follicle regeneration suggests that it could be used therapeutically in humans. (PMID:23727932)
• The results demonstrate that FGF9 protein increased in regions of active cellular hyperplasia, metaplasia, and fibrotic expansion of idiopathic pulmonary fibrosis lungs. (PMID:23797050)
• In addition to the role of sex determination, FGF9 is expressed in postnatal Leydig cells and is involved in cell-to-cell interaction of testicular function. Aberrant expression of testicular FGF9 is associated with SCOS. (PMID:24011613)
• FGF9 was proved to be a direct target of miR-26a (PMID:24015269)
• MAP3K1 mutations tilt the balance in the sex-determining pathways by downregulating SOX9 and FGF9. (PMID:24135036)
• expression is associated with poor prognosis in lung cancer (PMID:24239165)
• The data demonstrates that FGF9 IRES functions as a cellular switch to turn FGF9 protein synthesis ‘on’ during hypoxia, a likely mechanism underlying FGF9 overexpression in cancer cells. (PMID:24334956)
• FGF9 can be associated with epithelial-to-mesenchymal transition and invasion by inducing VEGF-A expression in prostate cancer cells. (PMID:24511001)
• we found that Kl treatment impairs Nodal mRNA expression and Fgf9-mediated Nanos2 induction, reinforcing the antagonistic effect of these two growth factors on the meiotic fate of male germ cells (PMID:25766327)
• our data demonstrate that FGF9 can initiate a complex astrocytic response predicted to compromise remyelination, while at the same time stimulating microglial/macrophage recruitment in multiple sclerosis lesions (PMID:25907862)
• FGF9 was strongly expressed in CAFs in comparison with NGFs, being compatible with microarray data indicating that FGF9 was a novel growth factor overexpressed in Cancer-associated fibroblasts (PMID:25925261)
• These studies identify FGF9 as a target of DICER1 in lung epithelium that functions as an initiating factor for pleuropulmonary blastoma. (PMID:25978641)
• Data indicate that expressing either human FGF9 in the kidney subcapsular space of female BALB/c mice yielded rapidly expanding local tumors. (PMID:26183774)
• the relative levels of FGF9 in relation to other members of the FGF family may prove key to understanding vulnerability or resilience in affective disorders. (PMID:26351673)
• FGF9 and FGF18 increased the migratory capacities of human lung fibroblasts, and FGF9 actively modulated matrix metalloproteinase activity in idiopathic pulmonary fibrosis. (PMID:26773067)
• In FGF9-overexpressing colorectal cancer cell lines, FGF9 overexpression induced strong resistance to anti-EGFR therapies via the enforced FGFR signal, and this resistance was cancelled by the application of an FGFR inhibitor. (PMID:26916220)
• Data suggest that fibroblast growth factor 9 (FGF9) may provide the anti-apoptotic function and be useful as a novel independent marker for evaluating gastric cancer (GC) prognosis. (PMID:27166269)
• The present data indicate that non-natural FGFR2 ligands, such as FGF10 and FGF19, are important factors in the pathophysiology of Aspert syndrome. (PMID:27339175)
• The results suggest that FGF2/rs1048201, FGF5/rs3733336 and FGF9/rs546782 are associated with the risk of non-syndromic orofacial cleft and that these miRNA-FGF interactions may affect non-syndromic orofacial cleft development. (PMID:27511275)
• CCND1 mRNA expression is increased by FGF9 in bovine theca cells and granulosa cells. (PMID:27816766)
• we conclude that the S99N mutation in Fgf9 causes multiple synostoses syndrome (SYNS) via the disturbance of joint interzone formation. These results further implicate the crucial role of Fgf9 during embryonic joint development (PMID:28169396)
• The upregulation of FGF9 or the downregulation of miR-372-3p substantially retarded lung squamous cell carcinoma (LSCC) cell growth, mitosis, and invasion. MiR-372-3p enhanced LSCC cell proliferation and invasion through inhibiting FGF9. (PMID:28440022)
• We have demonstrated for the first time that mutations in FGF9 cause craniosynostosis in humans and confirm that FGF9 mutations cause multiple synostoses. (PMID:28730625)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Fgf9	ENSMUSG00000021974
rattus_norvegicus	Fgf9	ENSRNOG00000011471

Paralogs (21): FGF10 (ENSG00000070193), FGF22 (ENSG00000070388), FGF4 (ENSG00000075388), FGF20 (ENSG00000078579), FGF14 (ENSG00000102466), FGF21 (ENSG00000105550), FGF8 (ENSG00000107831), FGF6 (ENSG00000111241), FGF1 (ENSG00000113578), FGF12 (ENSG00000114279), FGF23 (ENSG00000118972), FGF13 (ENSG00000129682), FGF5 (ENSG00000138675), FGF2 (ENSG00000138685), FGF7 (ENSG00000140285), FGF18 (ENSG00000156427), FGF17 (ENSG00000158815), FGF11 (ENSG00000161958), FGF19 (ENSG00000162344), FGF3 (ENSG00000186895), FGF16 (ENSG00000196468)

Protein

Protein identifiers

Fibroblast growth factor 9 — P31371 (reviewed: P31371)

Alternative names: Glia-activating factor, Heparin-binding growth factor 9

All UniProt accessions (2): P31371, A0A7U3L6D0

UniProt curated annotations — full annotation on UniProt →

Function. Plays an important role in the regulation of embryonic development, cell proliferation, cell differentiation and cell migration. May have a role in glial cell growth and differentiation during development, gliosis during repair and regeneration of brain tissue after damage, differentiation and survival of neuronal cells, and growth stimulation of glial tumors.

Subunit / interactions. Monomer. Homodimer. Interacts with FGFR1, FGFR2, FGFR3 and FGFR4. Affinity between fibroblast growth factors (FGFs) and their receptors is increased by heparan sulfate glycosaminoglycans that function as coreceptors.

Subcellular location. Secreted.

Tissue specificity. Glial cells.

Post-translational modifications. Three molecular species were found (30 kDa, 29 kDa and 25 kDa), cleaved at Leu-4, Val-13 and Ser-34 respectively. The smaller ones might be products of proteolytic digestion. Furthermore, there may be a functional signal sequence in the 30 kDa species which is uncleavable in the secretion step. N-glycosylated.

Disease relevance. Multiple synostoses syndrome 3 (SYNS3) [MIM:612961] A bone disease characterized by multiple progressive joint fusions that commonly involve proximal interphalangeal, tarsal-carpal, humeroradial and cervical spine joints. Additional features can include progressive conductive deafness and facial dysmorphism. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Biochemical analysis of the Asn-99 mutation reveals a significantly impaired FGF signaling, as evidenced by diminished activity of the MAPK1/MAPK2 pathway and decreases CTNNB1 and MYC expression when compared with wild-type protein. Binding of mutant protein to the receptor FGFR3 is severely impaired, although homodimerization of mutant to itself or wild-type is not detectably affected, providing a basis for the observed defective FGF9 signaling.

Similarity. Belongs to the heparin-binding growth factors family.

RefSeq proteins (1): NP_002001* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002209	Fibroblast_GF_fam	Family
IPR008996	IL1/FGF	Homologous_superfamily

Pfam: PF00167

UniProt features (28 total): strand 11, helix 7, turn 3, sequence variant 2, sequence conflict 2, propeptide 1, chain 1, glycosylation site 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
1IHK	X-RAY DIFFRACTION	2.2
5W59	X-RAY DIFFRACTION	2.5
1G82	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P31371-F1	84.19	0.66

Functional residue map

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

Glycosylation sites (1): 79

Function

Pathways and Gene Ontology

Reactome pathways

38 pathways

ID	Pathway
R-HSA-109704	PI3K Cascade
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-1839122	Signaling by activated point mutants of FGFR1
R-HSA-1839130	Signaling by activated point mutants of FGFR3
R-HSA-190322	FGFR4 ligand binding and activation
R-HSA-190371	FGFR3b ligand binding and activation
R-HSA-190372	FGFR3c ligand binding and activation
R-HSA-190373	FGFR1c ligand binding and activation
R-HSA-190375	FGFR2c ligand binding and activation
R-HSA-2033519	Activated point mutants of FGFR2
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-5654219	Phospholipase C-mediated cascade: FGFR1
R-HSA-5654221	Phospholipase C-mediated cascade; FGFR2
R-HSA-5654227	Phospholipase C-mediated cascade; FGFR3
R-HSA-5654228	Phospholipase C-mediated cascade; FGFR4
R-HSA-5654687	Downstream signaling of activated FGFR1
R-HSA-5654688	SHC-mediated cascade:FGFR1
R-HSA-5654689	PI-3K cascade:FGFR1
R-HSA-5654693	FRS-mediated FGFR1 signaling
R-HSA-5654695	PI-3K cascade:FGFR2
R-HSA-5654699	SHC-mediated cascade:FGFR2
R-HSA-5654700	FRS-mediated FGFR2 signaling
R-HSA-5654704	SHC-mediated cascade:FGFR3
R-HSA-5654706	FRS-mediated FGFR3 signaling
R-HSA-5654710	PI-3K cascade:FGFR3
R-HSA-5654712	FRS-mediated FGFR4 signaling
R-HSA-5654719	SHC-mediated cascade:FGFR4
R-HSA-5654720	PI-3K cascade:FGFR4
R-HSA-5654726	Negative regulation of FGFR1 signaling
R-HSA-5654727	Negative regulation of FGFR2 signaling

MSigDB gene sets: 610 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, MODULE_92, REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, AP1_01, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, FREAC2_01, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, HNF3ALPHA_Q6, TGCGCANK_UNKNOWN, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, RORA1_01

GO Biological Process (49): negative regulation of transcription by RNA polymerase II (GO:0000122), angiogenesis (GO:0001525), osteoblast differentiation (GO:0001649), eye development (GO:0001654), positive regulation of mesenchymal cell proliferation (GO:0002053), chondrocyte differentiation (GO:0002062), protein import into nucleus (GO:0006606), signal transduction (GO:0007165), smoothened signaling pathway (GO:0007224), cell-cell signaling (GO:0007267), positive regulation of cell population proliferation (GO:0008284), fibroblast growth factor receptor signaling pathway (GO:0008543), male gonad development (GO:0008584), mesenchymal cell proliferation (GO:0010463), positive regulation of gene expression (GO:0010628), substantia nigra development (GO:0021762), neurogenesis (GO:0022008), negative regulation of Wnt signaling pathway (GO:0030178), male sex determination (GO:0030238), embryonic limb morphogenesis (GO:0030326), regulation of cell migration (GO:0030334), positive regulation of vascular endothelial growth factor receptor signaling pathway (GO:0030949), activin receptor signaling pathway (GO:0032924), positive regulation of activin receptor signaling pathway (GO:0032927), inner ear morphogenesis (GO:0042472), positive regulation of MAPK cascade (GO:0043410), positive regulation of smoothened signaling pathway (GO:0045880), vascular endothelial growth factor receptor signaling pathway (GO:0048010), regulation of timing of cell differentiation (GO:0048505), embryonic digestive tract development (GO:0048566), embryonic skeletal system development (GO:0048706), positive regulation of epithelial cell proliferation (GO:0050679), positive regulation of cell division (GO:0051781), Sertoli cell proliferation (GO:0060011), cardiac muscle cell proliferation (GO:0060038), positive regulation of cardiac muscle cell proliferation (GO:0060045), canonical Wnt signaling pathway (GO:0060070), lung-associated mesenchyme development (GO:0060484), stem cell proliferation (GO:0072089), positive regulation of canonical Wnt signaling pathway (GO:0090263)

GO Molecular Function (3): fibroblast growth factor receptor binding (GO:0005104), growth factor activity (GO:0008083), heparin binding (GO:0008201)

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

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Downstream signaling of activated FGFR1	4
FGFR3 ligand binding and activation	2
Downstream signaling of activated FGFR2	2
IRS-mediated signalling	1
Intracellular signaling by second messengers	1
FGFR1 mutant receptor activation	1
FGFR3 mutant receptor activation	1
Signaling by FGFR4	1
FGFR1 ligand binding and activation	1
FGFR2 ligand binding and activation	1
FGFR2 mutant receptor activation	1
PI3K/AKT Signaling in Cancer	1
Downstream signaling of activated FGFR3	1
Downstream signaling of activated FGFR4	1
Signaling by FGFR1	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell differentiation	3
cell communication	2
signaling	2
cell population proliferation	2
cellular anatomical structure	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
ossification	1
sensory organ development	1
visual system development	1
positive regulation of cell population proliferation	1
mesenchymal cell proliferation	1
regulation of mesenchymal cell proliferation	1
cartilage development	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
cellular process	1
regulation of cellular process	1
cellular response to stimulus	1
cell surface receptor signaling pathway	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to fibroblast growth factor stimulus	1
gonad development	1
development of primary male sexual characteristics	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
midbrain development	1
neural nucleus development	1
nervous system development	1
negative regulation of signal transduction	1
Wnt signaling pathway	1
regulation of Wnt signaling pathway	1

Protein interactions and networks

STRING

4009 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FGF9	FGFR1	P11362	998
FGF9	FGFR2	P18443	996
FGF9	FGFR3	P22607	995
FGF9	FGFR4	P22455	990
FGF9	EGF	P01133	988
FGF9	KL	Q9UEF7	987
FGF9	HSPG2	P98160	948
FGF9	FGFBP1	Q14512	941
FGF9	DCN	P07585	936
FGF9	SHH	Q15465	883
FGF9	CDH2	P19022	881
FGF9	CD44	P16070	875
FGF9	HGF	P14210	866
FGF9	FGF23	Q9GZV9	863
FGF9	KLB	Q86Z14	848

IntAct

5 interactions, top by confidence:

A	B	Type	Score
FGF9	PPID	psi-mi:“MI:0914”(association)	0.530
FGFR1	FGF9	psi-mi:“MI:0407”(direct interaction)	0.440
FGFR3	FGF9	psi-mi:“MI:0407”(direct interaction)	0.440
FGF9	GTF2F1	psi-mi:“MI:0914”(association)	0.350

BioGRID (22): FGF9 (Protein-peptide), FGF9 (Protein-peptide), EIF2A (Affinity Capture-MS), MLLT4 (Affinity Capture-MS), FRA10AC1 (Affinity Capture-MS), SUPT4H1 (Affinity Capture-MS), GTF2F1 (Affinity Capture-MS), TMED7 (Affinity Capture-MS), NAA15 (Affinity Capture-MS), PPID (Affinity Capture-MS), FGF20 (Affinity Capture-MS), FGF9 (Co-crystal Structure), FGF9 (Reconstituted Complex), FGF20 (Affinity Capture-MS), TMED7 (Affinity Capture-MS)

ESM2 similar proteins: A0MTF4, A4Q9F4, M3X9S6, O15520, O35565, O43189, O43320, O54693, O54769, O73754, O95750, P05524, P08620, P11487, P12034, P15656, P31371, P36364, P36386, P48801, P48802, P48803, P48804, P48807, P54130, P70492, P97401, P98172, Q20FD0, Q2HXK8, Q3ZFI5, Q5RF67, Q5T6S3, Q5XI70, Q91875, Q92765, Q92838, Q95117, Q95L12, Q96GD3

Diamond homologs: A0MTF4, A6P7H6, M3X9S6, O15520, O35565, O43320, O54769, P03968, P03969, P05230, P05524, P08620, P09038, P10767, P11403, P11487, P12034, P12226, P13109, P15655, P15656, P19596, P20002, P20003, P21658, P21781, P31371, P34004, P36363, P36364, P36386, P48798, P48799, P48800, P48801, P48802, P48803, P48804, P48805, P48806

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
FGF9	“up-regulates quantity by expression”	BMP2	“transcriptional regulation”
FGF9	“up-regulates quantity by expression”	TGFB1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	2
Uncertain significance	85
Likely benign	29
Benign	40

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
1678668	NM_002010.3(FGF9):c.566C>G (p.Pro189Arg)	Pathogenic
444874	NM_002010.3(FGF9):c.184A>G (p.Arg62Gly)	Pathogenic
8705	NM_002010.3(FGF9):c.296G>A (p.Ser99Asn)	Pathogenic
1804963	NM_002010.3(FGF9):c.11T>C (p.Leu4Ser)	Likely pathogenic
2413189	NM_002010.3(FGF9):c.430T>C (p.Trp144Arg)	Likely pathogenic

SpliceAI

1076 predictions. Top by Δscore:

Variant	Effect	Δscore
13:21681039:CA:C	acceptor_loss	1.0000
13:21681040:A:AG	acceptor_gain	1.0000
13:21681040:AGGC:A	acceptor_loss	1.0000
13:21681041:G:GG	acceptor_gain	1.0000
13:21681041:GGC:G	acceptor_gain	1.0000
13:21681141:GATCA:G	donor_gain	1.0000
13:21681142:ATCA:A	donor_gain	1.0000
13:21681143:TCA:T	donor_gain	1.0000
13:21681144:CA:C	donor_gain	1.0000
13:21681144:CAGTA:C	donor_loss	1.0000
13:21681145:AGT:A	donor_loss	1.0000
13:21681146:G:GG	donor_gain	1.0000
13:21681146:GTAA:G	donor_loss	1.0000
13:21681147:TAAGT:T	donor_loss	1.0000
13:21681148:AA:A	donor_loss	1.0000
13:21681149:AG:A	donor_loss	1.0000
13:21681150:G:C	donor_loss	1.0000
13:21701184:TTACA:T	acceptor_loss	1.0000
13:21701185:TACA:T	acceptor_loss	1.0000
13:21701187:CAGGA:C	acceptor_loss	1.0000
13:21701188:A:AG	acceptor_gain	1.0000
13:21701188:A:AT	acceptor_loss	1.0000
13:21701188:AG:A	acceptor_gain	1.0000
13:21701189:G:GT	acceptor_gain	1.0000
13:21701189:GG:G	acceptor_gain	1.0000
13:21701189:GGA:G	acceptor_gain	1.0000
13:21701189:GGAA:G	acceptor_gain	1.0000
13:21701189:GGAAA:G	acceptor_gain	1.0000
13:21672190:G:GG	donor_gain	0.9900
13:21681033:T:A	acceptor_gain	0.9900

AlphaMissense

1349 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:21672097:G:C	R62T	1.000
13:21672097:G:T	R62M	1.000
13:21672098:G:C	R62S	1.000
13:21672098:G:T	R62S	1.000
13:21672103:G:T	R64M	1.000
13:21672104:G:C	R64S	1.000
13:21672104:G:T	R64S	1.000
13:21672106:A:C	Q65P	1.000
13:21672109:T:A	L66Q	1.000
13:21672109:T:C	L66P	1.000
13:21672111:T:G	Y67D	1.000
13:21672114:T:C	C68R	1.000
13:21672115:G:A	C68Y	1.000
13:21672115:G:T	C68F	1.000
13:21672116:C:G	C68W	1.000
13:21672118:G:T	R69M	1.000
13:21672124:G:A	G71E	1.000
13:21672124:G:T	G71V	1.000
13:21672126:T:C	F72L	1.000
13:21672128:T:A	F72L	1.000
13:21672128:T:G	F72L	1.000
13:21672133:T:C	L74S	1.000
13:21672162:G:A	G84R	1.000
13:21672162:G:C	G84R	1.000
13:21672163:G:A	G84E	1.000
13:21672163:G:T	G84V	1.000
13:21681048:T:C	L95P	1.000
13:21681054:T:C	F97S	1.000
13:21681059:A:C	S99R	1.000
13:21681060:G:T	S99I	1.000

dbSNP variants (sampled 300 via entrez): RS1000040010 (13:21698745 C>T), RS1000155659 (13:21692196 A>G), RS1000205518 (13:21670274 C>T), RS1000295211 (13:21676183 C>G), RS1000315604 (13:21693027 C>G,T), RS1000648288 (13:21679709 C>A,T), RS1000660239 (13:21675156 G>T), RS1000661110 (13:21703964 A>G), RS1000672295 (13:21698074 C>T), RS1000674274 (13:21673855 G>A,C,T), RS1000882075 (13:21670025 C>G,T), RS1000898581 (13:21702621 A>G), RS1000957931 (13:21669144 G>A,C), RS1001199623 (13:21670921 GCTCCTCGACTGC>G), RS1001242342 (13:21704751 T>C)

Disease associations

OMIM: gene MIM:600921 | disease phenotypes: MIM:612961

GenCC curated gene-disease

Disease	Classification	Inheritance
multiple synostoses syndrome	Definitive	Autosomal dominant
multiple synostoses syndrome 3	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
multiple synostoses syndrome	Definitive	AD

Mondo (2): multiple synostoses syndrome 3 (MONDO:0013064), multiple synostoses syndrome (MONDO:0017923)

Orphanet (1): Multiple synostoses syndrome (Orphanet:3237)

HPO phenotypes

21 total (21 of 21 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000175	Cleft palate
HP:0000268	Dolichocephaly
HP:0000324	Facial asymmetry
HP:0000405	Conductive hearing impairment
HP:0000520	Proptosis
HP:0001156	Brachydactyly
HP:0001387	Joint stiffness
HP:0001440	Metatarsal synostosis
HP:0001597	Abnormal nail morphology
HP:0002967	Cubitus valgus
HP:0003041	Humeroradial synostosis
HP:0004279	Short palm
HP:0006064	Limited interphalangeal movement
HP:0007598	Bilateral single transverse palmar creases
HP:0008080	Hallux varus
HP:0009701	Metacarpal synostosis
HP:0010055	Broad hallux
HP:0010579	Cone-shaped epiphysis
HP:0010621	Cutaneous syndactyly of toes
HP:0011304	Broad thumb

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST001806_18	Corneal structure	4.000000e-09
GCST002337_26	Amyotrophic lateral sclerosis (sporadic)	1.000000e-06
GCST003659_8	Modified Stumvoll Insulin Sensitivity Index (BMI interaction)	4.000000e-09
GCST003832_14	Asthma (childhood onset)	9.000000e-06
GCST003989_27	Chin dimples	3.000000e-13
GCST005667_31	Central corneal thickness	1.000000e-09
GCST006624_113	Systolic blood pressure	4.000000e-20
GCST007928_63	Medication use (diuretics)	5.000000e-16
GCST007929_4	Medication use (calcium channel blockers)	2.000000e-14
GCST007930_39	Medication use (agents acting on the renin-angiotensin system)	5.000000e-12
GCST010118_90	Type 2 diabetes	3.000000e-09
GCST90011899_8	Aspartate aminotransferase levels	6.000000e-11

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004345	corneal topography
EFO:0004340	body mass index
EFO:0004471	insulin sensitivity measurement
EFO:0005213	central corneal thickness
EFO:0006335	systolic blood pressure
EFO:0009928	Diuretic use measurement
EFO:0009930	Calcium channel blocker use measurement
EFO:0009931	Agents acting on the renin-angiotensin system use measurement
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567839	Multiple Synostoses Syndrome 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

77 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression	6
Estradiol	increases expression, affects abundance, affects cotreatment, decreases reaction, increases abundance (+2 more)	5
Tetrachlorodibenzodioxin	decreases reaction, increases expression, affects expression	5
Benzo(a)pyrene	increases expression, increases methylation, decreases reaction	4
methylmercuric chloride	decreases expression, increases expression	3
trichostatin A	affects cotreatment, decreases expression, increases expression	3
bisphenol A	decreases expression, decreases methylation	2
entinostat	decreases expression, affects cotreatment	2
belinostat	decreases expression, affects cotreatment	2
Fulvestrant	affects cotreatment, increases methylation, decreases expression	2
Vorinostat	affects cotreatment, decreases expression	2
Panobinostat	affects cotreatment, decreases expression	2
Arsenic	decreases expression, increases abundance, affects methylation, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Polycyclic Aromatic Hydrocarbons	increases expression	2
Progesterone	affects cotreatment, decreases reaction, increases abundance, increases reaction, decreases expression (+1 more)	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
Particulate Matter	increases abundance, decreases reaction, increases expression, decreases methylation	2
bisphenol F	affects cotreatment, increases methylation	1
isopentenyl pyrophosphate	increases expression	1
trilostane	affects cotreatment, decreases reaction, increases abundance	1
ethyl-p-hydroxybenzoate	decreases expression	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
butyraldehyde	increases expression	1
benzo(k)fluoranthene	increases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	increases expression	1
manganese chloride	increases abundance, affects cotreatment, decreases expression	1
1,2,5,6-dibenzanthracene	increases expression	1
ferrous chloride	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D8LA	Ubigene HCT 116 FGF9 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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