FGF8

Summary

FGF8 (fibroblast growth factor 8, HGNC:3686) is a protein-coding gene on chromosome 10q24.32, encoding Fibroblast growth factor 8 (P55075). 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 is known to be a factor that supports androgen and anchorage independent growth of mammary tumor cells. Overexpression of this gene has been shown to increase tumor growth and angiogensis. The adult expression of this gene is restricted to testes and ovaries. Temporal and spatial pattern of this gene expression suggests its function as an embryonic epithelial factor. Studies of the mouse and chick homologs revealed roles in midbrain and limb development, organogenesis, embryo gastrulation and left-right axis determination. The alternative splicing of this gene results in four transcript variants.

Source: NCBI Gene 2253 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypogonadotropic hypogonadism 6 with or without anosmia (Strong, GenCC) — +5 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 135 total — 5 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 186
• MANE Select transcript: NM_033163

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3686
Approved symbol	FGF8
Name	fibroblast growth factor 8
Location	10q24.32
Locus type	gene with protein product
Status	Approved
Aliases	AIGF
Ensembl gene	ENSG00000107831
Ensembl biotype	protein_coding
OMIM	600483
Entrez	2253

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000320185, ENST00000344255, ENST00000346714, ENST00000347978, ENST00000469792, ENST00000485728, ENST00000618991

RefSeq mRNA: 5 — MANE Select: NM_033163 NM_001206389, NM_006119, NM_033163, NM_033164, NM_033165

CCDS: CCDS73185, CCDS7515, CCDS7516, CCDS7517, CCDS7518

Canonical transcript exons

ENST00000320185 — 6 exons

Exon	Start	End
ENSE00000721888	101775130	101775216
ENSE00001137548	101775740	101775776
ENSE00003508711	101771463	101771569
ENSE00003572448	101774732	101774912
ENSE00003664237	101775869	101776114
ENSE00003722786	101770109	101770619

Expression profiles

Bgee: expression breadth ubiquitous, 109 present calls, max score 79.77.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3708 / max 31.2921, expressed in 132 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
111097	0.3075	126
111096	0.0632	33

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	79.77	gold quality
metanephric glomerulus	UBERON:0004736	79.44	gold quality
endometrium epithelium	UBERON:0004811	76.82	gold quality
Brodmann (1909) area 10	UBERON:0013541	68.92	gold quality
paraflocculus	UBERON:0005351	67.72	gold quality
sural nerve	UBERON:0015488	67.40	silver quality
cerebellar vermis	UBERON:0004720	67.07	gold quality
middle frontal gyrus	UBERON:0002702	66.50	gold quality
frontal pole	UBERON:0002795	66.32	gold quality
tendon of biceps brachii	UBERON:0008188	64.25	gold quality
Brodmann (1909) area 9	UBERON:0013540	59.25	gold quality
monocyte	CL:0000576	58.10	gold quality
buccal mucosa cell	CL:0002336	57.43	gold quality
medial globus pallidus	UBERON:0002477	57.06	gold quality
anterior cingulate cortex	UBERON:0009835	56.85	gold quality
leukocyte	CL:0000738	56.74	gold quality
prefrontal cortex	UBERON:0000451	55.73	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	55.62	gold quality
right frontal lobe	UBERON:0002810	54.62	gold quality
lower esophagus mucosa	UBERON:0035834	54.25	gold quality
neocortex	UBERON:0001950	53.90	gold quality
frontal cortex	UBERON:0001870	53.69	gold quality
globus pallidus	UBERON:0001875	53.44	gold quality
seminal vesicle	UBERON:0000998	52.90	gold quality
tendon	UBERON:0000043	52.69	silver quality
cerebral cortex	UBERON:0000956	52.20	gold quality
primary visual cortex	UBERON:0002436	51.94	gold quality
vastus lateralis	UBERON:0001379	51.73	gold quality
stromal cell of endometrium	CL:0002255	51.61	silver quality
hypothalamus	UBERON:0001898	50.86	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.81

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
MYOD1	Activation
WNT1	Activation

Upstream regulators (CollecTRI, top): AR, CREB1, EMX2, EN1, EN2, ESR1, FMR1, FOXC2, GBX2, GLI2, GLI3, HAND1, HOXA13, LMX1B, MYC, MYOG, NFKB1, NFKB, OTX2, PAX5, PAX6, PBX1, PBX2, PBX3, PBX4, POU5F1, RARA, RELA, SOX3, SP8, TBX1, TBX6, TWIST1, VDR, WT1

miRNA regulators (miRDB)

4 targeting FGF8, 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-545-3P	99.95	70.74	2783
HSA-MIR-3120-3P	99.54	70.28	2669
HSA-MIR-548AS-3P	99.12	69.12	2294
HSA-MIR-6796-5P	95.37	66.08	1120

Literature-anchored findings (GeneRIF, showing 40)

• widespread expression pattern suggests FGF8 has physiological roles in adult tissue as well as in development (PMID:11953856)
• Promoter of FGF8 reveals a unique regulation by unliganded RARalpha. (PMID:12054865)
• Regulation of FGF8 expression by the androgen receptor in human prostate cancer. (PMID:12140757)
• isoform b isoform expressed in prostate cancer, and is of prognostic value (PMID:12778074)
• Repression of fgf8 might be directly or indirectly involved in this transcriptional control by TGF-beta. (PMID:15935652)
• We also show that the mode of FGF8 receptor-binding specificity is distinct from that of other FGFs and provide the first biochemical evidence for a physiological FGF8b-FGFR1c interaction during mid-hindbrain development. (PMID:16384934)
• novel role for nuclear factor-kappaB in the regulation of fibroblast growth factor 8(FGF8) expression in prostate cancer cells is uncovered (PMID:16683270)
• These results indicate that mutations are rare in FGF8 and FGFR2 in hypospadias, but gene variants may influence the risk. (PMID:17264867)
• FGF8 has a role in regulation of autocrine and paracrine loops in the growth regulation of breast, prostate and ovarian cancer [review] (PMID:17512240)
• Fgf8 is required for the node to impart left-right asymmetry on specific tissues Excess Fgf8 signaling following a loss of RA may stimulate the node to generate asymmetry in presomitic mesoderm, leading to left-right asymmetry in somitogenesis clock (PMID:17600781)
• FGF-8 is expressed at a high frequency in bone metastases of human prostate cancer and expression of FGF-8 in PC-3 prostate cancer cells increases their growth as intratibial tumors. (PMID:18386787)
• Decreased FGF8 signaling causes deficiency of GnRH in humans. (PMID:18596921)
• associated gene expression signature suggests potential mediators for FGF-8b actions on prostate cancer progression and metastasis (PMID:19415685)
• We identified the first nonsense mutations in the FGF8 gene in familial isolated hypogonadotropic hypogonadism with variable degrees of GnRH deficiency and olfactory phenotypes, confirming that loss-of-function mutations in FGF8 cause GnRH deficiency. (PMID:20463092)
• FGF8b is able to induce fast growth in strongly hypoxic tumour microenvironment whereas VEGF-stimulated growth advantage is associated with improved perfusion and oxygenation of prostate tumour xenografts (PMID:21034500)
• Results suggest that increased FGF-8 in human prostate may also contribute to prostate tumorigenesis by stromal activation. (PMID:21076617)
• This novel mechanism of viral-mediated FGF8 upregulation may implicate a new role of oncoviruses in human carcinogenesis. (PMID:21119603)
• FGF8, FGF17, and FGF18 are involved in autocrine and paracrine signaling in HCC and enhance the survival of tumor cells under stress conditions, malignant behavior, and neoangiogenesis. (PMID:21319186)
• We implicate FGF8 in the etiology of recessive holoprosencephaly and potentially septo-optic dysplasia/Moebius syndrome (PMID:21832120)
• In vivo stimulation of BT-474 cell growth by progesterone is associated with down-regulation of FGF-8. (PMID:22237711)
• genetic association studies in 103 patients from US and UK: Mutations in FGF8, FGFR1, or PROKR2 contributed to 7.8% of patients with combined pituitary hormone deficiency or septo-optic dysplasia. Data suggest genetic overlap with Kallmann syndrome. (PMID:22319038)
• The results suggest that prolonged and enhanced human fibroblast growth factor 8b signaling induces dramatic changes in the epididymis and testis that lead to infertility in a portion of the human fibroblast growth factor 8b transgenic male mice. (PMID:22423049)
• A novel FGF8b-binding peptide with anti-tumor effect on prostate cancer. (PMID:23466786)
• genetic association study in population in Massachusetts: Data suggest that clinical features in Kallmann syndrome (KS) are associated with genetic causes: dental agenesis/digital bony abnormalities are associated with variations/mutations in FGF8. (PMID:23533228)
• Together, these data demonstrate that FGF (FGFR-2 and Fgf8)signaling regulates cell proliferation and cell polarity and that these cell processes contribute to facial morphogenesis. (PMID:23906837)
• Regulation of neurogenesis by Fgf8a requires Cdc42 signaling and a novel Cdc42 effector protein (PMID:23994638)
• The oncoprotein HBXIP enhances angiogenesis and growth of breast cancer through modulating FGF8 and VEGF. (PMID:24464787)
• Scube3 may be a critical upstream regulator of fast fiber myogenesis by modulating fgf8 signaling during zebrafish embryogenesis (PMID:24849601)
• FGF8 mutations (p.Gly29_Arg34dup and p.Pro26Leu) contribute to the formation of the VATER/VACTERL association. (PMID:25131394)
• Data indicate that overexpression of fibroblast growth factor 8 (FGF8) correlates with lymph node metastasis and poor prognosis in colorectal cancer (CRC). (PMID:25473897)
• Our results link FGF8, c-Abl and p300 in a regulatory pathway that controls DeltaNp63alpha protein stability and transcriptional activity. (PMID:25911675)
• in one holoprosencephaly (HPE) family, a deleterious FGFR1 allele was transmitted from one parent and a loss-of-function allele in FGF8 from the other parent to both affected daughters. This family is one of the clearest examples to date of gene:gene synergistic interactions causing HPE in humans. (PMID:26931467)
• Bonferroni adjusted p-value: 0.04). No statistically significant associations were identified in the other ethnic groups. In conclusion, variant/s in FGF2 and FGF8 may predispose diabetics with CKD to LEA. (PMID:27237708)
• Fgf8 activates Ras-ERK pathway to specify hindbrain. Downstream of ERK, Pea3 specifies isthmus (rhombomere 0, r0), and Irx2 may specify r1, where the cerebellum is formed. (PMID:27273073)
• The FBLN1/FGF8 interaction may also be involved in the survival of neural crest cell population during development. (PMID:27402846)
• Genetic testing identified a de novo, heterozygous mutation in fibroblast growth factor receptor 1 (FGFR1 p.L630P). L630 resides on the ATP binding cleft of the FGFR1 tyrosine kinase domain, and L630P is predicted to cause a complete loss of receptor function. Cell-based assays confirmed that L630P abolishes FGF8 signaling activity (PMID:28195315)
• we also found that FGF8 increased the expression of YAP1 and knockdown of YAP1 eliminated the upregulation of EGFR and the resistance to EGFR inhibition induced by FGF8. Our study provides evidence that FGF8 plays an important role in the resistance to EGFR inhibition of human hepatocellular carcinoma cells (PMID:28791365)
• Study demonstrated that FGF8 can regulate germ cell fate by modulating the dynamic equilibrium between differentiation and self-renewal. (PMID:28898437)
• we employ a sensitive assay of human FGF8 variants in zebrafish to demonstrate that the spectrum of isoforms of FGF8 produced by alternative splicing can provide key insights into the genetic susceptibility to human malformations (PMID:29584859)
• FGF8 and FGFR3 may therefore play an important role in the onset of deep zone necrosis and pathogenesis in Kashin-Beck disease in adolescent children. (PMID:29626475)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	fgf8a	ENSDARG00000003399
danio_rerio	fgf8b	ENSDARG00000039615
mus_musculus	Fgf8	ENSMUSG00000025219
rattus_norvegicus	Fgf8	ENSRNOG00000017524

Paralogs (21): FGF10 (ENSG00000070193), FGF22 (ENSG00000070388), FGF4 (ENSG00000075388), FGF20 (ENSG00000078579), FGF14 (ENSG00000102466), FGF9 (ENSG00000102678), FGF21 (ENSG00000105550), 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 8 — P55075 (reviewed: P55075)

Alternative names: Androgen-induced growth factor, Heparin-binding growth factor 8

All UniProt accessions (3): P55075, A0A087X1S5, R4GMQ3

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. Required for normal brain, eye, ear and limb development during embryogenesis. Required for normal development of the gonadotropin-releasing hormone (GnRH) neuronal system. Plays a role in neurite outgrowth in hippocampal cells.

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.

Disease relevance. Hypogonadotropic hypogonadism 6 with or without anosmia (HH6) [MIM:612702] A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. In some cases, it is associated with non-reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. The genetics of hypogonadotropic hypogonadism involves various modes of transmission. Oligogenic inheritance has been reported in some patients carrying mutations in FGF8 as well as in other HH-associated genes including FGFR1. Hypoplastic femurs and pelvis (HYPOFP) [MIM:619545] An autosomal dominant disorder characterized by isolated bilateral hypoplasia of the femoral and pelvic bones. The gene represented in this entry is involved in disease pathogenesis. Duplications encompassing the FGF8 locus have been found in unrelated families with isolated bilateral hypoplasia of the femoral and pelvic bone. The phenotype is most likely the result of position effects causing altered FGF8 expression rather than gene dosage.

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

Isoforms (4)

UniProt ID	Names	Canonical?
P55075-1	FGF-8E	yes
P55075-2	FGF-8A
P55075-3	FGF-8B
P55075-4	FGF-8F

RefSeq proteins (5): NP_001193318, NP_006110, NP_149353, NP_149354, NP_149355 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002209	Fibroblast_GF_fam	Family
IPR008996	IL1/FGF	Homologous_superfamily

Pfam: PF00167

UniProt features (31 total): strand 11, sequence variant 6, helix 5, turn 3, splice variant 3, signal peptide 1, chain 1, glycosylation site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2FDB	X-RAY DIFFRACTION	2.28

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P55075-F1	81.34	0.63

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): 155

Function

Pathways and Gene Ontology

Reactome pathways

40 pathways

ID	Pathway
R-HSA-9832991	Formation of the posterior neural plate
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

MSigDB gene sets: 718 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_FOREBRAIN_NEURON_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_POSITIVE_REGULATION_OF_MITOTIC_NUCLEAR_DIVISION, REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, LEE_NEURAL_CREST_STEM_CELL_DN, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, GOBP_GLAND_MORPHOGENESIS, GOBP_OUTFLOW_TRACT_SEPTUM_MORPHOGENESIS, GOBP_METANEPHROS_DEVELOPMENT

GO Biological Process (85): MAPK cascade (GO:0000165), branching involved in blood vessel morphogenesis (GO:0001569), metanephros development (GO:0001656), branching involved in ureteric bud morphogenesis (GO:0001658), organ induction (GO:0001759), mesonephros development (GO:0001823), neural plate morphogenesis (GO:0001839), heart looping (GO:0001947), blood vessel remodeling (GO:0001974), outflow tract septum morphogenesis (GO:0003148), epithelial to mesenchymal transition involved in endocardial cushion formation (GO:0003198), response to oxidative stress (GO:0006979), gastrulation (GO:0007369), motor neuron axon guidance (GO:0008045), mesodermal cell migration (GO:0008078), positive regulation of cell population proliferation (GO:0008284), gonad development (GO:0008406), fibroblast growth factor receptor signaling pathway (GO:0008543), response to xenobiotic stimulus (GO:0009410), anatomical structure morphogenesis (GO:0009653), dorsal/ventral pattern formation (GO:0009953), positive regulation of gene expression (GO:0010628), pallium development (GO:0021543), subpallium development (GO:0021544), forebrain dorsal/ventral pattern formation (GO:0021798), cell proliferation in forebrain (GO:0021846), forebrain neuron development (GO:0021884), neurogenesis (GO:0022008), signal transduction involved in regulation of gene expression (GO:0023019), regulation of cell migration (GO:0030334), male genitalia development (GO:0030539), thyroid gland development (GO:0030878), otic vesicle formation (GO:0030916), midbrain-hindbrain boundary development (GO:0030917), dorsal/ventral axon guidance (GO:0033563), embryonic hindlimb morphogenesis (GO:0035116), organ growth (GO:0035265), aorta morphogenesis (GO:0035909), odontogenesis (GO:0042476), regulation of odontogenesis of dentin-containing tooth (GO:0042487)

GO Molecular Function (4): type 1 fibroblast growth factor receptor binding (GO:0005105), type 2 fibroblast growth factor receptor binding (GO:0005111), growth factor activity (GO:0008083), chemoattractant activity (GO:0042056)

GO Cellular Component (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), external side of plasma membrane (GO:0009897)

Reactome top-level categories

Rollup of top-16 pathways:

Category	Pathways
Downstream signaling of activated FGFR1	4
FGFR3 ligand binding and activation	2
Gastrulation	1
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 FGFR2	1
Downstream signaling of activated FGFR3	1
Downstream signaling of activated FGFR4	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
branching morphogenesis of an epithelial tube	2
kidney development	2
fibroblast growth factor receptor binding	2
receptor ligand activity	2
cellular anatomical structure	2
intracellular signaling cassette	1
angiogenesis	1
blood vessel morphogenesis	1
ureteric bud morphogenesis	1
regulation of animal organ formation	1
specification of animal organ identity	1
developmental induction	1
positive regulation of animal organ morphogenesis	1
neural plate development	1
morphogenesis of embryonic epithelium	1
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
tissue remodeling	1
outflow tract morphogenesis	1
cardiac septum morphogenesis	1
endocardial cushion formation	1
cardiac epithelial to mesenchymal transition	1
response to stress	1
ectoderm formation	1
endoderm formation	1
mesoderm formation	1
embryonic morphogenesis	1
axon guidance	1
ameboidal-type cell migration	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
development of primary sexual characteristics	1
animal organ development	1
reproductive structure development	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to fibroblast growth factor stimulus	1
response to chemical	1
developmental process	1
anatomical structure development	1

Protein interactions and networks

STRING

4356 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FGF8	FGFR1	P11362	999
FGF8	FGFR3	P22607	995
FGF8	FGFR2	P18443	992
FGF8	EGF	P01133	991
FGF8	FGFR4	P22455	991
FGF8	KL	Q9UEF7	990
FGF8	SHH	Q15465	954
FGF8	HSPG2	P98160	946
FGF8	DCN	P07585	936
FGF8	FGFBP1	Q14512	912
FGF8	FGF23	Q9GZV9	893
FGF8	CDH2	P19022	883
FGF8	CD44	P16070	873
FGF8	BMP4	P12644	868
FGF8	HGF	P14210	867

IntAct

7 interactions, top by confidence:

A	B	Type	Score
FGF8	AP3B1	psi-mi:“MI:0914”(association)	0.350
FGF17	ANKHD1-EIF4EBP3	psi-mi:“MI:0914”(association)	0.350
FGF8	ANKHD1-EIF4EBP3	psi-mi:“MI:0914”(association)	0.350
SLC4A8	PSMA7	psi-mi:“MI:0914”(association)	0.350
FGFR2	FGF8	psi-mi:“MI:2364”(proximity)	0.270
FGFR1	FGF8	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (173): FGF8 (Co-localization), FGF8 (Co-localization), FGF8 (Protein-peptide), FGF8 (Protein-peptide), TTC30A (Affinity Capture-MS), IFT80 (Affinity Capture-MS), IFT88 (Affinity Capture-MS), FAM91A1 (Affinity Capture-MS), ANKHD1 (Affinity Capture-MS), IFT52 (Affinity Capture-MS), IFT57 (Affinity Capture-MS), IFT81 (Affinity Capture-MS), HIST1H1T (Affinity Capture-MS), ANKHD1-EIF4EBP3 (Affinity Capture-MS), YTHDC2 (Affinity Capture-MS)

ESM2 similar proteins: B0LPN4, E9PZQ0, E9Q401, F1LMY4, O14926, O18728, O95834, P10767, P11403, P11716, P16960, P21658, P21817, P30957, P47823, P55075, P85845, Q13144, Q16658, Q24498, Q24524, Q32M02, Q3U7R1, Q4R4H3, Q5CZL1, Q5E9M9, Q5XGM5, Q61553, Q64350, Q6P6T4, Q6P9Z4, Q6PFQ7, Q6SZW1, Q7TNG5, Q7TSA0, Q7Z6L1, Q8CHW4, Q8IXI1, Q8JZN7, Q8K2J0

Diamond homologs: A0MTF4, A6P7H6, M3X9S6, O15520, O35565, O43320, O54769, O57341, P03968, P05230, P05524, P10767, P11403, P11487, P12034, P12226, P15656, P19596, P20002, P21658, P21781, P31371, P34004, P36363, P36364, P36386, P37237, P41444, P48801, P48802, P48803, P48804, P48805, P48806, P48807, P48808, P54130, P55075, P61148, P61149

SIGNOR signaling

14 interactions.

A	Effect	B	Mechanism
FGF8	“up-regulates quantity by expression”	MYOD1	“transcriptional regulation”
EN2	“down-regulates quantity by repression”	FGF8	“transcriptional regulation”
EN1	“down-regulates quantity by repression”	FGF8	“transcriptional regulation”
PBX1	“down-regulates quantity by repression”	FGF8	“transcriptional regulation”
PBX2	“down-regulates quantity by repression”	FGF8	“transcriptional regulation”
PBX3	“down-regulates quantity by repression”	FGF8	“transcriptional regulation”
PBX4	“down-regulates quantity by repression”	FGF8	“transcriptional regulation”
GLI3	“down-regulates quantity”	FGF8	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	11
Uncertain significance	66
Likely benign	28
Benign	8

Top pathogenic / likely-pathogenic (16)

Variant ID	HGVS	Classification
599013	NM_033163.5(FGF8):c.379C>T (p.Arg127Ter)	Pathogenic
9121	NM_033163.5(FGF8):c.40C>A (p.His14Asn)	Pathogenic
9123	NM_033163.5(FGF8):c.118T>C (p.Phe40Leu)	Pathogenic
9124	NM_033163.5(FGF8):c.298A>G (p.Lys100Glu)	Pathogenic
9125	NM_033163.5(FGF8):c.379C>G (p.Arg127Gly)	Pathogenic
235080	NM_033163.5(FGF8):c.317C>A (p.Ala106Glu)	Likely pathogenic
235081	NM_033163.5(FGF8):c.356C>T (p.Thr119Met)	Likely pathogenic
235083	NM_033163.5(FGF8):c.617G>A (p.Arg206Gln)	Likely pathogenic
2690947	NM_033163.5(FGF8):c.290T>C (p.Leu97Pro)	Likely pathogenic
3393569	NM_033163.5(FGF8):c.32+1G>C	Likely pathogenic
392880	NM_033163.5(FGF8):c.287T>A (p.Val96Asp)	Likely pathogenic
435185	NM_033163.5(FGF8):c.628_629dup (p.His211fs)	Likely pathogenic
545413	NM_033163.5(FGF8):c.157-1G>A	Likely pathogenic
545456	NM_033163.5(FGF8):c.469G>T (p.Val157Phe)	Likely pathogenic
545459	NM_033163.5(FGF8):c.157G>C (p.Val53Leu)	Likely pathogenic
545517	NM_033163.5(FGF8):c.444+1G>A	Likely pathogenic

SpliceAI

626 predictions. Top by Δscore:

Variant	Effect	Δscore
10:101770615:TTGCT:T	acceptor_gain	1.0000
10:101770616:TGCT:T	acceptor_gain	1.0000
10:101770618:CT:C	acceptor_gain	1.0000
10:101770620:C:CC	acceptor_gain	1.0000
10:101770620:C:CG	acceptor_loss	1.0000
10:101770621:T:A	acceptor_loss	1.0000
10:101770626:G:C	acceptor_gain	1.0000
10:101770626:G:GC	acceptor_gain	1.0000
10:101771460:CA:C	donor_loss	1.0000
10:101771462:C:CT	donor_loss	1.0000
10:101771565:CTTTG:C	acceptor_gain	1.0000
10:101771566:TTTG:T	acceptor_gain	1.0000
10:101771567:TTG:T	acceptor_gain	1.0000
10:101771567:TTGCT:T	acceptor_loss	1.0000
10:101771568:TG:T	acceptor_gain	1.0000
10:101771570:C:CA	acceptor_loss	1.0000
10:101771570:C:CC	acceptor_gain	1.0000
10:101771574:C:CT	acceptor_gain	1.0000
10:101771575:A:T	acceptor_gain	1.0000
10:101774725:GCCTT:G	donor_loss	1.0000
10:101774726:CCTTA:C	donor_loss	1.0000
10:101774729:T:TG	donor_loss	1.0000
10:101774730:A:AC	donor_gain	1.0000
10:101774731:C:CA	donor_loss	1.0000
10:101774731:C:CC	donor_gain	1.0000
10:101775867:A:AC	donor_gain	1.0000
10:101775868:C:CC	donor_gain	1.0000
10:101775868:CAGG:C	donor_gain	1.0000
10:101770617:GCT:G	acceptor_gain	0.9900
10:101770618:CTC:C	acceptor_gain	0.9900

AlphaMissense

1583 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:101770449:C:A	K194N	1.000
10:101770449:C:G	K194N	1.000
10:101770455:G:C	F192L	1.000
10:101770455:G:T	F192L	1.000
10:101770456:A:C	F192C	1.000
10:101770456:A:G	F192S	1.000
10:101770457:A:G	F192L	1.000
10:101770507:C:A	G175V	1.000
10:101770507:C:T	G175D	1.000
10:101770508:C:A	G175C	1.000
10:101770508:C:G	G175R	1.000
10:101770518:G:C	F171L	1.000
10:101770518:G:T	F171L	1.000
10:101770519:A:C	F171C	1.000
10:101770519:A:G	F171S	1.000
10:101770520:A:G	F171L	1.000
10:101770555:A:G	L159P	1.000
10:101770564:T:C	Y156C	1.000
10:101770569:G:C	N154K	1.000
10:101770569:G:T	N154K	1.000
10:101770570:T:A	N154I	1.000
10:101770576:A:G	L152P	1.000
10:101770590:G:C	F147L	1.000
10:101770590:G:T	F147L	1.000
10:101770591:A:C	F147C	1.000
10:101770591:A:G	F147S	1.000
10:101770592:A:C	F147V	1.000
10:101770592:A:G	F147L	1.000
10:101770596:G:C	C145W	1.000
10:101770597:C:A	C145F	1.000

dbSNP variants (sampled 300 via entrez): RS1001002866 (10:101779224 G>A,C), RS1001461327 (10:101779525 G>A), RS1001559496 (10:101771324 C>T), RS1001879235 (10:101770583 T>C), RS1002062805 (10:101777965 G>A), RS1002327496 (10:101771667 G>T), RS1002998549 (10:101774844 G>A,T), RS1003464578 (10:101776491 C>T), RS1003524842 (10:101781249 G>A,C), RS1003577185 (10:101781458 T>C,G), RS1003733813 (10:101780105 C>T), RS1004231474 (10:101779827 G>C), RS1004628195 (10:101776717 C>A,T), RS1005019941 (10:101773966 C>G), RS1005630194 (10:101774554 C>T)

Disease associations

OMIM: gene MIM:600483 | disease phenotypes: MIM:612702, MIM:236100, MIM:147950, MIM:261540

GenCC curated gene-disease

Disease	Classification	Inheritance
hypogonadotropic hypogonadism 6 with or without anosmia	Strong	Autosomal dominant
congenital heart disease	Moderate	Autosomal dominant
femoral agenesis/hypoplasia	Moderate	Autosomal dominant
holoprosencephaly	Supportive	Autosomal recessive
hypogonadotropic hypogonadism	Supportive	Autosomal dominant
Kallmann syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
congenital heart disease	Moderate	AD

Mondo (10): hypogonadotropic hypogonadism 6 with or without anosmia (MONDO:0012988), semilobar holoprosencephaly (MONDO:0700419), holoprosencephaly (MONDO:0016296), hypogonadotropic hypogonadism (MONDO:0018555), Peters plus syndrome (MONDO:0009856), holoprosencephaly 1 (MONDO:0009349), microcephaly (MONDO:0001149), congenital heart disease (MONDO:0005453), Kallmann syndrome (MONDO:0018800), femoral agenesis/hypoplasia (MONDO:0016032)

Orphanet (6): Kallmann syndrome (Orphanet:478), Semilobar holoprosencephaly (Orphanet:220386), Holoprosencephaly (Orphanet:2162), Male infertility with azoospermia or oligozoospermia due to single gene mutation (Orphanet:399805), Normosmic congenital hypogonadotropic hypogonadism (Orphanet:432), Peters plus syndrome (Orphanet:709)

HPO phenotypes

186 total (30 of 186 shown, HPO-id order):

HPO	Term
HP:0000002	Abnormality of body height
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000008	Abnormal morphology of female internal genitalia
HP:0000013	Hypoplasia of the uterus
HP:0000026	Male hypogonadism
HP:0000027	Azoospermia
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000054	Micropenis
HP:0000062	Ambiguous genitalia
HP:0000104	Renal agenesis
HP:0000118	Phenotypic abnormality
HP:0000119	Abnormality of the genitourinary system
HP:0000134	Female hypogonadism
HP:0000144	Decreased fertility
HP:0000161	Median cleft upper lip
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000193	Bifid uvula
HP:0000202	Orofacial cleft
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000407	Sensorineural hearing impairment
HP:0000446	Narrow nasal bridge
HP:0000453	Choanal atresia

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST005316_351	Intelligence (MTAG)	1.000000e-17
GCST006269_742	General cognitive ability	1.000000e-08
GCST007267_76	Systolic blood pressure	4.000000e-08
GCST009524_243	Household income (MTAG)	2.000000e-14

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence
EFO:0006335	systolic blood pressure
EFO:0009695	household income

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
D016142	Holoprosencephaly	C05.660.207.410; C10.500.034.875; C16.131.077.410; C16.131.260.380; C16.131.621.207.410; C16.131.666.034.875; C16.320.180.380
D017436	Kallmann Syndrome	C12.050.351.875.253.096.750; C12.200.706.316.096.750; C12.800.316.096.750; C16.131.939.316.096.750; C16.320.467; C19.391.119.096.750; C19.391.482.600
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C567199	Kallmann Syndrome 6 (supp.)
C537617	Krause-Kivlin syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression, increases methylation	8
trichostatin A	affects cotreatment, decreases expression	3
Tretinoin	increases expression, decreases expression, affects expression, affects cotreatment	3
entinostat	decreases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, increases reaction, affects cotreatment, decreases expression	2
Panobinostat	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
aristolochic acid I	increases expression	1
N(4)-hydroxycytidine	decreases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
glycolic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
Chir 99021	increases expression, increases reaction	1
thifluzamide	decreases expression	1
ramelteon	decreases expression	1
5-(4-((6-(allyloxy)-2,5,7,8-tetramethylchroman-2-yl)methoxy)-3-methoxybenzylidene)thiazolidine-2,4-dione	decreases expression	1
pyrachlostrobin	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	increases expression	1
bis-N,N-dimethylamino-2-(N-methylpyrrolyl)methyl cyclopentadienyl titanium (IV)	increases expression	1
Dabigatran	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Microplastics	decreases expression, increases abundance	1
Dolutegravir	increases expression	1
Abacavir	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Androgens	increases expression	1
Benzo(a)pyrene	increases methylation	1
Estradiol	affects cotreatment, decreases reaction, increases abundance, increases reaction	1
Folic Acid	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_D8L9	Ubigene HCT 116 FGF8 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT00328926	PHASE4	TERMINATED	Luveris® (Lutropin Alfa for Injection) in Women With Hypogonadotropic Hypogonadism (Luteinizing Hormone [LH] Less Than [<] 1.2 International Unit Per Liter [IU/L])
NCT01403532	PHASE4	COMPLETED	Sequential Therapy for Hypogonadotropic Hypogonadism
NCT01454011	PHASE4	COMPLETED	The Effect of Testosterone Replacement on the High Density Lipoprotein Cholesterol Subgroups
NCT01601327	PHASE4	COMPLETED	Effects of Medications in Patients With Hypogonadism
NCT02310074	PHASE4	UNKNOWN	Efficacy and Safety of Pulsatile Gonadotropin Releasing Hormone Pump Treatment in Patients With Idiopathic Hypogonadotropic Hypogonadism
NCT02880280	PHASE4	UNKNOWN	Human Menopausal Gonadotropin Combining With Human Chorionic Gonadotropin Treat Congenital Hypogonadotropic Hypogonadism
NCT03490513	PHASE4	COMPLETED	Aromatase Inhibitors and Weight Loss in Severely Obese Men With Hypogonadism
NCT04456296	PHASE4	COMPLETED	A Study of the Effect of Testosterone Replacement Therapy on Blood Pressure in Adult Male Participants With Hypogonadism
NCT05205837	PHASE4	TERMINATED	A Randomized, Double-blinded, Clinical, Placebo-controlled Trial on the Effects of Therapy With Letrozole and hUman Choriongonadotropin in Male Hypogonadism Induced by Illicit Use of Anabolic Androgenic Steroids- The LUCAS Trial
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494	PHASE3	COMPLETED	Management of Patent Ductus in Premature Infants
NCT01134302	PHASE3	UNKNOWN	Hybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983	PHASE3	WITHDRAWN	Effects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011	PHASE3	UNKNOWN	Application of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669	PHASE3	COMPLETED	Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262	PHASE3	COMPLETED	Intraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476	PHASE3	COMPLETED	Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194	PHASE3	COMPLETED	Dopamine Versus Norepinephrine Under General Anesthesia
NCT04702373	PHASE3	ACTIVE_NOT_RECRUITING	Training in Exercise Activities and Motion for Growth (TEAM 4 Growth) RCT
NCT05049590	PHASE3	COMPLETED	Acute Normovolemic Hemodilution in Complex Cardiac Surgery
NCT06406517	PHASE3	UNKNOWN	Comparative Effectiveness of Gadopiclenol for Evaluation of Adult Congenital Heart Anatomy and Hemodynamics
NCT06693674	PHASE3	RECRUITING	Effect of Sacubitril-Valsartan on Cardiac Structure and Function
NCT06955260	PHASE3	NOT_YET_RECRUITING	SGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure
NCT00467870	PHASE3	COMPLETED	Long-term Safety Study of Intramuscular Injections of 750 mg and 1000 mg Testosterone Undecanoate in Hypogonadal Men
NCT00962637	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Androxal™ Treatment in Men With Secondary Hypogonadism
NCT01067365	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Androxal Treatment in Men With Secondary Hypogonadism
NCT01532414	PHASE3	COMPLETED	Phase III Study to Evaluated Morning Testosterone Normalization in Men With Secondary Hypogonadism