IRX6

Summary

IRX6 (iroquois homeobox 6, HGNC:14675) is a protein-coding gene on chromosome 16q12.2, encoding Iroquois-class homeodomain protein IRX-6 (P78412). Transcription factor.

Predicted to enable DNA-binding transcription activator activity, RNA polymerase II-specific; DNA-binding transcription repressor activity, RNA polymerase II-specific; and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in cell development; neuron differentiation; and regulation of DNA-templated transcription. Predicted to act upstream of or within detection of visible light; negative regulation of DNA-templated transcription; and retina morphogenesis in camera-type eye. Predicted to be located in chromatin. Predicted to be active in nucleus.

Source: NCBI Gene 79190 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cone dystrophy (Moderate, GenCC)
• GWAS associations: 4
• Clinical variants (ClinVar): 107 total — 1 pathogenic
• MANE Select transcript: NM_024335

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14675
Approved symbol	IRX6
Name	iroquois homeobox 6
Location	16q12.2
Locus type	gene with protein product
Status	Approved
Aliases	IRX-3
Ensembl gene	ENSG00000159387
Ensembl biotype	protein_coding
OMIM	606196
Entrez	79190

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 11 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000290552, ENST00000558315, ENST00000869145, ENST00000869146, ENST00000869147, ENST00000934845, ENST00000944933, ENST00000944934, ENST00000944935, ENST00000944936, ENST00000944937, ENST00000944938

RefSeq mRNA: 1 — MANE Select: NM_024335 NM_024335

CCDS: CCDS32449

Canonical transcript exons

ENST00000290552 — 6 exons

Exon	Start	End
ENSE00001045264	55324203	55325136
ENSE00001170255	55327586	55327893
ENSE00001338726	55328700	55329311
ENSE00002679720	55330298	55330756
ENSE00003611330	55326336	55326593
ENSE00003671419	55327296	55327405

Expression profiles

Bgee: expression breadth broad, 95 present calls, max score 85.85.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0492 / max 9.7678, expressed in 26 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
154120	0.0492	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	85.85	gold quality
skin of abdomen	UBERON:0001416	79.38	gold quality
hindlimb stylopod muscle	UBERON:0004252	78.82	gold quality
zone of skin	UBERON:0000014	78.69	gold quality
skin of leg	UBERON:0001511	78.67	gold quality
subcutaneous adipose tissue	UBERON:0002190	77.78	gold quality
heart left ventricle	UBERON:0002084	77.35	gold quality
adipose tissue	UBERON:0001013	76.51	gold quality
omental fat pad	UBERON:0010414	74.88	gold quality
lower esophagus mucosa	UBERON:0035834	71.59	gold quality
thoracic mammary gland	UBERON:0005200	70.01	gold quality
gastrocnemius	UBERON:0001388	68.87	gold quality
skeletal muscle tissue	UBERON:0001134	67.44	gold quality
muscle of leg	UBERON:0001383	66.91	gold quality
metanephros cortex	UBERON:0010533	66.85	gold quality
saliva-secreting gland	UBERON:0001044	64.71	gold quality
minor salivary gland	UBERON:0001830	64.65	gold quality
heart	UBERON:0000948	61.22	gold quality
muscle tissue	UBERON:0002385	60.98	gold quality
upper lobe of left lung	UBERON:0008952	60.69	gold quality
lung	UBERON:0002048	59.63	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	58.67	gold quality
nucleus accumbens	UBERON:0001882	58.28	gold quality
cortex of kidney	UBERON:0001225	57.52	gold quality
right lung	UBERON:0002167	56.81	gold quality
tonsil	UBERON:0002372	56.52	gold quality
spleen	UBERON:0002106	54.34	gold quality
kidney	UBERON:0002113	53.93	gold quality
adult mammalian kidney	UBERON:0000082	52.18	gold quality
putamen	UBERON:0001874	50.97	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.08

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

20 targeting IRX6, 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-4481	100.00	66.42	1669
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-143-3P	99.49	69.05	1457
HSA-MIR-4770	99.49	69.09	1451
HSA-MIR-6088	99.29	68.45	1284
HSA-MIR-4477B	99.23	70.49	1733
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-4451	98.82	68.17	1455
HSA-MIR-4266	98.53	67.29	1035
HSA-MIR-6880-5P	98.08	65.59	1282
HSA-MIR-649	97.96	67.21	704
HSA-MIR-490-3P	97.79	65.54	606
HSA-MIR-4670-3P	97.37	68.35	1378

Literature-anchored findings (GeneRIF, showing 2)

• Genetic variations of HAAO and IRX6 influence susceptibility to hypospadias in the Japanese population. (PMID:30063927)
• A duplication on chromosome 16q12 affecting the IRXB gene cluster is associated with autosomal dominant cone dystrophy with early tritanopic color vision defect. (PMID:33891002)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	irx6a	ENSDARG00000034420
mus_musculus	Irx6	ENSMUSG00000031738
rattus_norvegicus	Irx6	ENSRNOG00000011037

Paralogs (6): IRX4 (ENSG00000113430), MKX (ENSG00000150051), IRX1 (ENSG00000170549), IRX2 (ENSG00000170561), IRX5 (ENSG00000176842), IRX3 (ENSG00000177508)

Protein

Protein identifiers

Iroquois-class homeodomain protein IRX-6 — P78412 (reviewed: P78412)

Alternative names: Homeodomain protein IRXB3, Iroquois homeobox protein 6

All UniProt accessions (1): P78412

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor. Binds to the iroquois binding site (IBS) motif of target genes to regulate gene expression; functions as a transcriptional activator or repressor. Modulates expression of RCVRN, VSX1, BHLHE22/BHLHB5 and TACR3/Nk3r. Required downstream of retinal bipolar cell specification for the terminal differentiation of type 2, type 3a and possibly type 6 bipolar cells.

Subcellular location. Nucleus.

Similarity. Belongs to the TALE/IRO homeobox family.

RefSeq proteins (1): NP_077311* (*=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 (8 total): region of interest 2, compositionally biased region 2, sequence conflict 2, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P78412-F1	55.29	0.11

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 75 (showing top): ATF_B, GOBP_NEUROGENESIS, CREBP1_Q2, LHX3_01, GGGTGGRR_PAX4_03, COUP_01, CREB_Q4, NKX62_Q2, ATF1_Q6, HNF4_DR1_Q3, E4F1_Q6, ATF3_Q6, CCCNNNNNNAAGWT_UNKNOWN, AFP1_Q6, ATF4_Q2

GO Biological Process (6): regulation of transcription by RNA polymerase II (GO:0006357), neuron differentiation (GO:0030182), positive regulation of DNA-templated transcription (GO:0045893), cell development (GO:0048468), regulation of DNA-templated transcription (GO:0006355), positive regulation of transcription by RNA polymerase II (GO:0045944)

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 transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), protein binding (GO:0005515)

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

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 DNA-templated transcription	2
transcription by RNA polymerase II	2
cell differentiation	2
DNA-templated transcription	2
regulation of transcription by RNA polymerase II	2
generation of neurons	1
positive regulation of RNA biosynthetic process	1
anatomical structure development	1
cellular developmental process	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
nucleic acid binding	1
binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1454 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IRX6	FTO	Q9C0B1	785
IRX6	NKX2-2	O95096	735
IRX6	SIX3	O95343	712
IRX6	OLIG2	Q13516	697
IRX6	RPGRIP1L	Q68CZ1	688
IRX6	ARID5B	Q14865	607
IRX6	DBX2	Q6ZNG2	592
IRX6	IRX5	P78411	556
IRX6	PAX6	P26367	552
IRX6	NKX6-1	P78426	545
IRX6	NKX6-2	Q9C056	545
IRX6	SMYD1	Q8NB12	533
IRX6	DBX1	A6NMT0	528
IRX6	IRX1	P78414	526
IRX6	SHH	Q15465	521

IntAct

60 interactions, top by confidence:

A	B	Type	Score
IRX6	MYL2	psi-mi:“MI:0915”(physical association)	0.560
GLRX3	IRX6	psi-mi:“MI:0915”(physical association)	0.560
MYL2	IRX6	psi-mi:“MI:0915”(physical association)	0.560
CRX	IRX6	psi-mi:“MI:0915”(physical association)	0.560
IRX6	TLE5	psi-mi:“MI:0915”(physical association)	0.560
TBX19	IRX6	psi-mi:“MI:0915”(physical association)	0.560
IRX6	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
IRX6	PFDN5	psi-mi:“MI:0915”(physical association)	0.560
IRX6	ARID5A	psi-mi:“MI:0915”(physical association)	0.560
IRX6	NFKBID	psi-mi:“MI:0915”(physical association)	0.560
IRX6	TRIB3	psi-mi:“MI:0915”(physical association)	0.560
HOXA1	IRX6	psi-mi:“MI:0915”(physical association)	0.560
IRX6	KRTAP19-7	psi-mi:“MI:0915”(physical association)	0.560
CCL5	IRX6	psi-mi:“MI:0915”(physical association)	0.370
	IRX6	psi-mi:“MI:0915”(physical association)	0.370
IFNA1	IRX6	psi-mi:“MI:0915”(physical association)	0.370
IFNA10	IRX6	psi-mi:“MI:0915”(physical association)	0.370
IFNA16	IRX6	psi-mi:“MI:0915”(physical association)	0.370
IFNA17	IRX6	psi-mi:“MI:0915”(physical association)	0.370
IFNA21	IRX6	psi-mi:“MI:0915”(physical association)	0.370
IFNA4	IRX6	psi-mi:“MI:0915”(physical association)	0.370
IFNA7	IRX6	psi-mi:“MI:0915”(physical association)	0.370
IFNL1	IRX6	psi-mi:“MI:0915”(physical association)	0.370
IL15	IRX6	psi-mi:“MI:0915”(physical association)	0.370
IL33	IRX6	psi-mi:“MI:0915”(physical association)	0.370
TNFSF14	IRX6	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (19): IRX6 (Two-hybrid), IRX6 (Two-hybrid), IRX6 (Two-hybrid), IRX6 (Two-hybrid), IRX6 (Two-hybrid), IRX6 (Two-hybrid), IRX6 (Two-hybrid), IRX6 (Two-hybrid), NFKBID (Two-hybrid), ARID5A (Two-hybrid), KRTAP19-7 (Two-hybrid), IRX6 (Proximity Label-MS), IRX6 (Proximity Label-MS), IRX6 (Proximity Label-MS), IRX6 (Proximity Label-MS)

ESM2 similar proteins: A0A2Z4LIS9, A6QPM6, A7X8B3, A7X8B5, A7X8B7, A7X8C4, A7X8C7, A7X8C9, A7XW16, A7XW20, A7XW25, O08664, O15054, O43151, O70218, O89113, P09066, P14652, P17542, P19419, P19622, P22091, P23683, P49640, P70061, P78412, P82976, P97503, Q00587, Q04890, Q05916, Q05917, Q12950, Q15270, Q17QW1, Q3U133, Q5JPB2, Q5NCY0, Q6ZW13, Q80WY3

Diamond homologs: A1YGI6, A6NDR6, A8K0S8, A8WL06, B7ZRT8, O00470, O04136, O14770, O22300, O42261, O46339, O65685, O70477, P41779, P41817, P46606, P48000, P48001, P48002, P48731, P53147, P54269, P55347, P56659, P56660, P56664, P56665, P56669, P70284, P78412, P78413, P78414, P78415, P79937, P81067, P81068, P97367, P97368, Q0E3C3, Q0J6N4

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 27 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Regulation of IFNA/IFNB signaling	7	139.8×	1e-12
TRAF6 mediated IRF7 activation	7	121.1×	1e-12
Evasion by RSV of host interferon responses	7	103.8×	3e-12
Interferon alpha/beta signaling	7	48.5×	7e-10
SARS-CoV-2 activates/modulates innate and adaptive immune responses	7	28.4×	2e-08
Factors involved in megakaryocyte development and platelet production	7	21.1×	2e-07

GO biological processes:

GO term	Partners	Fold	FDR
B cell activation involved in immune response	6	252.8×	9e-12
natural killer cell activation involved in immune response	6	237.9×	9e-12
T cell activation involved in immune response	6	168.5×	5e-11
response to exogenous dsRNA	6	126.4×	3e-10
type I interferon-mediated signaling pathway	6	82.5×	3e-09
humoral immune response	6	67.4×	1e-08
cellular response to virus	8	64.2×	2e-11
response to virus	5	28.8×	2e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	103
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
997022	NC_000016.10:g.54801236_55533834dup	Pathogenic

SpliceAI

1060 predictions. Top by Δscore:

Variant	Effect	Δscore
16:55325133:CCAGG:C	donor_loss	1.0000
16:55326334:A:AG	acceptor_gain	1.0000
16:55326335:G:GG	acceptor_gain	1.0000
16:55326591:CTG:C	donor_gain	1.0000
16:55326594:G:GG	donor_gain	1.0000
16:55326594:GTG:G	donor_loss	1.0000
16:55327294:A:AG	acceptor_gain	1.0000
16:55327295:G:GA	acceptor_gain	1.0000
16:55327295:GA:G	acceptor_gain	1.0000
16:55327404:CG:C	donor_loss	1.0000
16:55327405:GG:G	donor_loss	1.0000
16:55327406:G:T	donor_loss	1.0000
16:55327583:CA:C	acceptor_loss	1.0000
16:55327584:A:AC	acceptor_loss	1.0000
16:55327585:G:T	acceptor_loss	1.0000
16:55327585:GGT:G	acceptor_gain	1.0000
16:55327788:A:T	donor_gain	1.0000
16:55328696:GCA:G	acceptor_loss	1.0000
16:55328698:A:AG	acceptor_gain	1.0000
16:55328699:G:A	acceptor_loss	1.0000
16:55328699:G:GA	acceptor_gain	1.0000
16:55328699:GA:G	acceptor_gain	1.0000
16:55328699:GAA:G	acceptor_gain	1.0000
16:55328699:GAAGT:G	acceptor_gain	1.0000
16:55325137:G:GG	donor_gain	0.9900
16:55325138:T:A	donor_loss	0.9900
16:55326333:T:G	acceptor_gain	0.9900
16:55326335:GT:G	acceptor_gain	0.9900
16:55326335:GTTT:G	acceptor_gain	0.9900
16:55326592:TG:T	donor_gain	0.9900

AlphaMissense

2831 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:55327717:T:C	L182P	1.000
16:55327761:T:C	F197L	1.000
16:55327763:C:A	F197L	1.000
16:55327763:C:G	F197L	1.000
16:55327654:T:A	L161H	0.999
16:55327662:T:A	W164R	0.999
16:55327662:T:C	W164R	0.999
16:55327664:G:C	W164C	0.999
16:55327664:G:T	W164C	0.999
16:55327674:C:G	H168D	0.999
16:55327692:C:T	P174S	0.999
16:55327693:C:A	P174H	0.999
16:55327700:G:C	K176N	0.999
16:55327700:G:T	K176N	0.999
16:55327705:A:T	E178V	0.999
16:55327717:T:A	L182Q	0.999
16:55327720:C:A	A183D	0.999
16:55327735:T:C	M188T	0.999
16:55327736:G:A	M188I	0.999
16:55327736:G:C	M188I	0.999
16:55327736:G:T	M188I	0.999
16:55327758:T:A	W196R	0.999
16:55327758:T:C	W196R	0.999
16:55327760:G:C	W196C	0.999
16:55327760:G:T	W196C	0.999
16:55327762:T:C	F197S	0.999
16:55327762:T:G	F197C	0.999
16:55327777:G:C	R202P	0.999
16:55327779:C:A	R203S	0.999
16:55327787:G:C	K205N	0.999

dbSNP variants (sampled 300 via entrez): RS1000101716 (16:55329968 C>G), RS1000983083 (16:55324626 G>C), RS1001267972 (16:55324850 C>G), RS1001532066 (16:55327735 T>A,C), RS1002719303 (16:55323478 C>G,T), RS1003062217 (16:55328431 G>A), RS1003181092 (16:55323219 G>C), RS1005157630 (16:55324378 G>A,T), RS1005305579 (16:55324121 G>T), RS1005825404 (16:55327019 G>A), RS1005954376 (16:55330933 G>A), RS1006008309 (16:55331165 G>A), RS1006575874 (16:55328138 A>G), RS1006621826 (16:55325535 G>A), RS1006687942 (16:55322563 C>A,T)

Disease associations

OMIM: gene MIM:606196 | disease phenotypes: MIM:619649

GenCC curated gene-disease

Disease	Classification	Inheritance
cone dystrophy	Moderate	Autosomal dominant

Mondo (2): chromosome 16q12 duplication syndrome (MONDO:0859210), cone dystrophy (MONDO:0000455)

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001525_39	Visceral fat	9.000000e-06
GCST002563_17	Hypospadias	1.000000e-08
GCST005411_8	Thrombin-activatable fibrinolysis inhibitor activation peptide	4.000000e-07
GCST007623_1	Lack of premeditation	8.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006946	behavioural disinhibition measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D000077765	Cone Dystrophy	C11.270.151; C11.768.216

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

12 total (human), top 12 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
S-(1,2-dichlorovinyl)cysteine	increases expression, decreases reaction	1
Temozolomide	decreases expression	1
Decitabine	affects expression	1
Sunitinib	decreases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Cisplatin	affects expression	1
Doxorubicin	increases expression	1
Lipopolysaccharides	increases expression, decreases reaction	1
Tobacco Smoke Pollution	affects expression	1
Asbestos, Crocidolite	decreases methylation	1
Asbestos, Amosite	decreases methylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02435940	Not specified	RECRUITING	Inherited Retinal Degenerative Disease Registry
NCT03990727	Not specified	UNKNOWN	Phenotype Correlates Genotype of Inherited Retina Dystrophies, Retinitis Pigmentosa, Con>Rod Dystrophies.
NCT04658251	Not specified	TERMINATED	Study of New Mutations in Cone Disorders
NCT05355415	Not specified	RECRUITING	Adaptive Optics Imaging of Outer Retinal Diseases