NKX1-2

Summary

NKX1-2 (NK1 homeobox 2, HGNC:31652) is a protein-coding gene on chromosome 10q26.13, encoding NK1 transcription factor-related protein 2 (Q9UD57). Transcriptional repressor.

Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in cell differentiation and regulation of transcription by RNA polymerase II. Predicted to be located in chromatin. Predicted to be active in nucleus.

Source: NCBI Gene 390010 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 80 total — 1 pathogenic
• MANE Select transcript: NM_001146340

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:31652
Approved symbol	NKX1-2
Name	NK1 homeobox 2
Location	10q26.13
Locus type	gene with protein product
Status	Approved
Aliases	bB238F13.2
Ensembl gene	ENSG00000229544
Ensembl biotype	protein_coding
OMIM	621058
Entrez	390010

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000451024

RefSeq mRNA: 1 — MANE Select: NM_001146340 NM_001146340

CCDS: CCDS59221

Canonical transcript exons

ENST00000451024 — 2 exons

Exon	Start	End
ENSE00001653075	124445243	124448147
ENSE00001771985	124449730	124450035

Expression profiles

Bgee: expression breadth broad, 53 present calls, max score 85.03.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.0009 / max 72.2331, expressed in 149 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
111834	0.7672	128
111835	0.1790	82
111833	0.0547	34

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	85.03	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.06	gold quality
oocyte	CL:0000023	70.21	gold quality
prefrontal cortex	UBERON:0000451	54.02	gold quality
upper leg skin	UBERON:0004262	53.10	silver quality
lower esophagus mucosa	UBERON:0035834	52.70	gold quality
Brodmann (1909) area 9	UBERON:0013540	50.38	gold quality
esophagus mucosa	UBERON:0002469	49.56	gold quality
frontal cortex	UBERON:0001870	49.07	gold quality
cerebellar vermis	UBERON:0004720	48.93	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	48.22	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	48.15	gold quality
primary visual cortex	UBERON:0002436	47.59	gold quality
neocortex	UBERON:0001950	47.52	gold quality
right frontal lobe	UBERON:0002810	46.70	gold quality
nucleus accumbens	UBERON:0001882	45.82	gold quality
occipital lobe	UBERON:0002021	45.63	gold quality
cerebral cortex	UBERON:0000956	45.48	gold quality
lower lobe of lung	UBERON:0008949	45.36	silver quality
nasal cavity mucosa	UBERON:0001826	44.55	gold quality
skin of hip	UBERON:0001554	44.28	silver quality
tonsil	UBERON:0002372	43.70	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
anterior cingulate cortex	UBERON:0009835	43.20	gold quality
thymus	UBERON:0002370	43.05	gold quality
putamen	UBERON:0001874	43.04	silver quality
skin of abdomen	UBERON:0001416	42.94	gold quality
quadriceps femoris	UBERON:0001377	42.59	gold quality
epithelium of nasopharynx	UBERON:0001951	42.54	gold quality
caudate nucleus	UBERON:0001873	42.38	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.31

Regulation

Is transcription factor: no

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	nkx1.2la	ENSDARG00000006350
mus_musculus	Nkx1-2	ENSMUSG00000048528
rattus_norvegicus	Nkx1-2	ENSRNOG00000071386
drosophila_melanogaster	NK7.1	FBGN0024321
drosophila_melanogaster	HGTX	FBGN0040318
drosophila_melanogaster	scro	FBGN0287186
caenorhabditis_elegans	ceh-9	WBGENE00000434
caenorhabditis_elegans		WBGENE00000447
caenorhabditis_elegans		WBGENE00000450
caenorhabditis_elegans		WBGENE00000584

Paralogs (13): NKX3-2 (ENSG00000109705), NKX2-3 (ENSG00000119919), NKX2-4 (ENSG00000125816), NKX2-2 (ENSG00000125820), NKX2-8 (ENSG00000136327), NKX2-1 (ENSG00000136352), NKX6-2 (ENSG00000148826), NKX6-1 (ENSG00000163623), NKX6-3 (ENSG00000165066), NKX3-1 (ENSG00000167034), NKX2-6 (ENSG00000180053), NKX2-5 (ENSG00000183072), NKX1-1 (ENSG00000235608)

Protein

Protein identifiers

NK1 transcription factor-related protein 2 — Q9UD57 (reviewed: Q9UD57)

Alternative names: Homeobox protein SAX-1, NKX-1.1

All UniProt accessions (1): Q9UD57

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional repressor. May play a role in early development as a Wnt/beta-catenin effector, hence controlling pluripotency and preimplantation development of embryonic stem cells. May promote adipogenesis in mesenchymal stem cells, possibly by inhibiting the expression of the antiadipogenic factor NR2F2. May inhibit osteoblastogenic differentiation.

Subunit / interactions. Interacts (via the homeodomain) with HIPK1, HIPK2, and HIPK3.

Subcellular location. Nucleus. Nucleolus.

Similarity. Belongs to the NK-1 homeobox family.

RefSeq proteins (1): NP_001139812* (*=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
IPR050394	Homeobox_NK-like	Family

Pfam: PF00046

UniProt features (10 total): compositionally biased region 6, region of interest 2, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UD57-F1	65.31	0.20

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 38 (showing top): CHARAFE_BREAST_CANCER_LUMINAL_VS_BASAL_DN, LEE_AGING_NEOCORTEX_DN, GOCC_NUCLEOLUS, GOMF_SEQUENCE_SPECIFIC_DNA_BINDING, MEISSNER_BRAIN_HCP_WITH_H3K4ME3_AND_H3K27ME3, MEISSNER_NPC_HCP_WITH_H3K4ME2, MIKKELSEN_MEF_HCP_WITH_H3K27ME3, BRUINS_UVC_RESPONSE_VIA_TP53_GROUP_A, MIYAGAWA_TARGETS_OF_EWSR1_ETS_FUSIONS_UP, RAO_BOUND_BY_SALL4_ISOFORM_B, GOMF_TRANSCRIPTION_REGULATOR_ACTIVITY, SMN1_SMN2_TARGET_GENES, PEREZ_TP53_TARGETS, GOMF_DNA_BINDING_TRANSCRIPTION_FACTOR_ACTIVITY, GOMF_CIS_REGULATORY_REGION_SEQUENCE_SPECIFIC_DNA_BINDING

GO Biological Process (3): regulation of transcription by RNA polymerase II (GO:0006357), cell differentiation (GO:0030154), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (3): 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)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), nucleolus (GO:0005730)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
cellular developmental process	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
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

468 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NKX1-2	FOXB1	Q99853	340
NKX1-2	FOXD4L5	Q5VV16	339
NKX1-2	TBX6	O95947	332
NKX1-2	POU5F2	Q8N7G0	322
NKX1-2	PAX9	P55771	318
NKX1-2	ZNF227	Q86WZ6	306
NKX1-2	CCDC15	Q0P6D6	305
NKX1-2	IRX3	P78415	279
NKX1-2	SLC66A3	Q8N755	270
NKX1-2	FOXH1	O75593	267
NKX1-2	PAX1	P15863	265
NKX1-2	SIX3	O95343	263
NKX1-2	ZNF232	Q9UNY5	259
NKX1-2	LHX4	Q969G2	259
NKX1-2	TBC1D22B	Q9NU19	259

IntAct

0 interactions, top by confidence:

BioGRID (4): NKX1-2 (Two-hybrid), NKX1-2 (Two-hybrid), NKX1-2 (Cross-Linking-MS (XL-MS)), STX7 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A286YF58, A0A494C0N9, A0A494C0Y3, A0A7I2V3R4, A2VDX9, A6NIN4, D3YXK1, G3UXB3, O15370, O15522, O35392, O70218, O70220, O89113, P0DPE3, P12980, P17542, P22091, P28283, P82976, Q04890, Q05916, Q05917, Q13461, Q14V87, Q15270, Q19A40, Q5T230, Q5VY09, Q63244, Q6F5E0, Q6SPE9, Q6SPF0, Q7RTU7, Q80WY3, Q8TD94, Q8WY41, Q8WZ71, Q91XV7, Q96Q04

Diamond homologs: A1YF16, A1YG93, A2RU54, A2T764, A6NCS4, A6NHT5, G5EE18, M0R6D8, O02786, O35767, O42230, O57601, O60479, O70218, P10181, P13297, P15857, P19601, P20009, P23410, P28360, P28361, P28362, P35548, P35993, P40764, P42580, P42581, P43687, P43688, P48031, P50219, P50223, P50574, P50575, P50576, P50577, P52953, P53547, P53770

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	76
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3244810	NC_000010.10:g.(?126100603)(126140009_?)del	Pathogenic

SpliceAI

341 predictions. Top by Δscore:

Variant	Effect	Δscore
10:124449722:CATCT:C	donor_loss	0.9800
10:124449723:ATCTT:A	donor_loss	0.9800
10:124449724:TCTTA:T	donor_loss	0.9800
10:124449725:CTTAC:C	donor_loss	0.9800
10:124449726:TTA:T	donor_loss	0.9800
10:124449727:T:TG	donor_loss	0.9800
10:124449728:ACCA:A	donor_loss	0.9800
10:124448606:C:A	donor_gain	0.9600
10:124449728:A:AC	donor_gain	0.9600
10:124449729:C:CC	donor_gain	0.9600
10:124449783:TCG:T	donor_gain	0.9500
10:124448145:CAT:C	acceptor_gain	0.9400
10:124448148:C:CC	acceptor_gain	0.9400
10:124448611:T:A	donor_gain	0.9400
10:124448146:ATCTA:A	acceptor_loss	0.9300
10:124448147:TCTAG:T	acceptor_loss	0.9300
10:124448148:C:G	acceptor_loss	0.9300
10:124448829:T:TG	acceptor_gain	0.9300
10:124450005:G:A	donor_gain	0.9300
10:124448150:A:C	acceptor_loss	0.8900
10:124449436:AAG:A	donor_gain	0.8700
10:124449721:GCATC:G	donor_loss	0.8600
10:124448830:C:A	acceptor_gain	0.8300
10:124448144:GCAT:G	acceptor_gain	0.8100
10:124448145:CATC:C	acceptor_gain	0.8100
10:124449267:A:AC	donor_gain	0.8000
10:124449268:C:CC	donor_gain	0.8000
10:124449730:C:A	donor_loss	0.8000
10:124449004:C:A	donor_gain	0.7500
10:124449292:G:C	donor_gain	0.7500

AlphaMissense

1953 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:124447717:C:A	R215S	1.000
10:124447717:C:G	R215S	1.000
10:124447718:C:A	R215M	1.000
10:124447718:C:G	R215T	1.000
10:124447722:G:T	R214S	1.000
10:124447723:A:C	N213K	1.000
10:124447723:A:T	N213K	1.000
10:124447724:T:A	N213I	1.000
10:124447724:T:C	N213S	1.000
10:124447724:T:G	N213T	1.000
10:124447725:T:C	N213D	1.000
10:124447726:C:A	Q212H	1.000
10:124447726:C:G	Q212H	1.000
10:124447729:G:C	F211L	1.000
10:124447729:G:T	F211L	1.000
10:124447730:A:C	F211C	1.000
10:124447730:A:G	F211S	1.000
10:124447731:A:C	F211V	1.000
10:124447731:A:G	F211L	1.000
10:124447731:A:T	F211I	1.000
10:124447732:C:A	W210C	1.000
10:124447732:C:G	W210C	1.000
10:124447734:A:G	W210R	1.000
10:124447734:A:T	W210R	1.000
10:124447738:T:A	K208N	1.000
10:124447738:T:G	K208N	1.000
10:124447739:T:A	K208I	1.000
10:124447740:T:C	K208E	1.000
10:124447802:T:C	Y187C	1.000
10:124447816:G:C	F182L	1.000

dbSNP variants (sampled 300 via entrez): RS1000207542 (10:124451787 T>C), RS1000344495 (10:124450551 T>C), RS1000620270 (10:124446571 C>A,G), RS1001054341 (10:124446094 T>A), RS1001179202 (10:124451056 C>G,T), RS1001678111 (10:124445652 A>G,T), RS1001721853 (10:124449751 C>G), RS1002106474 (10:124448117 G>A,C,T), RS1003733645 (10:124447061 C>T), RS1003785712 (10:124446835 C>A), RS1004060628 (10:124445642 G>A), RS1004112861 (10:124445359 A>G), RS1004123978 (10:124447879 G>C), RS1004334383 (10:124449690 G>A), RS1004609472 (10:124449847 G>A,T)

Disease associations

OMIM: gene MIM:621058 | disease phenotypes: MIM:258870

GenCC curated gene-disease

Mondo (1): ornithine aminotransferase deficiency (MONDO:0009796)

Orphanet (1): Gyrate atrophy of choroid and retina (Orphanet:414)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST004573_10	Iron status biomarkers (ferritin levels)	9.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004459	ferritin measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D015799	Gyrate Atrophy	C11.270.468; C11.941.160.578; C16.320.290.468

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
perfluorooctanoic acid	decreases expression	1
aflatoxin B2	increases methylation	1
perfluoro-n-nonanoic acid	decreases expression	1
perfluorohexanesulfonic acid	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Resveratrol	increases phosphorylation	1
Acetaminophen	decreases expression	1
Cisplatin	affects cotreatment, increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Tobacco Smoke Pollution	increases expression	1
Aflatoxin B1	increases methylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00001735	PHASE1	COMPLETED	Gene Therapy for Gyrate Atrophy
NCT00001166	Not specified	COMPLETED	Gyrate Atrophy of the Choroid and Retina
NCT02435940	Not specified	RECRUITING	Inherited Retinal Degenerative Disease Registry
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05312736	Not specified	ACTIVE_NOT_RECRUITING	Gyrate Atrophy Ocular and Systemic Study