FOXI3

Summary

FOXI3 (forkhead box I3, HGNC:35123) is a protein-coding gene on chromosome 2p11.2, encoding Forkhead box protein I3 (A8MTJ6). Transcription factor required for pharyngeal arch development, which is involved in hair, ear, jaw and dental development.

Enables DNA-binding transcription factor activity, RNA polymerase II-specific. Involved in pharyngeal system development. Is active in nucleus.

Source: NCBI Gene 344167 — RefSeq curated summary.

At a glance

• Gene–disease (curated): craniofacial microsomia 2 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 410 total — 6 likely-pathogenic
• Phenotypes (HPO): 11
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001135649

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:35123
Approved symbol	FOXI3
Name	forkhead box I3
Location	2p11.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000214336
Ensembl biotype	protein_coding
OMIM	612351
Entrez	344167

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000428390

RefSeq mRNA: 1 — MANE Select: NM_001135649 NM_001135649

CCDS: CCDS77433

Canonical transcript exons

ENST00000428390 — 2 exons

Exon	Start	End
ENSE00001512786	88451896	88452693
ENSE00003555951	88446787	88448829

Expression profiles

Bgee: expression breadth broad, 13 present calls, max score 85.66.

FANTOM5 (CAGE): breadth broad, TPM avg 1.5800 / max 93.0304, expressed in 267 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
29596	1.0393	213
29597	0.3500	143
29598	0.1907	109

Top tissues by expression

123 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	85.66	gold quality
placenta	UBERON:0001987	76.40	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.07	gold quality
ganglionic eminence	UBERON:0004023	51.99	gold quality
cortical plate	UBERON:0005343	44.00	silver quality
lower esophagus mucosa	UBERON:0035834	38.80	gold quality
colonic epithelium	UBERON:0000397	37.20	gold quality
bone marrow cell	CL:0002092	36.16	gold quality
prefrontal cortex	UBERON:0000451	34.72	gold quality
granulocyte	CL:0000094	34.39	gold quality
lymph node	UBERON:0000029	33.47	gold quality
skeletal muscle tissue	UBERON:0001134	33.38	gold quality
adenohypophysis	UBERON:0002196	33.19	silver quality
duodenum	UBERON:0002114	32.40	gold quality
muscle tissue	UBERON:0002385	32.17	gold quality
hindlimb stylopod muscle	UBERON:0004252	32.15	gold quality
bone marrow	UBERON:0002371	31.74	gold quality
sural nerve	UBERON:0015488	30.93	gold quality
skin of abdomen	UBERON:0001416	30.80	gold quality
zone of skin	UBERON:0000014	30.79	gold quality
skin of leg	UBERON:0001511	30.69	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	30.31	gold quality
stromal cell of endometrium	CL:0002255	29.87	gold quality
liver	UBERON:0002107	29.61	gold quality
superior frontal gyrus	UBERON:0002661	29.41	gold quality
right uterine tube	UBERON:0001302	29.22	gold quality
vermiform appendix	UBERON:0001154	29.20	gold quality
leukocyte	CL:0000738	28.94	gold quality
tonsil	UBERON:0002372	28.67	gold quality
cortex of kidney	UBERON:0001225	28.51	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-3929	yes	105.04
E-MTAB-7606	no	3.40
E-ANND-3	no	1.80

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
JAG2	Unknown
RPL26

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 2)

• Data show that Foxi3 contains at least two important functional domains, a nuclear localization sequence and a C-terminal transactivation domain, and that it directly binds its targets in a sequence specific. The transcriptional activity of Foxi3 seems to be regulated by phosphorylation, and that the activity of Foxi3 can be attenuated by its physical interaction with the protein phosphatase 2A (PP2A) complex. (PMID:30467319)
• Damaging variants in FOXI3 cause microtia and craniofacial microsomia. (PMID:36260083)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Foxi3	ENSMUSG00000055874
rattus_norvegicus	Foxi3	ENSRNOG00000006491

Paralogs (41): FOXP3 (ENSG00000049768), FOXC1 (ENSG00000054598), FOXJ2 (ENSG00000065970), FOXF1 (ENSG00000103241), FOXN1 (ENSG00000109101), FOXM1 (ENSG00000111206), FOXP1 (ENSG00000114861), FOXO3 (ENSG00000118689), FOXA2 (ENSG00000125798), FOXA1 (ENSG00000129514), FOXJ1 (ENSG00000129654), FOXK2 (ENSG00000141568), FOXO1 (ENSG00000150907), FOXH1 (ENSG00000160973), FOXQ1 (ENSG00000164379), FOXK1 (ENSG00000164916), FOXD4 (ENSG00000170122), FOXA3 (ENSG00000170608), FOXB1 (ENSG00000171956), FOXR1 (ENSG00000176302), FOXL1 (ENSG00000176678), FOXC2 (ENSG00000176692), FOXE1 (ENSG00000178919), FOXS1 (ENSG00000179772), FOXL2 (ENSG00000183770), FOXO4 (ENSG00000184481), FOXD4L1 (ENSG00000184492), FOXD4L4 (ENSG00000184659), FOXD2 (ENSG00000186564), FOXI2 (ENSG00000186766), FOXE3 (ENSG00000186790), FOXD3 (ENSG00000187140), FOXD4L3 (ENSG00000187559), FOXR2 (ENSG00000189299), FOXJ3 (ENSG00000198815), FOXO6 (ENSG00000204060), FOXB2 (ENSG00000204612), FOXD4L5 (ENSG00000204779), FOXL3 (ENSG00000248767), FOXD1 (ENSG00000251493)

Protein

Protein identifiers

Forkhead box protein I3 — A8MTJ6 (reviewed: A8MTJ6)

All UniProt accessions (1): A8MTJ6

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor required for pharyngeal arch development, which is involved in hair, ear, jaw and dental development. May act as a pioneer transcription factor during pharyngeal arch development. Required for epithelial cell differentiation within the epidermis. Acts at multiple stages of otic placode induction: necessary for preplacodal ectoderm to execute an inner ear program. Required for hair follicle stem cell specification. Acts downstream of TBX1 for the formation of the thymus and parathyroid glands from the third pharyngeal pouch.

Subcellular location. Nucleus.

Post-translational modifications. Phosphorylation promotes the transcription factor activity. Dephosphorylation by protein phosphatase 2A (PP2A) reduces its activity.

Disease relevance. Craniofacial microsomia 2 (CFM2) [MIM:620444] A form of craniofacial microsomia, a disorder characterized by a spectrum of craniofacial malformations ranging from isolated microtia with or without aural atresia to underdevelopment of the mandible, maxilla, orbit, facial soft tissue, and/or facial nerve. Most CFM2 patients exhibit isolated unilateral or bilateral grade II/III microtia, with or without atresia, although some patients show only minor external ear defects. Mandibular hypoplasia, micrognathia, and dental anomalies have also been observed. CFM2 inheritance can be autosomal dominant or autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors.

RefSeq proteins (1): NP_001129121* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001766	Fork_head_dom	Domain
IPR018122	TF_fork_head_CS_1	Conserved_site
IPR030456	TF_fork_head_CS_2	Conserved_site
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR050211	FOX_domain-containing	Family

Pfam: PF00250

UniProt features (30 total): sequence variant 17, modified residue 4, region of interest 3, short sequence motif 2, compositionally biased region 2, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A8MTJ6-F1	59.00	0.18

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 (4): 277, 285, 287, 119

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 60 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_THYMUS_DEVELOPMENT, GOBP_EPIDERMAL_CELL_DIFFERENTIATION, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_HEMATOPOIETIC_OR_LYMPHOID_ORGAN_DEVELOPMENT, GOBP_MOLTING_CYCLE, GOBP_EPIDERMIS_DEVELOPMENT, chr2p11, GOBP_PHARYNGEAL_SYSTEM_DEVELOPMENT, GOBP_ODONTOGENESIS_OF_DENTIN_CONTAINING_TOOTH, GOBP_EMBRYO_DEVELOPMENT, GOBP_ENDOCRINE_SYSTEM_DEVELOPMENT, GOBP_CELL_FATE_SPECIFICATION, GOBP_SKIN_DEVELOPMENT

GO Biological Process (11): hair follicle development (GO:0001942), regulation of transcription by RNA polymerase II (GO:0006357), anatomical structure morphogenesis (GO:0009653), epidermal cell fate specification (GO:0009957), cell differentiation (GO:0030154), odontogenesis of dentin-containing tooth (GO:0042475), thymus development (GO:0048538), parathyroid gland development (GO:0060017), pharyngeal system development (GO:0060037), otic placode development (GO:1905040), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (5): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (1): nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure development	2
regulation of DNA-templated transcription	2
gland development	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
hair cycle process	1
skin epidermis development	1
transcription by RNA polymerase II	1
developmental process	1
cell fate specification	1
epidermal cell differentiation	1
cellular developmental process	1
odontogenesis	1
hematopoietic or lymphoid organ development	1
endocrine system development	1
chordate embryonic development	1
system development	1
ectodermal placode development	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
nucleic acid binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
DNA binding	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

874 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FOXI3	GCM2	O75603	606
FOXI3	SPMIP9	Q96LM6	515
FOXI3	THNSL2	Q86YJ6	479
FOXI3	KRT71	Q3SY84	457
FOXI3	CDCP2	Q5VXM1	428
FOXI3	KRCC1	Q9NPI7	400
FOXI3	EYA2	O00167	398
FOXI3	PAX9	P55771	387
FOXI3	PAX2	Q02962	356
FOXI3	EYA1	Q99502	353
FOXI3	PAX1	P15863	351
FOXI3	DLX5	P56178	351
FOXI3	HR	O43593	346
FOXI3	SIX1	Q15475	346
FOXI3	RIT2	Q99578	345

IntAct

0 interactions, top by confidence:

BioGRID (2): FOXI3 (Affinity Capture-RNA), FOXI3 (Affinity Capture-MS)

ESM2 similar proteins: A0A8V0YY16, A0JPN1, A1YG01, A2D4R4, A2D649, A2T6H5, A2T6Z0, A2T7J2, A3KNJ3, A7MB54, A8MTJ6, B5RHS5, D3Z120, O54743, P09027, P14653, P17919, P31249, P32183, P35584, P55316, P55318, P56260, Q00939, Q12946, Q12947, Q12948, Q12951, Q1A1A1, Q1A1A2, Q1A1A3, Q1A1A4, Q1A1A5, Q1A1A6, Q28D67, Q28HT3, Q3I5G5, Q3Y598, Q60987, Q61080

Diamond homologs: A0A078BQN7, A0A1W2PRP0, A0A8V0YY16, A1L1S5, A3KNJ3, A8MTJ6, A8XJN7, B5RHS5, D3Z120, F1R8Z9, O00358, O17617, O43638, O54743, O60129, O88470, P32027, P32028, P32030, P32315, P42128, P55316, P56260, P58012, P79772, P85037, P91278, Q00939, Q01167, Q02360, Q12946, Q12947, Q12948, Q12950, Q12951, Q12952, Q13461, Q19802, Q1A1A1, Q1A1A2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	6
Uncertain significance	270
Likely benign	127
Benign	4

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
2430158	NM_001135649.3(FOXI3):c.703C>T (p.Arg235Cys)	Likely pathogenic
2431343	NM_001135649.3(FOXI3):c.706C>T (p.Arg236Trp)	Likely pathogenic
2431347	NM_001135649.3(FOXI3):c.305T>A (p.Phe102Tyr)	Likely pathogenic
2431348	NM_001135649.3(FOXI3):c.673T>C (p.Cys225Arg)	Likely pathogenic
3075660	NM_001135649.3(FOXI3):c.596T>G (p.Leu199Arg)	Likely pathogenic
932705	NM_001135649.3(FOXI3):c.308del (p.Gly103fs)	Likely pathogenic

SpliceAI

117 predictions. Top by Δscore:

Variant	Effect	Δscore
2:88451891:CTCA:C	donor_loss	1.0000
2:88451893:CACC:C	donor_loss	1.0000
2:88451895:C:CG	donor_loss	1.0000
2:88448825:CTTTC:C	acceptor_gain	0.9900
2:88448826:TTTC:T	acceptor_gain	0.9900
2:88448827:TTC:T	acceptor_gain	0.9900
2:88448828:TC:T	acceptor_gain	0.9900
2:88448829:CC:C	acceptor_gain	0.9900
2:88448830:C:CC	acceptor_gain	0.9900
2:88448831:T:C	acceptor_loss	0.9900
2:88451894:A:AC	donor_gain	0.9900
2:88451895:C:CC	donor_gain	0.9900
2:88448838:A:AC	acceptor_gain	0.9700
2:88448838:A:C	acceptor_gain	0.9700
2:88448830:C:T	acceptor_gain	0.9600
2:88451697:A:AC	donor_gain	0.9600
2:88451698:C:CC	donor_gain	0.9600
2:88451904:T:TA	donor_gain	0.9600
2:88451706:T:TA	donor_gain	0.9500
2:88451892:TCA:T	donor_gain	0.9300
2:88451893:CAC:C	donor_gain	0.9300
2:88451894:ACCTG:A	donor_gain	0.9300
2:88448826:TTTCC:T	acceptor_gain	0.9200
2:88448827:TTCC:T	acceptor_gain	0.9200
2:88448828:TCC:T	acceptor_gain	0.9200
2:88448829:CCTG:C	acceptor_gain	0.9200
2:88448830:C:A	acceptor_gain	0.9200
2:88451895:CCTGG:C	donor_gain	0.9200
2:88448831:T:A	acceptor_gain	0.9100
2:88451890:CCTCA:C	donor_gain	0.9000

AlphaMissense

2711 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:88448767:G:T	R235S	1.000
2:88448768:G:C	F234L	1.000
2:88448768:G:T	F234L	1.000
2:88448769:A:C	F234C	1.000
2:88448769:A:G	F234S	1.000
2:88448770:A:C	F234V	1.000
2:88448770:A:G	F234L	1.000
2:88448770:A:T	F234I	1.000
2:88448771:G:C	N233K	1.000
2:88448771:G:T	N233K	1.000
2:88448775:C:A	G232V	1.000
2:88448775:C:T	G232E	1.000
2:88448776:C:A	G232W	1.000
2:88448776:C:G	G232R	1.000
2:88448776:C:T	G232R	1.000
2:88448783:A:C	F229L	1.000
2:88448783:A:T	F229L	1.000
2:88448784:A:C	F229C	1.000
2:88448784:A:G	F229S	1.000
2:88448785:A:C	F229V	1.000
2:88448785:A:G	F229L	1.000
2:88448785:A:T	F229I	1.000
2:88448786:C:A	M228I	1.000
2:88448786:C:G	M228I	1.000
2:88448786:C:T	M228I	1.000
2:88448787:A:G	M228T	1.000
2:88448797:A:G	C225R	1.000
2:88448808:A:G	L221P	1.000
2:88448808:A:T	L221H	1.000
2:88448813:C:A	W219C	1.000

dbSNP variants (sampled 300 via entrez): RS1000990640 (2:88449183 T>A,C), RS1001058870 (2:88452228 C>A), RS1001093258 (2:88451757 A>G), RS1001915281 (2:88446858 T>C), RS1002036825 (2:88449580 G>A), RS1002367749 (2:88447205 C>T), RS1003043119 (2:88451039 G>A), RS1004371452 (2:88451817 C>A,G,T), RS1004424740 (2:88446434 T>A), RS1004845615 (2:88451037 T>C), RS1005216400 (2:88447283 T>C), RS1005377257 (2:88454009 T>C), RS1005655142 (2:88454419 G>T), RS1005995411 (2:88452867 C>A,G), RS1006718751 (2:88447639 G>A)

Disease associations

OMIM: gene MIM:612351 | disease phenotypes: MIM:164210, MIM:620444

GenCC curated gene-disease

Disease	Classification	Inheritance
craniofacial microsomia 2	Strong	Autosomal dominant
dysostosis with predominant craniofacial involvement	Strong	Autosomal dominant
T-cell immunodeficiency	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
T-cell immunodeficiency	Limited	AD

Mondo (5): craniofacial microsomia 1 (MONDO:0958175), craniofacial microsomia (MONDO:0015397), craniofacial microsomia 2 (MONDO:0958194), T-cell immunodeficiency (MONDO:0003780), (MONDO:0800085)

Orphanet (3): Goldenhar syndrome (Orphanet:374), Oculo-auriculo-vertebral spectrum (Orphanet:141132), Otomandibular syndrome (Orphanet:141136)

HPO phenotypes

11 total (11 of 11 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000193	Bifid uvula
HP:0000347	Micrognathia
HP:0003577	Congenital onset
HP:0008551	Microtia
HP:0008569	Microtia, second degree
HP:0010609	Skin tags
HP:0011266	Microtia, first degree
HP:0011267	Microtia, third degree
HP:0020223	Dermal sinus tract
HP:5201016	Submucous cleft palate

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST005389_2	Tooth agenesis	6.000000e-15
GCST009462_34	Optic disc size	3.000000e-08

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D006053	Goldenhar Syndrome	C05.116.099.370.231.576.410; C05.660.207.231.576.410; C16.131.621.207.231.576.410

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

5 total (human), top 5 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
ethyl-p-hydroxybenzoate	increases expression	1
abrine	increases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases methylation	1
Triclosan	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01674439	PHASE2	COMPLETED	Clinical Trial of Fat Grafts Supplemented With Adipose-derived Regenerative Cells
NCT05610878	PHASE1	RECRUITING	Efficacy of Preconditioned Adipose-Derived Stem Cells in Fat Grafting
NCT07015801	Not specified	ACTIVE_NOT_RECRUITING	CMV-specific Donor-derived T Lymphocytes for the Treatment of Recalcitrant CMV Infection in a Patient With Primary Immunodeficiency
NCT02224677	Not specified	COMPLETED	Craniofacial Microsomia: Longitudinal Outcomes in Children Pre-Kindergarten (CLOCK)
NCT02494752	Not specified	UNKNOWN	Role of Mesenchymal Stem Cells in Fat Grafting
NCT03806361	Not specified	COMPLETED	Fat Grafts With Adipose-derived Regenerative Cells for Soft Tissue Reconstruction in Children
NCT03861650	Not specified	COMPLETED	Evaluation of Effect of Bone Marrow Aspirate Concentrate on Distracted Mandibular Bone Properties
NCT03869021	Not specified	COMPLETED	Computer Guided for Mandibular Distraction Osteogenesis
NCT04056858	Not specified	COMPLETED	Study of a Candidate Gene Involved in Goldenhar Syndrome.
NCT04351893	Not specified	COMPLETED	Craniofacial Microsomia: Accelerating Understanding of the Significance and Etiology
NCT04931056	Not specified	COMPLETED	A Post Market Clinical Follow-up Study on Biomet Microfixation HTR PEKK (Midface), Facial & Mandibular Plates.