UNCX

Summary

UNCX (UNC homeobox, HGNC:33194) is a protein-coding gene on chromosome 7p22.3, encoding Homeobox protein unc-4 homolog (A6NJT0). Transcription factor involved in somitogenesis and neurogenesis.

This gene encodes a homeobox transcription factor that is involved in somitogenesis and neurogenesis and is required for the maintenance and differentiation of specific elements of the axial skeleton. This gene also plays a role in controlling the development of connections of hypothalamic neurons to pituitary elements, allowing central neurons to reach the peripheral blood circulation and deliver hormones that control peripheral functions. The expression of this gene is associated with an increased frequency of acute myeloid leukemia.

Source: NCBI Gene 340260 — RefSeq curated summary.

At a glance

• GWAS associations: 42
• Clinical variants (ClinVar): 106 total
• MANE Select transcript: NM_001080461

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:33194
Approved symbol	UNCX
Name	UNC homeobox
Location	7p22.3
Locus type	gene with protein product
Status	Approved
Aliases	Uncx4.1
Ensembl gene	ENSG00000164853
Ensembl biotype	protein_coding
Entrez	340260

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000316333

RefSeq mRNA: 1 — MANE Select: NM_001080461 NM_001080461

CCDS: CCDS34583

Canonical transcript exons

ENST00000316333 — 3 exons

Exon	Start	End
ENSE00001156936	1232872	1233291
ENSE00001216591	1233520	1233695
ENSE00001492647	1235832	1237326

Expression profiles

Bgee: expression breadth broad, 24 present calls, max score 82.93.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.6045 / max 106.5408, expressed in 108 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
76922	0.2894	80
76921	0.2467	74
76920	0.0684	30

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellum	UBERON:0002037	82.93	gold quality
cerebellar cortex	UBERON:0002129	82.85	gold quality
cerebellar hemisphere	UBERON:0002245	82.75	gold quality
right hemisphere of cerebellum	UBERON:0014890	81.67	gold quality
hypothalamus	UBERON:0001898	55.48	gold quality
substantia nigra	UBERON:0002038	53.90	gold quality
adult mammalian kidney	UBERON:0000082	51.03	gold quality
metanephros cortex	UBERON:0010533	50.91	gold quality
kidney	UBERON:0002113	49.40	gold quality
pituitary gland	UBERON:0000007	45.42	gold quality
adenohypophysis	UBERON:0002196	43.64	gold quality
ganglionic eminence	UBERON:0004023	42.55	gold quality
bone marrow cell	CL:0002092	42.44	gold quality
colonic epithelium	UBERON:0000397	41.07	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	40.71	gold quality
ventricular zone	UBERON:0003053	39.99	gold quality
cortex of kidney	UBERON:0001225	39.03	gold quality
mucosa of transverse colon	UBERON:0004991	37.07	silver quality
brain	UBERON:0000955	36.87	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
sural nerve	UBERON:0015488	35.83	gold quality
bone marrow	UBERON:0002371	34.95	gold quality
skeletal muscle tissue	UBERON:0001134	33.38	gold quality
muscle tissue	UBERON:0002385	32.28	gold quality
hindlimb stylopod muscle	UBERON:0004252	32.15	gold quality
liver	UBERON:0002107	31.70	gold quality
monocyte	CL:0000576	31.16	gold quality
leukocyte	CL:0000738	30.84	gold quality
stromal cell of endometrium	CL:0002255	29.87	gold quality
prefrontal cortex	UBERON:0000451	29.20	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.66

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

4 targets.

Target	Regulation
EGLN1
EGLN3
NEUROG2	Activation
UNCX

JASPAR motifs

Motif	Name	Family
MA0721.1	UNCX	Paired-related HD factors
MA0721.2	UNCX	Paired-related HD factors

JASPAR matrix evidence (PMIDs): PMID:18585360

Upstream regulators (CollecTRI, top): ARNT, MESP2, UNCX

Literature-anchored findings (GeneRIF, showing 1)

• our findings suggest a novel leukemogenic role of UNCX, associated with epigenetic modifications and with impaired cell proliferation and differentiation in AML. (PMID:28411256)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	uncx4.1	ENSDARG00000037760
danio_rerio	uncx	ENSDARG00000102976
mus_musculus	Uncx	ENSMUSG00000029546
rattus_norvegicus	Uncx	ENSRNOG00000001284

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), PHOX2A (ENSG00000165462), OTX2 (ENSG00000165588), DRGX (ENSG00000165606), PRRX2 (ENSG00000167157), SHOX2 (ENSG00000168779), OTP (ENSG00000171540), RAX2 (ENSG00000173976), EVX2 (ENSG00000174279), PROP1 (ENSG00000175325), ISX (ENSG00000175329), ALX1 (ENSG00000180318), MIXL1 (ENSG00000185155), SHOX (ENSG00000185960)

Protein

Protein identifiers

Homeobox protein unc-4 homolog — A6NJT0 (reviewed: A6NJT0)

Alternative names: Homeobox protein Uncx4.1

All UniProt accessions (1): A6NJT0

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor involved in somitogenesis and neurogenesis. Required for the maintenance and differentiation of particular elements of the axial skeleton. May act upstream of PAX9. Plays a role in controlling the development of connections of hypothalamic neurons to pituitary elements, allowing central neurons to reach the peripheral blood circulation and to deliver hormones for control of peripheral functions.

Subcellular location. Nucleus.

Similarity. Belongs to the paired homeobox family. Unc-4 subfamily.

RefSeq proteins (1): NP_001073930* (*=MANE)

Domains & families (InterPro)

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

Pfam: PF00046

UniProt features (16 total): compositionally biased region 10, region of interest 4, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A6NJT0-F1	59.38	0.15

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 58 (showing top): GOBP_SPINAL_CORD_DEVELOPMENT, GOBP_OLFACTORY_BULB_INTERNEURON_DIFFERENTIATION, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_NEUROGENESIS, GOBP_FOREBRAIN_DEVELOPMENT, chr7p22, GOBP_FOREBRAIN_GENERATION_OF_NEURONS, MARTORIATI_MDM4_TARGETS_NEUROEPITHELIUM_DN, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_CELL_AGGREGATION, MARTIN_VIRAL_GPCR_SIGNALING_DN, GOBP_CENTRAL_NERVOUS_SYSTEM_NEURON_DIFFERENTIATION, GOBP_HEAD_DEVELOPMENT, GOBP_OLFACTORY_LOBE_DEVELOPMENT

GO Biological Process (11): cartilage condensation (GO:0001502), pattern specification process (GO:0007389), regulation of gene expression (GO:0010468), dorsal spinal cord development (GO:0021516), olfactory bulb interneuron differentiation (GO:0021889), common myeloid progenitor cell proliferation (GO:0035726), regulation of cell differentiation (GO:0045595), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), nervous system development (GO:0007399), cell differentiation (GO:0030154)

GO Molecular Function (3): DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677)

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
skeletal system morphogenesis	1
cartilage development	1
cell aggregation	1
multicellular organism development	1
multicellular organismal process	1
gene expression	1
regulation of macromolecule biosynthetic process	1
spinal cord development	1
anatomical structure development	1
olfactory bulb development	1
forebrain neuron differentiation	1
cell population proliferation	1
cell differentiation	1
regulation of developmental process	1
regulation of cellular process	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
system development	1
cellular developmental process	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
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1218 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UNCX	MESP2	Q0VG99	678
UNCX	PAX1	P15863	606
UNCX	UMOD	P07911	581
UNCX	SYPL2	Q5VXT5	575
UNCX	MARCHF11	A6NNE9	544
UNCX	TBX6	O95947	533
UNCX	RIPPLY2	Q5TAB7	532
UNCX	MSGN1	A6NI15	521
UNCX	TBX18	O95935	520
UNCX	RIPPLY1	Q0D2K3	509
UNCX	LFNG	Q8NES3	501
UNCX	IGFBP5	P24593	473
UNCX	DLL1	O00548	456
UNCX	AJAP1	Q9UKB5	454
UNCX	APOL1	O14791	434

IntAct

2 interactions, top by confidence:

A	B	Type	Score
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350

BioGRID (4): UNCX (Affinity Capture-RNA), UNCX (Proximity Label-MS), LMNA (Cross-Linking-MS (XL-MS)), UNCX (Affinity Capture-MS)

ESM2 similar proteins: A1YER7, A1YF08, A1YFD8, A1YFY3, A1YG85, A2D4P8, A2D5I1, A2T6X6, A2T756, A2T7H5, A6NCS4, A6NJT0, O08934, O14813, O42230, O43763, O70218, O93367, P06798, P09016, P10284, P10628, P13378, P17277, P17483, P18111, P23683, P23813, P31277, P31310, P35452, P47902, P49640, P50223, P52945, P52946, P52947, P70118, P82976, P97830

Diamond homologs: A1A546, A1YEV8, A1YG25, A2T711, A6NJT0, A6NNA5, A6YP92, G5EC89, G5EDS1, L8E946, O08934, O09113, O14813, O15266, O18381, O35085, O35137, O35602, O35690, O35750, O42115, O42201, O42250, O42356, O42357, O42358, O42477, O42567, O60902, O70137, O73917, O95076, O97039, P0DMV5, P23759, P23760, P24610, P26367, P26630, P29506

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	100
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

319 predictions. Top by Δscore:

Variant	Effect	Δscore
7:1233287:GTCAG:G	donor_gain	1.0000
7:1233288:TCAGG:T	donor_loss	1.0000
7:1233292:G:GG	donor_gain	1.0000
7:1233691:TTCAG:T	donor_loss	1.0000
7:1233692:TCAG:T	donor_loss	1.0000
7:1233693:CAGG:C	donor_loss	1.0000
7:1233694:AGGTA:A	donor_loss	1.0000
7:1233695:GGT:G	donor_loss	1.0000
7:1233696:GTAAA:G	donor_loss	1.0000
7:1233697:T:A	donor_loss	1.0000
7:1235817:ATCC:A	acceptor_gain	1.0000
7:1233507:T:TA	acceptor_gain	0.9900
7:1233511:T:A	acceptor_gain	0.9900
7:1233515:CGCAG:C	acceptor_loss	0.9900
7:1233516:GCA:G	acceptor_loss	0.9900
7:1233517:CAGAC:C	acceptor_loss	0.9900
7:1233518:A:AC	acceptor_loss	0.9900
7:1233518:A:AG	acceptor_gain	0.9900
7:1233519:G:GC	acceptor_gain	0.9900
7:1233519:GA:G	acceptor_gain	0.9900
7:1233519:GACTC:G	acceptor_gain	0.9900
7:1235817:ATCCG:A	acceptor_gain	0.9900
7:1235820:C:CA	acceptor_gain	0.9900
7:1235821:G:A	acceptor_gain	0.9900
7:1233519:GACT:G	acceptor_gain	0.9800
7:1235817:A:AG	acceptor_gain	0.9800
7:1235818:T:G	acceptor_gain	0.9800
7:1235826:CTCTA:C	acceptor_loss	0.9800
7:1235827:TCTA:T	acceptor_loss	0.9800
7:1235828:CTAGG:C	acceptor_loss	0.9800

AlphaMissense

3383 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:1233564:C:A	R107S	1.000
7:1233570:C:A	R109S	1.000
7:1233570:C:G	R109G	1.000
7:1233570:C:T	R109C	1.000
7:1233574:C:T	T110I	1.000
7:1233576:A:G	N111D	1.000
7:1233578:C:A	N111K	1.000
7:1233578:C:G	N111K	1.000
7:1233579:T:A	F112I	1.000
7:1233579:T:C	F112L	1.000
7:1233579:T:G	F112V	1.000
7:1233580:T:C	F112S	1.000
7:1233580:T:G	F112C	1.000
7:1233581:C:A	F112L	1.000
7:1233581:C:G	F112L	1.000
7:1233583:C:T	T113I	1.000
7:1233588:T:A	W115R	1.000
7:1233588:T:C	W115R	1.000
7:1233590:G:C	W115C	1.000
7:1233590:G:T	W115C	1.000
7:1233592:A:G	Q116R	1.000
7:1233593:G:C	Q116H	1.000
7:1233593:G:T	Q116H	1.000
7:1233595:T:A	L117Q	1.000
7:1233595:T:C	L117P	1.000
7:1233604:T:A	L120Q	1.000
7:1233604:T:C	L120P	1.000
7:1233604:T:G	L120R	1.000
7:1233607:A:T	E121V	1.000
7:1233608:G:C	E121D	1.000

dbSNP variants (sampled 300 via entrez): RS1000326471 (7:1237825 C>T), RS1000447305 (7:1233228 C>A,G), RS1000675869 (7:1237422 GC>G,GCC), RS1000818604 (7:1232129 C>CA,CG), RS1001026615 (7:1236970 T>A,C,G), RS1001496337 (7:1232388 C>A,T), RS1001516254 (7:1231249 G>C), RS1002301888 (7:1236076 G>C), RS1002580178 (7:1234683 C>T), RS1002608982 (7:1232293 G>A,C), RS1002924570 (7:1232538 C>G,T), RS1004016112 (7:1234498 C>A), RS1004263056 (7:1236461 C>T), RS1004358871 (7:1230989 A>C), RS1004503131 (7:1237434 C>T)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

42 associations (top):

Study	Trait	p-value
GCST001343_10	Fat distribution (HIV)	4.000000e-07
GCST001606_3	Renal function-related traits (sCR)	5.000000e-11
GCST001607_1	Renal function-related traits (eGRFcrea)	1.000000e-10
GCST001610_7	Renal function-related traits (BUN)	4.000000e-09
GCST002829_5	Urate levels in overweight individuals	1.000000e-06
GCST002934_21	Zinc levels	8.000000e-06
GCST003372_32	Glomerular filtration rate (creatinine)	9.000000e-14
GCST003372_62	Glomerular filtration rate (creatinine)	2.000000e-14
GCST003790_12	Glomerular filtration rate	5.000000e-15
GCST003790_40	Glomerular filtration rate	1.000000e-08
GCST003790_41	Glomerular filtration rate	4.000000e-06
GCST004215_4	Urea levels	2.000000e-08
GCST004292_45	Glomerular filtration rate (creatinine)	3.000000e-08
GCST005164_3	GLP-1 levels in response to oral glucose tolerance test (fasting)	5.000000e-06
GCST005983_32	Serum uric acid levels	3.000000e-08
GCST005984_32	Glomerular filtration rate	9.000000e-39
GCST005985_50	Creatinine levels	1.000000e-37
GCST005986_37	Blood urea nitrogen levels	2.000000e-31
GCST005994_2	Hematocrit	1.000000e-14
GCST005995_14	Hemoglobin	2.000000e-14
GCST005996_26	Red blood cell count	3.000000e-12
GCST007344_93	Estimated glomerular filtration rate	2.000000e-39
GCST007725_34	Serum uric acid levels	5.000000e-10
GCST007876_53	Estimated glomerular filtration rate	5.000000e-43
GCST008058_197	Estimated glomerular filtration rate	5.000000e-91
GCST008059_112	Estimated glomerular filtration rate	7.000000e-62
GCST008060_32	Estimated glomerular filtration rate	2.000000e-24
GCST008062_4	Blood urea nitrogen levels	7.000000e-57
GCST008064_37	Chronic kidney disease	9.000000e-13
GCST008522_93	Bitter alcoholic beverage consumption	8.000000e-06

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0004341	body fat distribution
EFO:0004531	urate measurement
EFO:0004307	glucose tolerance test
EFO:0008465	glucagon-like peptide-1 measurement
EFO:0004761	uric acid measurement
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0004305	erythrocyte count
EFO:0010092	bitter alcoholic beverage consumption measurement
EFO:0009749	age at first sexual intercourse measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tretinoin	affects cotreatment, decreases reaction, increases expression, decreases expression	2
Valproic Acid	decreases expression, increases methylation	2
glycolic 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, decreases reaction	1
Chir 99021	affects cotreatment, increases expression, decreases reaction	1
ramelteon	decreases expression	1
nilotinib	decreases expression	1
MT19c compound	decreases expression	1
Dabigatran	decreases expression	1
Abacavir	decreases expression	1
Arsenic	affects methylation	1
Vehicle Emissions	decreases methylation	1
Benzo(a)pyrene	increases methylation	1
Cadmium	increases abundance, decreases expression	1
Caffeine	decreases expression	1
Endosulfan	increases expression	1
Penicillins	affects cotreatment, increases expression	1
Phenytoin	decreases expression	1
Streptomycin	affects cotreatment, increases expression	1
Thalidomide	decreases expression	1
Triclosan	decreases expression	1
Isotretinoin	decreases expression	1
Cadmium Chloride	decreases expression, increases abundance	1
Ethylene Glycol	decreases expression	1

Clinical trials (associated diseases)

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