IRX2

Summary

IRX2 (iroquois homeobox 2, HGNC:14359) is a protein-coding gene on chromosome 5p15.33, encoding Iroquois-class homeodomain protein IRX-2 (Q9BZI1).

IRX2 is a member of the Iroquois homeobox gene family. Members of this family appear to play multiple roles during pattern formation of vertebrate embryos.

Source: NCBI Gene 153572 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 89 total
• MANE Select transcript: NM_033267

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14359
Approved symbol	IRX2
Name	iroquois homeobox 2
Location	5p15.33
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000170561
Ensembl biotype	protein_coding
OMIM	606198
Entrez	153572

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000302057, ENST00000382611, ENST00000925245

RefSeq mRNA: 2 — MANE Select: NM_033267 NM_001134222, NM_033267

CCDS: CCDS3868

Canonical transcript exons

ENST00000302057 — 4 exons

Exon	Start	End
ENSE00001338715	2748345	2749052
ENSE00001338718	2751165	2751677
ENSE00001530431	2746165	2747616
ENSE00003483902	2749382	2749787

Expression profiles

Bgee: expression breadth ubiquitous, 169 present calls, max score 96.25.

FANTOM5 (CAGE): breadth broad, TPM avg 9.3793 / max 604.4737, expressed in 783 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
60845	6.5995	745
60846	2.7798	535

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
upper arm skin	UBERON:0004263	96.25	gold quality
lower lobe of lung	UBERON:0008949	94.31	gold quality
mammary duct	UBERON:0001765	93.73	gold quality
epithelium of mammary gland	UBERON:0003244	93.72	gold quality
parotid gland	UBERON:0001831	93.26	gold quality
upper leg skin	UBERON:0004262	91.70	gold quality
kidney epithelium	UBERON:0004819	90.83	gold quality
pons	UBERON:0000988	89.99	gold quality
renal medulla	UBERON:0000362	89.92	gold quality
bronchial epithelial cell	CL:0002328	89.65	gold quality
bronchus	UBERON:0002185	89.13	gold quality
nipple	UBERON:0002030	88.78	gold quality
buccal mucosa cell	CL:0002336	88.65	gold quality
mammary gland	UBERON:0001911	88.28	gold quality
thoracic mammary gland	UBERON:0005200	88.24	gold quality
mammalian vulva	UBERON:0000997	88.21	gold quality
skin of abdomen	UBERON:0001416	87.86	gold quality
saliva-secreting gland	UBERON:0001044	87.77	gold quality
zone of skin	UBERON:0000014	86.79	gold quality
minor salivary gland	UBERON:0001830	86.61	gold quality
skin of hip	UBERON:0001554	86.32	gold quality
right lung	UBERON:0002167	85.98	gold quality
trachea	UBERON:0003126	85.79	gold quality
skin of leg	UBERON:0001511	85.75	gold quality
mouth mucosa	UBERON:0003729	84.97	gold quality
cardia of stomach	UBERON:0001162	84.37	gold quality
lung	UBERON:0002048	83.90	gold quality
upper lobe of lung	UBERON:0008948	82.75	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.04	gold quality
upper lobe of left lung	UBERON:0008952	81.86	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-MTAB-10662	yes	371.52
E-GEOD-81608	yes	233.92
E-ENAD-27	yes	104.86
E-GEOD-83139	yes	75.21
E-MTAB-5061	yes	32.79
E-CURD-114	yes	27.05
E-GEOD-81547	yes	21.40
E-ANND-3	yes	15.88
E-MTAB-6524	no	80.76
E-MTAB-3929	no	48.94

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
CCL5	Repression
CXCL10	Repression

JASPAR motifs

Motif	Name	Family
MA2679.1	IRX2	TALE-type HD

JASPAR matrix evidence (PMIDs): PMID:16203991

miRNA regulators (miRDB)

71 targeting IRX2, 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-340-5P	100.00	72.50	4437
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-4760-5P	99.80	69.88	1619

Literature-anchored findings (GeneRIF, showing 6)

• IRX2 represents a candidate target of 5p amplifications in soft tissue sarcomas and might play a crucial role during the progression of this disease. (PMID:16752383)
• Results revealed 3 genes highly predictive of event-free survival (EFS), beyond age and MLL status: FLT3, IRX2, and TACC2. (PMID:22210879)
• The mechanism by which IRX2 promoted cell proliferation and invasion by activating AKT and MMP9 was detected. (PMID:24806332)
• IRX2 modulates the expression levels of MMP2 and VEGF in an AKTdependent manner. (PMID:26062523)
• IRX2 transcription factor might represent a novel metastasis associated protein that acts as a negative regulator of cellular motility and as a repressor of chemokine expression and loss of IRX2 expression could therefore contribute to early hematogenous dissemination of breast cancer by sustaining chemokine secretion and enabling mobilization of tumor cells. (PMID:26560478)
• Iroquois Homeobox Protein 2 Identified as a Potential Biomarker for Parkinson’s Disease. (PMID:32422864)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	irx2a	ENSDARG00000001785
mus_musculus	Irx2	ENSMUSG00000001504
rattus_norvegicus	Irx2	ENSRNOG00000012742

Paralogs (6): IRX4 (ENSG00000113430), MKX (ENSG00000150051), IRX6 (ENSG00000159387), IRX1 (ENSG00000170549), IRX5 (ENSG00000176842), IRX3 (ENSG00000177508)

Protein

Protein identifiers

Iroquois-class homeodomain protein IRX-2 — Q9BZI1 (reviewed: Q9BZI1)

Alternative names: Homeodomain protein IRXA2, Iroquois homeobox protein 2

All UniProt accessions (1): Q9BZI1

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Nucleus.

Similarity. Belongs to the TALE/IRO homeobox family.

RefSeq proteins (2): NP_001127694, NP_150366* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR003893	Iroquois_homeo	Domain
IPR008422	KN_HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site

Pfam: PF05920

UniProt features (9 total): compositionally biased region 4, region of interest 2, chain 1, DNA-binding region 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BZI1-F1	55.26	0.11

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): 186

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-9831926	Nephron development
R-HSA-1266738	Developmental Biology
R-HSA-9830369	Kidney development

MSigDB gene sets: 154 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_METANEPHROS_DEVELOPMENT, PAX4_01, GOBP_LOOP_OF_HENLE_DEVELOPMENT, GOBP_NEUROGENESIS, GOBP_KIDNEY_EPITHELIUM_DEVELOPMENT, CHX10_01, GOBP_MORPHOGENESIS_OF_EMBRYONIC_EPITHELIUM, BILD_HRAS_ONCOGENIC_SIGNATURE, GOBP_PROXIMAL_DISTAL_PATTERN_FORMATION, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, GOBP_NEPHRON_EPITHELIUM_DEVELOPMENT, GOBP_RENAL_TUBULE_DEVELOPMENT

GO Biological Process (8): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of transcription by RNA polymerase II (GO:0006357), neuron differentiation (GO:0030182), cell development (GO:0048468), specification of loop of Henle identity (GO:0072086), proximal/distal pattern formation involved in metanephric nephron development (GO:0072272), metanephros development (GO:0001656), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (6): 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 transcription repressor activity, RNA polymerase II-specific (GO:0001227), sequence-specific DNA binding (GO:0043565), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Kidney development	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
cell differentiation	2
negative regulation of DNA-templated transcription	1
regulation of DNA-templated transcription	1
generation of neurons	1
anatomical structure development	1
cellular developmental process	1
loop of Henle development	1
specification of nephron tubule identity	1
proximal/distal pattern formation involved in nephron development	1
metanephric nephron development	1
pattern specification involved in metanephros development	1
kidney 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
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription repressor activity	1
DNA binding	1
nucleic acid binding	1
binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1284 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IRX2	AKAP11	Q9UKA4	697
IRX2	HOXB8	P17481	576
IRX2	GPC5	P78333	557
IRX2	NKX6-1	P78426	548
IRX2	POSTN	Q15063	504
IRX2	SMYD1	Q8NB12	501
IRX2	TBC1D4	O60343	490
IRX2	GATA4	P43694	478
IRX2	HHEX	Q03014	476
IRX2	CHCT1	Q86WR6	462
IRX2	NKX6-2	Q9C056	459
IRX2	MAFB	Q9Y5Q3	451
IRX2	PAX4	O43316	445
IRX2	DLX2	Q07687	438
IRX2	POU6F2	P78424	433

IntAct

10 interactions, top by confidence:

A	B	Type	Score
TLE5	IRX2	psi-mi:“MI:0915”(physical association)	0.560
PFDN5	IRX2	psi-mi:“MI:0915”(physical association)	0.560
IRX2	PLAGL2	psi-mi:“MI:0915”(physical association)	0.560
IRX2	TLE5	psi-mi:“MI:0915”(physical association)	0.000
IRX2	PLAGL2	psi-mi:“MI:0915”(physical association)	0.000
IRX2	PFDN5	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (8): IRX2 (Synthetic Lethality), IRX2 (Two-hybrid), IRX2 (Two-hybrid), IRX2 (Two-hybrid), IRX2 (Affinity Capture-MS), IRX2 (Affinity Capture-MS), IRX2 (Cross-Linking-MS (XL-MS)), IRX2 (Affinity Capture-RNA)

ESM2 similar proteins: A0JPN1, A6NHT5, A6YP92, A7MB54, M0R6D8, O02786, O35085, O35762, O42230, O57601, O88181, O95096, P09065, P13297, P28360, P42581, P43697, P50219, P52955, P70390, P78414, P78415, P79772, P81067, P81068, Q05925, Q0P4W6, Q14549, Q14774, Q1XID0, Q2VL76, Q2VL77, Q2VL78, Q2VL79, Q2VL80, Q2VL82, Q2VL83, Q2VL84, Q2VL85, Q2VL86

Diamond homologs: A1YER0, A2D5H2, A2Y007, A6NDR6, A8WL06, B3DM47, B4F6V6, B7ZRT8, O00470, O14770, O35317, O35984, O46339, O70477, O95343, P40424, P40425, P40426, P40427, P41778, P41779, P41817, P48002, P54269, P55347, P56663, P56668, P56669, P70284, P78411, P78412, P78413, P78415, P79937, P81066, P81067, P97367, P97368, Q15475, Q19503

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
IRX2	“down-regulates quantity by repression”	CXCL10	“transcriptional regulation”
IRX2	“down-regulates quantity by repression”	CCL5	“transcriptional regulation”
MAPK1	“up-regulates activity”	IRX2	phosphorylation
MAPK3	“up-regulates activity”	IRX2	phosphorylation
Gbeta	“up-regulates activity”	IRX2	phosphorylation
ERK1/2	“up-regulates activity”	IRX2	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	75
Likely benign	4
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

636 predictions. Top by Δscore:

Variant	Effect	Δscore
5:2749787:CCTGG:C	acceptor_loss	0.9900
5:2749788:C:CA	acceptor_loss	0.9900
5:2749789:T:A	acceptor_loss	0.9900
5:2751160:GTTAC:G	donor_loss	0.9900
5:2751161:TTAC:T	donor_loss	0.9900
5:2751162:TA:T	donor_loss	0.9900
5:2749784:CGCC:C	acceptor_gain	0.9800
5:2749786:CC:C	acceptor_gain	0.9800
5:2749787:CC:C	acceptor_gain	0.9800
5:2749788:C:CC	acceptor_gain	0.9800
5:2750262:AGAAG:A	donor_gain	0.9800
5:2751159:GGTTA:G	donor_loss	0.9800
5:2751163:A:AC	donor_gain	0.9800
5:2751164:C:CC	donor_gain	0.9800
5:2749783:GCGCC:G	acceptor_gain	0.9700
5:2749784:CGCCC:C	acceptor_gain	0.9700
5:2750227:CTG:C	donor_gain	0.9700
5:2748339:GCCTA:G	donor_loss	0.9600
5:2748340:CCTAC:C	donor_loss	0.9600
5:2748341:CTA:C	donor_loss	0.9600
5:2748342:TA:T	donor_loss	0.9600
5:2748343:A:AT	donor_loss	0.9600
5:2749785:GCC:G	acceptor_gain	0.9600
5:2749786:CCC:C	acceptor_gain	0.9600
5:2750226:A:AC	donor_gain	0.9600
5:2750227:C:CC	donor_gain	0.9600
5:2750227:CTGCT:C	donor_gain	0.9600
5:2750319:T:TA	donor_gain	0.9600
5:2747539:A:AC	donor_gain	0.9500
5:2747540:C:CC	donor_gain	0.9500

AlphaMissense

3000 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:2748701:G:T	A336D	1.000
5:2748718:C:A	W330C	1.000
5:2748718:C:G	W330C	1.000
5:2748720:A:G	W330R	1.000
5:2748720:A:T	W330R	1.000
5:2749497:C:A	W180C	1.000
5:2749497:C:G	W180C	1.000
5:2749499:A:G	W180R	1.000
5:2749499:A:T	W180R	1.000
5:2749506:C:A	K177N	1.000
5:2749506:C:G	K177N	1.000
5:2749508:T:C	K177E	1.000
5:2749510:T:A	N176I	1.000
5:2749513:T:A	E175V	1.000
5:2749515:C:A	K174N	1.000
5:2749515:C:G	K174N	1.000
5:2749516:T:A	K174M	1.000
5:2749517:T:C	K174E	1.000
5:2749517:T:G	K174Q	1.000
5:2749518:C:A	K173N	1.000
5:2749518:C:G	K173N	1.000
5:2749519:T:A	K173M	1.000
5:2749519:T:G	K173T	1.000
5:2749520:T:C	K173E	1.000
5:2749522:A:G	L172P	1.000
5:2749522:A:T	L172H	1.000
5:2749523:G:A	L172F	1.000
5:2749525:C:G	R171P	1.000
5:2749526:G:A	R171C	1.000
5:2749526:G:C	R171G	1.000

dbSNP variants (sampled 300 via entrez): RS1000194321 (5:2741105 G>C), RS1000241530 (5:2743756 T>C), RS1000294514 (5:2738703 C>G), RS1000637018 (5:2737640 T>C), RS1000678137 (5:2748332 G>A,C), RS1000799455 (5:2748055 T>C), RS1000865484 (5:2743616 C>G,T), RS1000971129 (5:2742342 T>A), RS1001239893 (5:2745086 T>G), RS1001306418 (5:2739664 C>A,T), RS1001344208 (5:2753211 G>A,T), RS1001401550 (5:2750836 G>A,C), RS1001749768 (5:2739038 T>C), RS1001774135 (5:2750671 C>A,G), RS1001852663 (5:2753450 C>A,T)

Disease associations

OMIM: gene MIM:606198 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002671_4	Toenail selenium levels	8.000000e-06
GCST004519_14	Body mass index (adult)	8.000000e-07
GCST004519_26	Body mass index (adult)	7.000000e-09
GCST009266_7	Dental caries (decayed and filled deciduous tooth surfaces)	4.000000e-06
GCST009439_16	Age-related cognitive decline (language) (slope of z-scores)	5.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0007710	cognitive decline measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases expression, increases methylation	6
methylmercuric chloride	increases expression, affects cotreatment	3
trichostatin A	decreases expression, affects cotreatment, increases expression	3
entinostat	decreases expression, increases expression, affects cotreatment	2
belinostat	increases expression, affects cotreatment	2
Panobinostat	increases expression, affects cotreatment	2
Estradiol	affects cotreatment, decreases expression, increases expression	2
bisphenol A	decreases expression	1
sodium arsenite	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	increases expression	1
Vorinostat	decreases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	decreases methylation	1
Cadmium	increases expression	1
Carbamazepine	affects expression	1
Cisplatin	increases expression	1
Lead	affects expression	1
Malathion	increases expression	1
Silicon Dioxide	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Vanadates	increases expression	1
Aflatoxin B1	decreases methylation	1
Gold Compounds	increases expression	1
Permethrin	increases expression	1
Particulate Matter	decreases expression, increases abundance	1

Cellosaurus cell lines

4 cell lines: 3 embryonic stem cell, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A3I0	SEES3-1V human IRX2, clone1	Embryonic stem cell	Male
CVCL_A3I1	SEES3-1V human IRX2, clone2	Embryonic stem cell	Male
CVCL_A3I2	SEES3-1V human IRX2, clone3	Embryonic stem cell	Male
CVCL_UZ55	HCB-514	Cancer cell line	Female

Clinical trials (associated diseases)

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