FGF16

Summary

FGF16 (fibroblast growth factor 16, HGNC:3672) is a protein-coding gene on chromosome Xq21.1, encoding Fibroblast growth factor 16 (O43320). Plays an important role in the regulation of embryonic development, cell proliferation and cell differentiation, and is required for normal cardiomyocyte proliferation and heart development.

This gene encodes a member of a family of proteins that are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This gene is expressed in cardiac cells and is required for proper heart development. Mutation in this gene was also observed in individuals with metacarpal 4-5 fusion.

Source: NCBI Gene 8823 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndactyly type 8 (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 17 total — 2 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 6
• MANE Select transcript: NM_003868

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3672
Approved symbol	FGF16
Name	fibroblast growth factor 16
Location	Xq21.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000196468
Ensembl biotype	protein_coding
OMIM	300827
Entrez	8823

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000439435

RefSeq mRNA: 1 — MANE Select: NM_003868 NM_003868

CCDS: CCDS75996

Canonical transcript exons

ENST00000439435 — 3 exons

Exon	Start	End
ENSE00001775138	77456277	77457278
ENSE00001796880	77454157	77454260
ENSE00003715543	77447389	77447948

Expression profiles

Bgee: expression breadth broad, 65 present calls, max score 81.42.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3260 / max 76.2912, expressed in 104 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
209739	0.3260	104

Top tissues by expression

252 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	81.42	gold quality
tibialis anterior	UBERON:0001385	63.91	silver quality
deltoid	UBERON:0001476	53.83	gold quality
upper leg skin	UBERON:0004262	53.74	silver quality
ileal mucosa	UBERON:0000331	52.24	silver quality
pancreatic ductal cell	CL:0002079	51.08	silver quality
oocyte	CL:0000023	50.50	gold quality
epithelial cell of pancreas	CL:0000083	49.65	gold quality
quadriceps femoris	UBERON:0001377	49.55	gold quality
hindlimb stylopod muscle	UBERON:0004252	49.40	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
hair follicle	UBERON:0002073	49.18	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
myocardium	UBERON:0002349	48.87	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
vastus lateralis	UBERON:0001379	48.25	gold quality
left ventricle myocardium	UBERON:0006566	48.24	gold quality
orbitofrontal cortex	UBERON:0004167	48.20	gold quality
upper arm skin	UBERON:0004263	48.06	gold quality
cervix epithelium	UBERON:0004801	48.04	gold quality
oviduct epithelium	UBERON:0004804	48.00	gold quality
tongue squamous epithelium	UBERON:0006919	47.92	gold quality
mucosa of urinary bladder	UBERON:0001259	47.80	gold quality
skeletal muscle tissue	UBERON:0001134	47.52	gold quality
metanephric glomerulus	UBERON:0004736	47.45	gold quality
thymus	UBERON:0002370	47.42	gold quality
kidney epithelium	UBERON:0004819	47.39	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.69

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXP1, MEF2A, NFKB, PITX2

Literature-anchored findings (GeneRIF, showing 8)

• HUVEC clearly demonstrated chemotaxis towards FGF16. FGF16 enhanced cell migration in response to mechanical damage & failed to induce endothelial cell proliferation or sprouting in a three-dimensional in vitro angiogenesis assay. (PMID:16756958)
• Fgf-16 gene is a target for NF-kappaB activation in the postnatal heart. (PMID:20097674)
• impaired FGF16 function may also be responsible for connective tissue symptoms in MF4 patients. (PMID:24706454)
• Identification of an FGF16 mutation in metacarpal 4-5 fusion. (PMID:24878828)
• Experiments demonstrated FGF16 could promote proliferation of NCL-H460 cells by activating Akt, Erk1/2, and p38 MAPK signaling, whereas JNK had no significant effect. (PMID:28409700)
• MiRNA-144-3p inhibits high glucose induced cell proliferation through suppressing FGF16. (PMID:31292167)
• FGF16 is capable of inducing proliferation of iPSC-derived cardiac progenitor cells. (PMID:31801200)
• Patient-specific iPSC-derived cardiomyocytes reveal abnormal regulation of FGF16 in a familial atrial septal defect. (PMID:33956078)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	fgf16	ENSDARG00000042233
mus_musculus	Fgf16	ENSMUSG00000031230
rattus_norvegicus	Fgf16	ENSRNOG00000061530

Paralogs (21): FGF10 (ENSG00000070193), FGF22 (ENSG00000070388), FGF4 (ENSG00000075388), FGF20 (ENSG00000078579), FGF14 (ENSG00000102466), FGF9 (ENSG00000102678), 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)

Protein

Protein identifiers

Fibroblast growth factor 16 — O43320 (reviewed: O43320)

All UniProt accessions (2): A0A7U3L5H2, O43320

UniProt curated annotations — full annotation on UniProt →

Function. Plays an important role in the regulation of embryonic development, cell proliferation and cell differentiation, and is required for normal cardiomyocyte proliferation and heart development.

Subunit / interactions. Interacts with FGFR1 and FGFR2.

Subcellular location. Secreted.

Disease relevance. Metacarpal 4-5 fusion (MF4) [MIM:309630] A rare congenital malformation of the hand characterized by the partial or complete fusion of the fourth and fifth metacarpals. The anomaly occurs as an isolated trait or part of a syndrome. The disease is caused by variants affecting the gene represented in this entry.

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

RefSeq proteins (1): NP_003859* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002209	Fibroblast_GF_fam	Family
IPR008996	IL1/FGF	Homologous_superfamily

Pfam: PF00167

UniProt features (4 total): chain 1, modified residue 1, glycosylation site 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43320-F1	82.42	0.62

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): 111

Glycosylation sites (1): 78

Function

Pathways and Gene Ontology

Reactome pathways

27 pathways

ID	Pathway
R-HSA-109704	PI3K Cascade
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-1839130	Signaling by activated point mutants of FGFR3
R-HSA-190322	FGFR4 ligand binding and activation
R-HSA-190372	FGFR3c 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-5654221	Phospholipase C-mediated cascade; FGFR2
R-HSA-5654227	Phospholipase C-mediated cascade; FGFR3
R-HSA-5654228	Phospholipase C-mediated cascade; FGFR4
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-5654727	Negative regulation of FGFR2 signaling
R-HSA-5654732	Negative regulation of FGFR3 signaling
R-HSA-5654733	Negative regulation of FGFR4 signaling
R-HSA-5655253	Signaling by FGFR2 in disease
R-HSA-5655332	Signaling by FGFR3 in disease
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling

MSigDB gene sets: 206 (showing top): REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_POSITIVE_REGULATION_OF_ENDOTHELIAL_CELL_CHEMOTAXIS, GOBP_CELL_CHEMOTAXIS, GOBP_REGULATION_OF_PHOSPHORYLATION, KEGG_MAPK_SIGNALING_PATHWAY, CMYB_01, REACTOME_FGFR2C_LIGAND_BINDING_AND_ACTIVATION, REACTOME_SIGNALING_BY_FGFR, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, GOBP_NEUROGENESIS, GOMF_GROWTH_FACTOR_ACTIVITY, GOBP_CELL_CELL_SIGNALING, GOBP_POSITIVE_REGULATION_OF_ENDOTHELIAL_CELL_MIGRATION

GO Biological Process (10): signal transduction (GO:0007165), cell-cell signaling (GO:0007267), positive regulation of cell population proliferation (GO:0008284), fibroblast growth factor receptor signaling pathway (GO:0008543), response to temperature stimulus (GO:0009266), animal organ morphogenesis (GO:0009887), neurogenesis (GO:0022008), regulation of cell migration (GO:0030334), positive regulation of MAPK cascade (GO:0043410), positive regulation of endothelial cell chemotaxis to fibroblast growth factor (GO:2000546)

GO Molecular Function (3): fibroblast growth factor receptor binding (GO:0005104), growth factor activity (GO:0008083), protein binding (GO:0005515)

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

Reactome top-level categories

Rollup of top-11 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell communication	2
signaling	2
cellular anatomical structure	2
cellular process	1
regulation of cellular process	1
cellular response to stimulus	1
cell population proliferation	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
response to abiotic stimulus	1
anatomical structure morphogenesis	1
animal organ development	1
nervous system development	1
cell differentiation	1
cell migration	1
regulation of cell motility	1
MAPK cascade	1
regulation of MAPK cascade	1
positive regulation of intracellular signal transduction	1
endothelial cell chemotaxis to fibroblast growth factor	1
positive regulation of cell chemotaxis to fibroblast growth factor	1
regulation of endothelial cell chemotaxis to fibroblast growth factor	1
positive regulation of endothelial cell chemotaxis	1
growth factor receptor binding	1
receptor ligand activity	1
binding	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

3667 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FGF16	FGFR1	P11362	995
FGF16	EGF	P01133	988
FGF16	KL	Q9UEF7	987
FGF16	FGFR4	P22455	974
FGF16	FGFR2	P18443	967
FGF16	HSPG2	P98160	948
FGF16	FGFBP1	Q14512	944
FGF16	DCN	P07585	937
FGF16	CDH2	P19022	881
FGF16	CD44	P16070	874
FGF16	HGF	P14210	868
FGF16	KLB	Q86Z14	848
FGF16	FGFR3	P22607	839
FGF16	NRP1	O14786	823
FGF16	TGFB1	P01137	819

IntAct

25 interactions, top by confidence:

A	B	Type	Score
CLP1	FGF16	psi-mi:“MI:0915”(physical association)	0.560
FGF16	HOOK2	psi-mi:“MI:0915”(physical association)	0.560
FGF16	KRT31	psi-mi:“MI:0915”(physical association)	0.560
FGF16	PICK1	psi-mi:“MI:0915”(physical association)	0.560
FGF16	MCC	psi-mi:“MI:0915”(physical association)	0.560
FGF16	DVL3	psi-mi:“MI:0915”(physical association)	0.560
FGF16	INCA1	psi-mi:“MI:0915”(physical association)	0.560
FGF16	CLP1	psi-mi:“MI:0915”(physical association)	0.560
	FGF16	psi-mi:“MI:0407”(direct interaction)	0.440
FGF16	MFHAS1	psi-mi:“MI:0407”(direct interaction)	0.440
FGF16	TMED7	psi-mi:“MI:0915”(physical association)	0.400
FGF16	HOOK2	psi-mi:“MI:0915”(physical association)	0.000
FGF16	KRT31	psi-mi:“MI:0915”(physical association)	0.000
FGF16	PICK1	psi-mi:“MI:0915”(physical association)	0.000
FGF16	MCC	psi-mi:“MI:0915”(physical association)	0.000
FGF16	DVL3	psi-mi:“MI:0915”(physical association)	0.000
FGF16	INCA1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (11): FGF16 (Reconstituted Complex), PTX3 (Reconstituted Complex), FGF16 (Two-hybrid), FGF16 (Two-hybrid), FGF16 (Two-hybrid), FGF16 (Two-hybrid), FGF16 (Two-hybrid), FGF16 (Two-hybrid), FGF16 (Two-hybrid), TMED7 (Affinity Capture-MS), APP (Reconstituted Complex)

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

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	2
Uncertain significance	4
Likely benign	6
Benign	1

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
66059	NM_003868.3(FGF16):c.535C>T (p.Arg179Ter)	Pathogenic
66060	NM_003868.3(FGF16):c.470C>A (p.Ser157Ter)	Pathogenic
160345	NM_003868.2(FGF16):c.275_293dup	Likely pathogenic
2633250	NM_003868.3(FGF16):c.412C>T (p.Gln138Ter)	Likely pathogenic

SpliceAI

289 predictions. Top by Δscore:

Variant	Effect	Δscore
X:77454257:GTCG:G	donor_gain	1.0000
X:77454258:TCGG:T	donor_loss	1.0000
X:77454261:GTAA:G	donor_loss	1.0000
X:77456276:GAAGA:G	acceptor_gain	1.0000
X:77454261:G:GG	donor_gain	0.9900
X:77454262:TAAG:T	donor_loss	0.9900
X:77456267:A:AG	acceptor_gain	0.9900
X:77456268:C:G	acceptor_gain	0.9900
X:77456271:TCACA:T	acceptor_loss	0.9900
X:77456272:CACA:C	acceptor_loss	0.9900
X:77456274:C:G	acceptor_gain	0.9900
X:77456274:CAG:C	acceptor_loss	0.9900
X:77456275:A:AG	acceptor_gain	0.9900
X:77456275:A:AT	acceptor_loss	0.9900
X:77456276:G:GC	acceptor_gain	0.9900
X:77456276:GA:G	acceptor_gain	0.9900
X:77456276:GAA:G	acceptor_gain	0.9900
X:77456304:C:CA	acceptor_gain	0.9900
X:77456305:G:A	acceptor_gain	0.9900
X:77456273:A:AG	acceptor_gain	0.9800
X:77456311:A:AG	acceptor_gain	0.9600
X:77456312:G:GG	acceptor_gain	0.9600
X:77454258:TCG:T	donor_gain	0.9500
X:77454263:AAGTT:A	donor_loss	0.9400
X:77454259:CG:C	donor_gain	0.9100
X:77454260:GG:G	donor_gain	0.9100
X:77454256:GGTCG:G	donor_gain	0.8500
X:77454257:GTCGG:G	donor_gain	0.8500
X:77454258:TCGGT:T	donor_gain	0.8500
X:77454263:AAGT:A	donor_gain	0.8200

AlphaMissense

1330 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:77447868:T:C	L65P	1.000
X:77447873:T:C	C67R	1.000
X:77447874:G:A	C67Y	1.000
X:77447874:G:T	C67F	1.000
X:77447875:C:G	C67W	1.000
X:77447921:G:A	G83R	1.000
X:77447921:G:C	G83R	1.000
X:77447921:G:T	G83W	1.000
X:77447922:G:A	G83E	1.000
X:77454163:T:C	L94P	1.000
X:77454174:A:C	S98R	1.000
X:77454176:C:A	S98R	1.000
X:77454176:C:G	S98R	1.000
X:77454226:T:C	L115P	1.000
X:77454244:G:A	G121E	1.000
X:77454244:G:T	G121V	1.000
X:77454255:G:T	G125W	1.000
X:77454256:G:A	G125E	1.000
X:77456302:T:C	F135S	1.000
X:77456302:T:G	F135C	1.000
X:77456333:C:A	N145K	1.000
X:77456333:C:G	N145K	1.000
X:77456337:T:G	Y147D	1.000
X:77456389:C:A	A164D	1.000
X:77456392:T:C	L165P	1.000
X:77456404:G:A	G169D	1.000
X:77456404:G:T	G169V	1.000
X:77456454:T:C	F186L	1.000
X:77456455:T:C	F186S	1.000
X:77456456:T:A	F186L	1.000

dbSNP variants (sampled 300 via entrez): RS1000164355 (X:77447818 C>T), RS1000682037 (X:77447479 G>A), RS1000962545 (X:77456224 G>T), RS1001078627 (X:77455612 C>A), RS1001283347 (X:77448256 G>A), RS1001398725 (X:77447977 C>A,G), RS1002182081 (X:77457017 G>A), RS1002290354 (X:77446205 G>A,T), RS1002404936 (X:77445786 C>T), RS1002974713 (X:77450716 G>A), RS1004090068 (X:77457076 G>A), RS1004245847 (X:77446266 G>A), RS1004306147 (X:77457481 C>T), RS1004868111 (X:77446662 T>C), RS1006133063 (X:77448735 C>G)

Disease associations

OMIM: gene MIM:300827 | disease phenotypes: MIM:309630

GenCC curated gene-disease

Disease	Classification	Inheritance
syndactyly type 8	Strong	X-linked

Mondo (1): syndactyly type 8 (MONDO:0010669)

Orphanet (1): Syndactyly type 8 (Orphanet:2498)

HPO phenotypes

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

HPO	Term
HP:0001419	X-linked recessive inheritance
HP:0003577	Congenital onset
HP:0004209	Clinodactyly of the 5th finger
HP:0005709	2-3 toe cutaneous syndactyly
HP:0005867	4-5 metacarpal synostosis
HP:0010047	Short 5th metacarpal

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008839_30	Height	1.000000e-42

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C564100	Metacarpal 4 5 Fusion (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

10 total (human), top 10 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Arsenic	affects expression	1
Benzo(a)pyrene	affects methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Tetradecanoylphorbol Acetate	affects cotreatment, affects expression	1
Zinc	affects expression, affects cotreatment	1
Antirheumatic Agents	increases expression	1

Clinical trials (associated diseases)

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