TLX2

Summary

TLX2 (T cell leukemia homeobox 2, HGNC:5057) is a protein-coding gene on chromosome 2p13.1, encoding T-cell leukemia homeobox protein 2 (O43763). Transcription activator that binds DNA elements with the consensus sequence 5’-CGGTAATTGG-3'.

This gene is a member of an orphan homeobox-containing transcription factor family. Studies of the mouse ortholog have shown that the encoded protein is crucial for the development of the enteric nervous system; in humans, loss-of-function may play a role in tumorigenesis of gastrointestinal stromal tumors.

Source: NCBI Gene 3196 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 38 total
• MANE Select transcript: NM_016170

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5057
Approved symbol	TLX2
Name	T cell leukemia homeobox 2
Location	2p13.1
Locus type	gene with protein product
Status	Approved
Aliases	Enx, NCX
Ensembl gene	ENSG00000115297
Ensembl biotype	protein_coding
OMIM	604240
Entrez	3196

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000233638, ENST00000464417, ENST00000497238, ENST00000621092

RefSeq mRNA: 1 — MANE Select: NM_016170 NM_016170

CCDS: CCDS1947

Canonical transcript exons

ENST00000233638 — 3 exons

Exon	Start	End
ENSE00000762883	74514450	74515206
ENSE00000762885	74515633	74515870
ENSE00000963409	74515973	74517148

Expression profiles

Bgee: expression breadth broad, 84 present calls, max score 72.59.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.6370 / max 306.9011, expressed in 121 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
21044	0.4905	98
21045	0.1140	26
21043	0.0325	8

Top tissues by expression

231 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	72.59	gold quality
transverse colon	UBERON:0001157	61.98	gold quality
small intestine Peyer’s patch	UBERON:0003454	61.82	gold quality
mucosa of transverse colon	UBERON:0004991	60.78	gold quality
small intestine	UBERON:0002108	60.47	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	60.12	gold quality
muscle layer of sigmoid colon	UBERON:0035805	59.22	gold quality
nasal cavity epithelium	UBERON:0005384	58.88	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	58.13	gold quality
intestine	UBERON:0000160	57.77	gold quality
colon	UBERON:0001155	57.60	gold quality
inferior olivary complex	UBERON:0002127	57.52	gold quality
parotid gland	UBERON:0001831	57.32	gold quality
large intestine	UBERON:0000059	57.01	gold quality
right testis	UBERON:0004534	56.62	gold quality
sigmoid colon	UBERON:0001159	55.74	gold quality
cerebellar vermis	UBERON:0004720	55.36	gold quality
endothelial cell	CL:0000115	54.60	gold quality
myocardium	UBERON:0002349	54.44	gold quality
left testis	UBERON:0004533	54.43	gold quality
middle temporal gyrus	UBERON:0002771	54.25	gold quality
heart right ventricle	UBERON:0002080	53.75	gold quality
primary visual cortex	UBERON:0002436	53.68	gold quality
testis	UBERON:0000473	53.09	gold quality
rectum	UBERON:0001052	52.52	gold quality
duodenum	UBERON:0002114	52.51	gold quality
Brodmann (1909) area 23	UBERON:0013554	52.12	gold quality
buccal mucosa cell	CL:0002336	51.60	gold quality
decidua	UBERON:0002450	51.18	gold quality
frontal pole	UBERON:0002795	50.41	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.47

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

6 targets.

Target	Regulation
ANXA5
NOTCH1
PHOX2A
PHOX2B
RET	Activation
SLC8A3

JASPAR motifs

Motif	Name	Family
MA1577.1	TLX2	NK
MA1577.2	TLX2	NK

JASPAR matrix evidence (PMIDs): PMID:10869550

Upstream regulators (CollecTRI, top): PHOX2A, PHOX2B

miRNA regulators (miRDB)

25 targeting TLX2, 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-6873-3P	100.00	71.42	2626
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-582-5P	99.47	70.79	2635
HSA-MIR-19A-5P	99.36	66.93	1675
HSA-MIR-19B-1-5P	99.36	67.07	1669
HSA-MIR-19B-2-5P	99.36	67.07	1669
HSA-MIR-1228-3P	99.00	66.53	857
HSA-MIR-4774-3P	98.90	67.82	737
HSA-MIR-500A-5P	98.76	69.13	1241
HSA-MIR-6782-3P	97.60	67.75	931
HSA-MIR-2467-5P	97.36	67.71	991
HSA-MIR-3152-5P	96.98	66.88	819
HSA-MIR-3059-3P	96.71	67.08	606
HSA-MIR-6834-5P	96.25	64.88	823
HSA-MIR-7108-3P	94.37	64.79	183

Literature-anchored findings (GeneRIF, showing 7)

• This paper describes sequencing and comparison of 5’ flanking regions of the gene, and expression in several neuroblastoma cell lines, in both mouse and human. (PMID:10446220)
• Alignment of sequences obtained from rat, human, and mouse indicates that putative regulatory elements of the Hox11L1 gene are conserved in rat, mice, and humans. (PMID:16291166)
• These results support the PHOX2B-TLX2 promoter interaction, suggesting a physiological role in the transcription-factor cascade underlying the differentiation of neuronal lineages of the Autonomic Nervous System during human embryogenesis. (PMID:16402914)
• Hox11L1 has a role in tumorigenesis in gastrointestinal stromal tumors (PMID:16969514)
• NCX is functionally expressed in developing ventricular human embryonic stem cell-derived ventricular cardiomyocytes and contributes to their excitation-contraction coupling. (PMID:19719399)
• TLX2 is an orphan homeodomain transcription factor whose expression is mainly associated with tissues derived from neural crest cells. (PMID:20044949)
• NCX-TRPC channel interaction constitutes an important functional unit in receptor-mediated divalent calcium ion influx in neuronal cells. (PMID:20728215)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tlx2	ENSMUSG00000068327
rattus_norvegicus	Tlx2	ENSRNOG00000055188

Paralogs (42): HOXA11 (ENSG00000005073), HOXC8 (ENSG00000037965), HOXA1 (ENSG00000105991), HOXA2 (ENSG00000105996), HOXA3 (ENSG00000105997), HOXA5 (ENSG00000106004), HOXA6 (ENSG00000106006), HOXA13 (ENSG00000106031), TLX1 (ENSG00000107807), HOXB6 (ENSG00000108511), HOXB8 (ENSG00000120068), HOXB5 (ENSG00000120075), HOXB3 (ENSG00000120093), HOXB1 (ENSG00000120094), HOXA7 (ENSG00000122592), HOXC13 (ENSG00000123364), HOXC11 (ENSG00000123388), HOXC12 (ENSG00000123407), HOXD1 (ENSG00000128645), HOXD3 (ENSG00000128652), HOXD9 (ENSG00000128709), HOXD10 (ENSG00000128710), HOXD11 (ENSG00000128713), HOXD13 (ENSG00000128714), PDX1 (ENSG00000139515), HOXB13 (ENSG00000159184), TLX3 (ENSG00000164438), HOXD4 (ENSG00000170166), HOXD12 (ENSG00000170178), HOXB9 (ENSG00000170689), HOXC5 (ENSG00000172789), HOXB2 (ENSG00000173917), HOXD8 (ENSG00000175879), GSX2 (ENSG00000180613), HOXC9 (ENSG00000180806), HOXC10 (ENSG00000180818), HOXB4 (ENSG00000182742), HOXA4 (ENSG00000197576), HOXC6 (ENSG00000197757), HOXC4 (ENSG00000198353)

Protein

Protein identifiers

T-cell leukemia homeobox protein 2 — O43763 (reviewed: O43763)

Alternative names: Homeobox protein Hox-11L1, Neural crest homeobox protein

All UniProt accessions (2): O43763, F1T0F2

UniProt curated annotations — full annotation on UniProt →

Function. Transcription activator that binds DNA elements with the consensus sequence 5’-CGGTAATTGG-3’. Binds DNA via its homeobox. Required for normal cell death of enteric neurons in the gastrointestinal tract. Required for normal development of the enteric nervous system, and for proper development of normal motility of the gastrointestinal tract.

Subcellular location. Nucleus.

RefSeq proteins (1): NP_057254* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR020479	HD_metazoa	Domain
IPR042247	TLX1/2/3	Family

Pfam: PF00046

UniProt features (19 total): sequence conflict 9, helix 3, region of interest 3, compositionally biased region 2, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3A03	X-RAY DIFFRACTION	1.54

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43763-F1	68.95	0.28

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 132 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, GOBP_DENDRITE_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_FORMATION_OF_PRIMARY_GERM_LAYER, AREB6_03, GOBP_REGULATION_OF_DENDRITE_MORPHOGENESIS, GOBP_NEUROGENESIS, GOBP_NEGATIVE_REGULATION_OF_DENDRITE_MORPHOGENESIS, TGACCTY_ERR1_Q2, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GGGTGGRR_PAX4_03, GOBP_NEGATIVE_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, IRF7_01

GO Biological Process (7): mesoderm formation (GO:0001707), regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of transcription by RNA polymerase II (GO:0045944), enteric nervous system development (GO:0048484), animal organ development (GO:0048513), negative regulation of dendrite morphogenesis (GO:0050774), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (7): DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), sequence-specific DNA binding (GO:0043565), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
cellular anatomical structure	2
formation of primary germ layer	1
mesoderm morphogenesis	1
positive regulation of DNA-templated transcription	1
autonomic nervous system development	1
system development	1
anatomical structure development	1
negative regulation of cell projection organization	1
dendrite morphogenesis	1
regulation of dendrite morphogenesis	1
negative regulation of neurogenesis	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	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
DNA binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
binding	1
chromosome	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

624 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TLX2	IVNS1ABP	Q9Y6Y0	825
TLX2	RANBP17	Q9H2T7	759
TLX2	SLC8A1	P32418	708
TLX2	PLN	P26678	702
TLX2	BCL11B	Q9C0K0	658
TLX2	LYL1	P12980	619
TLX2	RNF223	E7ERA6	609
TLX2	TAL1	P17542	546
TLX2	LMO1	P25800	535
TLX2	TIFAB	Q6ZNK6	512
TLX2	PRODH	O43272	497
TLX2	EDNRB	P24530	489
TLX2	ATP2A2	P16614	477
TLX2	NKX6-3	A6NJ46	471
TLX2	TRAM2	Q15035	469

IntAct

21 interactions, top by confidence:

A	B	Type	Score
TLX2	POU6F2	psi-mi:“MI:0915”(physical association)	0.560
TLX2	KRTAP6-2	psi-mi:“MI:0915”(physical association)	0.560
TLX2	TLE1	psi-mi:“MI:0915”(physical association)	0.520
NFIA	TLX2	psi-mi:“MI:0915”(physical association)	0.470
NFIB	TLX2	psi-mi:“MI:0915”(physical association)	0.470
NFIC	TLX2	psi-mi:“MI:0915”(physical association)	0.400
	TLX2	psi-mi:“MI:0915”(physical association)	0.400
TLX2	IRF9	psi-mi:“MI:0915”(physical association)	0.370
TLX2	GTF2A1L	psi-mi:“MI:0915”(physical association)	0.370
TLX2	IRF6	psi-mi:“MI:0915”(physical association)	0.370
TLX2	MCM4	psi-mi:“MI:0915”(physical association)	0.370
TLX2	MEIS1	psi-mi:“MI:0915”(physical association)	0.370
TLX2	POU2F1	psi-mi:“MI:0915”(physical association)	0.370
TLX2	ZNF502	psi-mi:“MI:0915”(physical association)	0.370
TLX2		psi-mi:“MI:0914”(association)	0.350
TLX2	IGF2BP3	psi-mi:“MI:2364”(proximity)	0.270
TLX2	POU6F2	psi-mi:“MI:0915”(physical association)	0.000
TLX2	KRTAP6-2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (147): TLX2 (Two-hybrid), KRTAP6-2 (Two-hybrid), YWHAH (Reconstituted Complex), TLX2 (Affinity Capture-Western), CUX1 (Proximity Label-MS), TLE1 (Proximity Label-MS), ZFHX3 (Proximity Label-MS), IGF2BP3 (Proximity Label-MS), BCL9 (Proximity Label-MS), NFIB (Proximity Label-MS), ARID1A (Proximity Label-MS), KMT2D (Proximity Label-MS), ZNF609 (Proximity Label-MS), TBL1X (Proximity Label-MS), NCOR1 (Proximity Label-MS)

ESM2 similar proteins: A1YEV8, A1YF08, A1YG25, A1YG85, A2RU54, A2T711, A2T756, A8MTQ0, O14813, O15522, O35160, O35602, O43763, O70218, P28360, P42580, P43687, P50223, P52945, P52946, P52947, P70118, P70354, P81062, Q06348, Q2VL79, Q2VL84, Q2VL85, Q2VL87, Q2VL88, Q61663, Q62066, Q62782, Q6XYB7, Q7YRX0, Q96IS3, Q99811, Q9DED6, Q9ER42, Q9GK08

Diamond homologs: A1YF16, A1YG93, A2RU54, A2T764, A6NCS4, A6NHT5, A8XJD0, F1R2J1, O02786, O35762, O35767, O43711, O43763, O55144, O57601, O70218, O88181, O93366, O93367, O93590, P13297, P19601, P22809, P23410, P26797, P28360, P28361, P28362, P31314, P35548, P35993, P42581, P42582, P42583, P43345, P43687, P50223, P52952, P52953, P56407

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	36
Likely benign	0
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

346 predictions. Top by Δscore:

Variant	Effect	Δscore
2:74515843:G:GA	donor_gain	1.0000
2:74515871:G:GG	donor_gain	1.0000
2:74515969:TTAG:T	acceptor_loss	1.0000
2:74515970:TAG:T	acceptor_loss	1.0000
2:74515971:A:AG	acceptor_gain	1.0000
2:74515971:A:AT	acceptor_loss	1.0000
2:74515972:G:A	acceptor_loss	1.0000
2:74515972:G:GA	acceptor_gain	1.0000
2:74515972:GGC:G	acceptor_gain	1.0000
2:74515627:C:A	acceptor_gain	0.9900
2:74515867:GGCG:G	donor_gain	0.9900
2:74515868:GCG:G	donor_gain	0.9900
2:74515868:GCGG:G	donor_gain	0.9900
2:74515971:AG:A	acceptor_gain	0.9900
2:74515971:AGGC:A	acceptor_gain	0.9900
2:74515972:GG:G	acceptor_gain	0.9900
2:74515972:GGCG:G	acceptor_gain	0.9900
2:74515972:GGCGC:G	acceptor_gain	0.9900
2:74514651:G:T	donor_gain	0.9800
2:74514901:G:GT	donor_gain	0.9800
2:74514913:GCC:G	donor_gain	0.9800
2:74515631:A:AG	acceptor_gain	0.9800
2:74515632:G:GG	acceptor_gain	0.9800
2:74515632:GCT:G	acceptor_gain	0.9800
2:74515632:GCTGC:G	acceptor_gain	0.9800
2:74515204:CGGGT:C	donor_loss	0.9700
2:74515205:GG:G	donor_gain	0.9700
2:74515205:GGG:G	donor_loss	0.9700
2:74515206:GG:G	donor_gain	0.9700
2:74515208:T:G	donor_loss	0.9700

AlphaMissense

1777 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:74515722:T:A	F164I	1.000
2:74515722:T:C	F164L	1.000
2:74515722:T:G	F164V	1.000
2:74515723:T:C	F164S	1.000
2:74515723:T:G	F164C	1.000
2:74515724:C:A	F164L	1.000
2:74515724:C:G	F164L	1.000
2:74515747:T:C	L172S	1.000
2:74515747:T:G	L172W	1.000
2:74515748:G:C	L172F	1.000
2:74515748:G:T	L172F	1.000
2:74515750:A:T	E173V	1.000
2:74515758:T:A	F176I	1.000
2:74515758:T:C	F176L	1.000
2:74515758:T:G	F176V	1.000
2:74515759:T:C	F176S	1.000
2:74515759:T:G	F176C	1.000
2:74515760:C:A	F176L	1.000
2:74515760:C:G	F176L	1.000
2:74515773:T:C	Y181H	1.000
2:74515774:A:G	Y181C	1.000
2:74515792:G:T	R187M	1.000
2:74515793:G:C	R187S	1.000
2:74515793:G:T	R187S	1.000
2:74515801:T:C	L190P	1.000
2:74515804:C:A	A191D	1.000
2:74515819:T:C	M196T	1.000
2:74515822:C:T	T197I	1.000
2:74515832:G:C	Q200H	1.000
2:74515832:G:T	Q200H	1.000

dbSNP variants (sampled 300 via entrez): RS1001269723 (2:74516524 C>A,G,T), RS1002299434 (2:74516533 C>A,T), RS1002650546 (2:74513174 G>A), RS1003302491 (2:74514315 T>C,G), RS1004568469 (2:74513134 A>G), RS1005000278 (2:74512927 C>T), RS1005981549 (2:74514373 C>A,T), RS1007609293 (2:74517328 G>A,C), RS1008139171 (2:74516890 A>G), RS1008817643 (2:74516857 A>C,G), RS1008970645 (2:74516592 G>A,C), RS1009563326 (2:74517302 T>A,C), RS1009594452 (2:74516730 A>G), RS1011426997 (2:74513462 G>A), RS1011872109 (2:74513225 G>A,C)

Disease associations

OMIM: gene MIM:604240 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	2
Valproic Acid	increases expression, affects expression	2
aristolochic acid I	increases expression	1
propionaldehyde	increases expression	1
bisphenol A	increases expression	1
terbufos	increases methylation	1
tris(2-butoxyethyl) phosphate	affects expression	1
dimethylselenide	increases expression, increases oxidation	1
beta-lapachone	decreases expression	1
butyraldehyde	increases expression	1
pentanal	increases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Air Pollutants	increases abundance, increases expression	1
Aldehydes	increases expression	1
Atrazine	decreases expression	1
Carbamazepine	affects expression	1
Diethylhexyl Phthalate	decreases expression	1
Fonofos	increases methylation	1
Estradiol	increases expression	1
Ozone	increases oxidation, increases expression	1
Parathion	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Silicon Dioxide	decreases expression	1
Tretinoin	increases expression	1
Asbestos, Serpentine	decreases methylation	1
Asbestos, Crocidolite	decreases methylation	1
Asbestos, Amosite	decreases methylation	1
Hydroxyl Radical	increases expression, increases oxidation	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

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