ISX

Summary

ISX (intestine specific homeobox, HGNC:28084) is a protein-coding gene on chromosome 22q12.3, encoding Intestine-specific homeobox (Q2M1V0). Transcription factor that regulates gene expression in intestine.

Homeobox genes encode DNA-binding proteins, many of which are thought to be involved in early embryonic development. Homeobox genes encode a DNA-binding domain of 60 to 63 amino acids referred to as the homeodomain. This gene is a member of the RAXLX homeobox gene family.

Source: NCBI Gene 91464 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 47 total
• MANE Select transcript: NM_001303508

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28084
Approved symbol	ISX
Name	intestine specific homeobox
Location	22q12.3
Locus type	gene with protein product
Status	Approved
Aliases	RAXLX
Ensembl gene	ENSG00000175329
Ensembl biotype	protein_coding
OMIM	612019
Entrez	91464

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000308700, ENST00000404699, ENST00000885876, ENST00000958093

RefSeq mRNA: 1 — MANE Select: NM_001303508 NM_001303508

CCDS: CCDS33640

Canonical transcript exons

ENST00000404699 — 5 exons

Exon	Start	End
ENSE00001186931	35084383	35084499
ENSE00001186935	35082518	35082669
ENSE00001186942	35085454	35087387
ENSE00001549473	35066752	35067316
ENSE00001554059	35066158	35066462

Expression profiles

Bgee: expression breadth broad, 35 present calls, max score 97.70.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0318 / max 11.1082, expressed in 17 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
191954	0.0318	17

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	97.70	gold quality
mucosa of transverse colon	UBERON:0004991	95.54	gold quality
jejunal mucosa	UBERON:0000399	93.05	gold quality
rectum	UBERON:0001052	89.40	gold quality
colonic mucosa	UBERON:0000317	88.52	gold quality
duodenum	UBERON:0002114	88.21	gold quality
mucosa of sigmoid colon	UBERON:0004993	87.52	gold quality
transverse colon	UBERON:0001157	80.38	gold quality
small intestine Peyer’s patch	UBERON:0003454	80.32	gold quality
small intestine	UBERON:0002108	79.95	gold quality
pancreatic ductal cell	CL:0002079	73.57	silver quality
colonic epithelium	UBERON:0000397	72.44	gold quality
intestine	UBERON:0000160	71.37	gold quality
jejunum	UBERON:0002115	69.53	gold quality
large intestine	UBERON:0000059	68.23	gold quality
tibialis anterior	UBERON:0001385	67.28	silver quality
colon	UBERON:0001155	67.23	gold quality
deltoid	UBERON:0001476	56.96	gold quality
epithelial cell of pancreas	CL:0000083	56.30	gold quality
caecum	UBERON:0001153	54.71	gold quality
vermiform appendix	UBERON:0001154	54.41	gold quality
cardiac muscle of right atrium	UBERON:0003379	54.34	gold quality
left ventricle myocardium	UBERON:0006566	54.23	gold quality
kidney epithelium	UBERON:0004819	53.93	gold quality
upper arm skin	UBERON:0004263	53.52	gold quality
myocardium	UBERON:0002349	50.25	gold quality
smooth muscle tissue	UBERON:0001135	48.57	gold quality
islet of Langerhans	UBERON:0000006	48.16	gold quality
quadriceps femoris	UBERON:0001377	47.58	gold quality
nasal cavity epithelium	UBERON:0005384	47.03	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.82

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
BCO1

JASPAR motifs

Motif	Name	Family
MA0654.1	ISX	Paired-related HD factors
MA0654.2	ISX	Paired-related HD factors

JASPAR matrix evidence (PMIDs): PMID:18585359

Upstream regulators (CollecTRI, top): THRA

Literature-anchored findings (GeneRIF, showing 9)

• our results highlight ISX as an important regulator in hepatoma progression with significant potential as a prognostic and therapeutic target in HCCs. (PMID:23221382)
• Genetics and diet regulate vitamin A production via the homeobox transcription factor ISX (PMID:23393141)
• ISX expression induced by H. pylori infection may lead to intestinal metaplasia and hyperproliferation of gastric mucosa through CDX1/2 and cyclinD1 expression, contributing to gastric carcinogenesis. (PMID:26872890)
• our results indicate that E2F1 is an important downstream gene of ISX in hepatoma progression. (PMID:27175585)
• Results show that ISX expression mediated AHR-induced tumorigenesis in hepatocellular carcinoma. (PMID:28398627)
• Overall, our results identified a feed-forward mechanism of immune suppression in hepatocellular carcinoma organized by ISX, which involves kynurenine-AHR signaling and PD-L1, offering insights into immune escape by hepatocellular carcinoma (PMID:28625979)
• Impact of bromodomain-containing protein 4 (BRD4) and intestine-specific homeobox (ISX) expression on the prognosis of patients with hepatocellular carcinoma’ for better clarity. (PMID:34173348)
• Phosphorylation of intestine-specific homeobox by ERK1 modulates oncogenic activity and sorafenib resistance. (PMID:34265398)
• Interaction between retinol intake and ISX rs5755368 polymorphism in colorectal cancer risk: a case-control study in a Korean population. (PMID:37349365)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Isx	ENSMUSG00000031621
rattus_norvegicus	Isx	ENSRNOG00000039808

Paralogs (50): ARX (ENSG00000004848), PAX6 (ENSG00000007372), PAX7 (ENSG00000009709), ALX4 (ENSG00000052850), GSC2 (ENSG00000063515), PITX1 (ENSG00000069011), PAX2 (ENSG00000075891), RHOXF1 (ENSG00000101883), CRX (ENSG00000105392), EVX1 (ENSG00000106038), PAX4 (ENSG00000106331), NOBOX (ENSG00000106410), PITX3 (ENSG00000107859), PHOX2B (ENSG00000109132), OTX1 (ENSG00000115507), PRRX1 (ENSG00000116132), VSX2 (ENSG00000119614), ESX1 (ENSG00000123576), PAX8 (ENSG00000125618), PAX1 (ENSG00000125813), RHOXF2 (ENSG00000131721), GSC (ENSG00000133937), RAX (ENSG00000134438), PAX3 (ENSG00000135903), ALX3 (ENSG00000156150), HESX1 (ENSG00000163666), PITX2 (ENSG00000164093), UNCX (ENSG00000164853), PHOX2A (ENSG00000165462), OTX2 (ENSG00000165588), DRGX (ENSG00000165606), PRRX2 (ENSG00000167157), SHOX2 (ENSG00000168779), OTP (ENSG00000171540), RAX2 (ENSG00000173976), EVX2 (ENSG00000174279), PROP1 (ENSG00000175325), ALX1 (ENSG00000180318), MIXL1 (ENSG00000185155), SHOX (ENSG00000185960)

Protein

Protein identifiers

Intestine-specific homeobox — Q2M1V0 (reviewed: Q2M1V0)

Alternative names: RAX-like homeobox

All UniProt accessions (1): Q2M1V0

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that regulates gene expression in intestine. May participate in vitamin A metabolism most likely by regulating BCO1 expression in the intestine.

Subcellular location. Nucleus.

RefSeq proteins (1): NP_001290437* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR050649	Paired_Homeobox_TFs	Family

Pfam: PF00046

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

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q2M1V0-F1	67.00	0.25

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 45 (showing top): AGGAAGC_MIR5163P, GOBP_NEUROGENESIS, GOCC_NUCLEAR_BODY, GOMF_SEQUENCE_SPECIFIC_DNA_BINDING, CERVERA_SDHB_TARGETS_2, ZWANG_TRANSIENTLY_UP_BY_2ND_EGF_PULSE_ONLY, GOMF_TRANSCRIPTION_REGULATOR_ACTIVITY, MIR548P, GSE10094_LCMV_VS_LISTERIA_IND_EFF_CD4_TCELL_DN, GSE10239_KLRG1INT_VS_KLRG1HIGH_EFF_CD8_TCELL_DN, MIR507, MIR5683, MIR557, GSE11864_UNTREATED_VS_CSF1_IN_MAC_DN, GSE11864_UNTREATED_VS_CSF1_IFNG_IN_MAC_DN

GO Biological Process (3): regulation of transcription by RNA polymerase II (GO:0006357), neuron development (GO:0048666), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (5): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), sequence-specific double-stranded DNA binding (GO:1990837), 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
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
neuron differentiation	1
cell development	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
transcription cis-regulatory region binding	1
chromatin	1
RNA polymerase II transcription regulatory region sequence-specific DNA binding	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
double-stranded DNA binding	1
sequence-specific 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

588 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ISX	BCO1	Q9HAY6	985
ISX	SCARB1	Q8WTV0	791
ISX	BCO2	Q9BYV7	623
ISX	RARS1	P54136	428
ISX	RDH12	Q96NR8	412
ISX	KLF5	Q13887	411
ISX	PLAAT2	Q9NWW9	410
ISX	LRAT	O95237	408
ISX	STRA6	Q9BX79	392
ISX	PLAAT1	Q9HDD0	384
ISX	LRATD1	Q96KN4	372
ISX	CTCF	P49711	370
ISX	CYP26A1	O43174	369
ISX	RBP2	P50120	367
ISX	PLAAT5	Q96KN8	366

IntAct

22 interactions, top by confidence:

A	B	Type	Score
ISX	DAZAP2	psi-mi:“MI:0915”(physical association)	0.560
ISX	ROR2	psi-mi:“MI:0915”(physical association)	0.560
DAZAP2	ISX	psi-mi:“MI:0915”(physical association)	0.560
POU6F2	ISX	psi-mi:“MI:0915”(physical association)	0.560
GSC2	ISX	psi-mi:“MI:0915”(physical association)	0.560
ROR2	ISX	psi-mi:“MI:0915”(physical association)	0.560
ISX	UBAP2	psi-mi:“MI:0915”(physical association)	0.560
ISX	MOCS3	psi-mi:“MI:0914”(association)	0.530
BASP1	ISX	psi-mi:“MI:0915”(physical association)	0.400
ISX	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.400
ISX	DCK	psi-mi:“MI:0914”(association)	0.350
ISX	GAPDHS	psi-mi:“MI:0914”(association)	0.350
ISX	ZNF609	psi-mi:“MI:2364”(proximity)	0.270
ISX	POU6F2	psi-mi:“MI:0915”(physical association)	0.000
ISX	GSC2	psi-mi:“MI:0915”(physical association)	0.000
ISX	UBAP2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (32): ISX (Affinity Capture-Western), ISX (Two-hybrid), ISX (Two-hybrid), ISX (Two-hybrid), ISX (Two-hybrid), ISX (Affinity Capture-RNA), TLE4 (Affinity Capture-MS), DCK (Affinity Capture-MS), CMC2 (Affinity Capture-MS), GAPDHS (Affinity Capture-MS), PRTN3 (Affinity Capture-MS), TPK1 (Affinity Capture-MS), MOCS3 (Affinity Capture-MS), PKLR (Affinity Capture-MS), TLE1 (Proximity Label-MS)

ESM2 similar proteins: A0A5F9ZHS7, A1YGK1, A2T7E6, A8MZG2, O08574, O43593, O60393, O75593, O88621, O95231, P0C1T1, P0CG20, P20428, P97609, Q04667, Q17QR5, Q2KIS6, Q2M1V0, Q2T9Q7, Q32LE6, Q497V6, Q5JUK2, Q5M844, Q5RJB0, Q5TGS1, Q61645, Q61657, Q6ZMY3, Q6ZN32, Q6ZNG2, Q7RTU1, Q8BZW2, Q8CGW9, Q8IWN7, Q8IXT2, Q8IZ20, Q8N1L9, Q8N7G0, Q8N944, Q8N9Y4

Diamond homologs: A0A1W2PPK0, A0A1W2PPM1, A1A546, A1YEY5, A1YFI3, A1YG57, A1YGA2, A2T733, A2T777, A2T7P4, A6NFQ7, G5EC89, L8E946, O14813, O15499, O35690, O42250, O42356, O42357, O42477, O70137, O73917, O75360, O95076, O97670, P0DMV5, P26367, P26630, P29454, P41935, P47237, P47238, P53544, P53545, P53546, P54366, P55813, P55864, P56915, P56916

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	42
Likely benign	2
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

917 predictions. Top by Δscore:

Variant	Effect	Δscore
22:35082516:A:AG	acceptor_gain	1.0000
22:35082517:G:GG	acceptor_gain	1.0000
22:35082665:TGCAG:T	donor_loss	1.0000
22:35082666:GCAG:G	donor_loss	1.0000
22:35082668:AG:A	donor_loss	1.0000
22:35082670:G:GA	donor_loss	1.0000
22:35082671:T:C	donor_loss	1.0000
22:35084374:T:A	acceptor_gain	1.0000
22:35084381:AGAT:A	acceptor_loss	1.0000
22:35084382:GAT:G	acceptor_gain	1.0000
22:35084382:GATC:G	acceptor_gain	1.0000
22:35084382:GATCT:G	acceptor_gain	1.0000
22:35084455:C:G	donor_gain	1.0000
22:35084496:GGCT:G	donor_gain	1.0000
22:35084497:GCTG:G	donor_gain	1.0000
22:35069820:GAA:G	donor_gain	0.9900
22:35082513:T:G	acceptor_gain	0.9900
22:35082513:T:TA	acceptor_gain	0.9900
22:35082516:AG:A	acceptor_loss	0.9900
22:35082516:AGAAG:A	acceptor_gain	0.9900
22:35082517:GA:G	acceptor_gain	0.9900
22:35082517:GAA:G	acceptor_gain	0.9900
22:35082517:GAAGG:G	acceptor_gain	0.9900
22:35084380:C:G	acceptor_gain	0.9900
22:35084381:A:AG	acceptor_gain	0.9900
22:35084382:G:GG	acceptor_gain	0.9900
22:35084382:GA:G	acceptor_gain	0.9900
22:35084497:GCT:G	donor_gain	0.9900
22:35084500:G:GG	donor_gain	0.9900
22:35067025:G:GT	donor_gain	0.9800

AlphaMissense

1588 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:35082553:T:C	F89L	0.998
22:35082555:C:A	F89L	0.998
22:35082555:C:G	F89L	0.998
22:35084389:T:C	F130L	0.997
22:35084391:C:A	F130L	0.997
22:35084391:C:G	F130L	0.997
22:35082554:T:C	F89S	0.995
22:35082589:T:C	F101L	0.995
22:35082591:C:A	F101L	0.995
22:35082591:C:G	F101L	0.995
22:35084390:T:C	F130S	0.995
22:35084395:A:G	N132D	0.995
22:35082554:T:G	F89C	0.993
22:35084396:A:C	N132T	0.993
22:35084396:A:G	N132S	0.993
22:35082569:T:C	L94P	0.991
22:35082578:T:C	L97P	0.991
22:35082650:T:C	L121P	0.989
22:35084390:T:G	F130C	0.989
22:35084414:G:C	R138P	0.989
22:35084388:G:C	W129C	0.988
22:35084388:G:T	W129C	0.988
22:35084386:T:A	W129R	0.987
22:35084386:T:C	W129R	0.987
22:35084389:T:G	F130V	0.987
22:35084396:A:T	N132I	0.987
22:35082632:T:C	L115P	0.986
22:35084384:T:C	I128T	0.986
22:35084394:G:C	Q131H	0.986
22:35084394:G:T	Q131H	0.986

dbSNP variants (sampled 300 via entrez): RS1000020131 (22:35082968 G>A), RS1000240302 (22:35086906 T>C), RS1000507135 (22:35076993 C>T), RS1000831719 (22:35071008 G>T), RS1000967032 (22:35071218 T>G), RS1001072915 (22:35069642 G>A), RS1001187930 (22:35086669 G>C), RS1001219252 (22:35075653 T>A), RS1001286791 (22:35087725 A>G), RS1001297240 (22:35082022 C>T), RS1001468626 (22:35082376 T>C), RS1001676350 (22:35087232 C>G), RS1001824077 (22:35064813 G>A), RS1001899295 (22:35064567 T>C), RS1002183694 (22:35076511 C>T)

Disease associations

OMIM: gene MIM:612019 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST003659_9	Modified Stumvoll Insulin Sensitivity Index (BMI interaction)	8.000000e-12
GCST003795_10	Age at first birth	3.000000e-09
GCST005958_13	Waist-to-hip ratio adjusted for BMI (age >50)	1.000000e-06
GCST005962_33	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	6.000000e-06
GCST006045_2	Age at first birth	2.000000e-06
GCST009391_408	Metabolite levels	2.000000e-06
GCST009391_448	Metabolite levels	4.000000e-06
GCST012282_11	BMI x environmental factors (excluding physical activity) interaction	5.000000e-06
GCST012283_7	BMI x environmental factors (including physical activity) interaction	3.000000e-06

EFO canonical traits (15, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004471	insulin sensitivity measurement
EFO:0009101	age at first birth measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0010387	phosphatidylcholine 38:5 measurement
EFO:0010386	phosphatidylcholine 38:4 measurement
EFO:0006527	smoking status measurement
EFO:0009374	energy intake measurement
EFO:0009695	household income
EFO:0010810	protein intake measurement
EFO:0010811	carbohydrate intake measurement
EFO:0011015	educational attainment
EFO:0008002	physical activity measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression	2
tungsten carbide	affects binding, decreases expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
indeno(1,2,3-cd)pyrene	increases expression	1
CGP 52608	affects binding, increases reaction	1
prothioconazole	decreases expression	1
Amiodarone	increases expression	1
Cadmium	decreases expression, increases abundance	1
Calcitriol	increases expression, affects cotreatment	1
Cobalt	affects binding, decreases expression	1
Quercetin	decreases expression	1
Testosterone	affects cotreatment, increases expression	1
Urethane	decreases expression	1
Oxyquinoline	increases expression	1
Cyclosporine	decreases expression	1
Cadmium Chloride	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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