GSX2

Summary

GSX2 (GS homeobox 2, HGNC:24959) is a protein-coding gene on chromosome 4q12, encoding GS homeobox 2 (Q9BZM3). Transcription factor that binds 5’-CNAATTAG-3’ DNA sequence and regulates the expression of numerous genes including genes important for brain development.

Enables DNA-binding transcription factor activity, RNA polymerase II-specific and sequence-specific double-stranded DNA binding activity. Predicted to be involved in generation of neurons; olfactory bulb development; and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including nervous system development; positive regulation of Notch signaling pathway; and positive regulation of oligodendrocyte differentiation. Located in cytoplasm and nucleus.

Source: NCBI Gene 170825 — RefSeq curated summary.

At a glance

• Gene–disease (curated): diencephalic-mesencephalic junction dysplasia syndrome 2 (Moderate, GenCC)
• GWAS associations: 8
• Clinical variants (ClinVar): 53 total — 1 pathogenic
• Phenotypes (HPO): 11
• MANE Select transcript: NM_133267

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24959
Approved symbol	GSX2
Name	GS homeobox 2
Location	4q12
Locus type	gene with protein product
Status	Approved
Aliases	Gsh2
Ensembl gene	ENSG00000180613
Ensembl biotype	protein_coding
OMIM	616253
Entrez	170825

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000326902, ENST00000503800, ENST00000507839

RefSeq mRNA: 1 — MANE Select: NM_133267 NM_133267

CCDS: CCDS3494

Canonical transcript exons

ENST00000326902 — 2 exons

Exon	Start	End
ENSE00001249628	54101582	54102498
ENSE00001249632	54100163	54100918

Expression profiles

Bgee: expression breadth broad, 58 present calls, max score 72.25.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1300 / max 86.0728, expressed in 34 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
47634	0.1300	34

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	72.25	gold quality
amygdala	UBERON:0001876	60.32	gold quality
superficial temporal artery	UBERON:0001614	56.08	gold quality
epithelium of nasopharynx	UBERON:0001951	55.67	gold quality
palpebral conjunctiva	UBERON:0001812	55.05	gold quality
putamen	UBERON:0001874	54.55	gold quality
caudate nucleus	UBERON:0001873	54.35	gold quality
temporal lobe	UBERON:0001871	54.31	gold quality
germinal epithelium of ovary	UBERON:0001304	53.78	gold quality
esophagus squamous epithelium	UBERON:0006920	52.96	gold quality
heart right ventricle	UBERON:0002080	52.43	gold quality
nasal cavity epithelium	UBERON:0005384	51.29	gold quality
prefrontal cortex	UBERON:0000451	50.67	gold quality
postcentral gyrus	UBERON:0002581	50.64	gold quality
anterior cingulate cortex	UBERON:0009835	49.58	gold quality
nucleus accumbens	UBERON:0001882	49.35	gold quality
frontal cortex	UBERON:0001870	49.11	gold quality
parietal lobe	UBERON:0001872	49.08	gold quality
neocortex	UBERON:0001950	48.95	gold quality
cerebellar vermis	UBERON:0004720	48.93	gold quality
quadriceps femoris	UBERON:0001377	48.88	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	48.66	gold quality
tibial nerve	UBERON:0001323	48.50	gold quality
Brodmann (1909) area 9	UBERON:0013540	48.37	gold quality
vastus lateralis	UBERON:0001379	48.25	gold quality
right frontal lobe	UBERON:0002810	48.18	gold quality
superior frontal gyrus	UBERON:0002661	48.16	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	48.11	gold quality
spinal cord	UBERON:0002240	48.00	gold quality
cerebral cortex	UBERON:0000956	47.76	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	20.50
E-ANND-3	no	1.15

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
ALDH1A3	Activation
GSX2
INS

JASPAR motifs

Motif	Name	Family
MA0893.1	GSX2	HOX
MA0893.2	GSX2	HOX
MA0893.3	GSX2	HOX

JASPAR matrix evidence (PMIDs): PMID:18585359

Upstream regulators (CollecTRI, top): GSX2, PAX6

Literature-anchored findings (GeneRIF, showing 8)

• ectopically expressed in myeloid leukemic cells with t(4;12)(q11-q12;p13), suggesting that expression of GSH2 was deregulated by the translocation, indicating a variant leukemogenic mechanism for translocations involving the 5’ end of ETV6 (PMID:11861295)
• Gsx2 specifies striatal projection neuron and olfactory bulb interneuron identity at distinct time points during neurogenesis in transgenic mice. (PMID:19709628)
• Transgenic mice lacking microRNAs miR-9-2 and miR-9-3 exhibit multiple defects of telencephalic structures which may be brought about by dysregulation of Foxg1, Nr2e1, Gsh2, and Meis2 expression. (PMID:21368052)
• Gsx2 negatively regulates neurogenesis from postnatal progenitor cells. (PMID:22242181)
• 4q12 translocations with GSX2 expression identify a CD7(+) acute myeloid leukaemia subset. (PMID:25816740)
• Data show that GS Homeobox 2 (Gsx2) and Early B-cell factor 1 (Ebf1) combined overexpression in human embryonic stem (hES) cells achieves high yields of medium spiny neurons (MSNs). (PMID:28137879)
• This study identified and validated a three-gene (EMP3, GSX2 and EMILIN3) prognostic signature in Lower-Grade Gliomas. (PMID:29794476)
• Silencing GS Homeobox 2 Alleviates Gemcitabine Resistance in Pancreatic Cancer Cells by Activating SHH/GLI1 Signaling Pathway. (PMID:34623580)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	gsx2	ENSDARG00000043322
mus_musculus	Gsx2	ENSMUSG00000035946
rattus_norvegicus	Gsx2	ENSRNOG00000002266
drosophila_melanogaster	zen	FBGN0004053
drosophila_melanogaster	zen2	FBGN0004054
drosophila_melanogaster	CG30480	FBGN0050480

Paralogs (42): HOXA11 (ENSG00000005073), HOXC8 (ENSG00000037965), HOXA1 (ENSG00000105991), HOXA2 (ENSG00000105996), HOXA3 (ENSG00000105997), HOXA5 (ENSG00000106004), HOXA6 (ENSG00000106006), HOXA13 (ENSG00000106031), TLX1 (ENSG00000107807), HOXB6 (ENSG00000108511), TLX2 (ENSG00000115297), 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), HOXC9 (ENSG00000180806), HOXC10 (ENSG00000180818), HOXB4 (ENSG00000182742), HOXA4 (ENSG00000197576), HOXC6 (ENSG00000197757), HOXC4 (ENSG00000198353)

Protein

Protein identifiers

GS homeobox 2 — Q9BZM3 (reviewed: Q9BZM3)

Alternative names: Genetic-screened homeobox 2, Homeobox protein GSH-2

All UniProt accessions (2): D6R903, Q9BZM3

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that binds 5’-CNAATTAG-3’ DNA sequence and regulates the expression of numerous genes including genes important for brain development. During telencephalic development, causes ventralization of pallial progenitors and, depending on the developmental stage, specifies different neuronal fates. At early stages, necessary and sufficient to correctly specify the ventral lateral ganglionic eminence (LGE) and its major derivatives, the striatal projection neurons. At later stages, may specify LGE progenitors toward dorsal LGE fates, including olfactory bulb interneurons.

Subcellular location. Nucleus. Cytoplasm.

Disease relevance. Diencephalic-mesencephalic junction dysplasia syndrome 2 (DMJDS2) [MIM:618646] An autosomal recessive neurodevelopmental disorder with onset at birth, characterized by severe global developmental delay, hypotonia, spastic tetraparesis, generalized dystonia and severe intellectual impairment. Brain imaging shows a unique brain malformation characterized by agenesis of putamina and globi pallidi, dysgenesis of the caudate nuclei, olfactory bulbs hypoplasia, and anomaly of the diencephalic-mesencephalic junction with abnormal corticospinal tract course. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the Antp homeobox family.

RefSeq proteins (1): NP_573574* (*=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
IPR042191	GSH1/2	Family

Pfam: PF00046

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

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BZM3-F1	61.18	0.20

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 122 (showing top): GOBP_SPINAL_CORD_DEVELOPMENT, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_OLFACTORY_BULB_INTERNEURON_DIFFERENTIATION, GOBP_RESPIRATORY_GASEOUS_EXCHANGE_BY_RESPIRATORY_SYSTEM, BENPORATH_ES_WITH_H3K27ME3, GOBP_FOREBRAIN_MORPHOGENESIS, GOBP_REGULATION_OF_RESPIRATORY_SYSTEM_PROCESS, GOBP_POSITIVE_REGULATION_OF_GLIAL_CELL_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_NOTCH_SIGNALING_PATHWAY, GOBP_RESPIRATORY_SYSTEM_PROCESS, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_CELL_DIFFERENTIATION_IN_SPINAL_CORD, GOBP_DORSAL_VENTRAL_PATTERN_FORMATION

GO Biological Process (23): regulation of respiratory gaseous exchange by nervous system process (GO:0002087), Notch signaling pathway (GO:0007219), spinal cord association neuron differentiation (GO:0021527), hindbrain morphogenesis (GO:0021575), forebrain dorsal/ventral pattern formation (GO:0021798), olfactory bulb interneuron differentiation (GO:0021889), telencephalon regionalization (GO:0021978), regulation of cell migration (GO:0030334), positive regulation of Notch signaling pathway (GO:0045747), neuron fate specification (GO:0048665), positive regulation of oligodendrocyte differentiation (GO:0048714), forebrain morphogenesis (GO:0048853), subpallium neuron fate commitment (GO:0060163), GABAergic neuron differentiation (GO:0097154), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), pattern specification process (GO:0007389), central nervous system development (GO:0007417), brain development (GO:0007420), subpallium development (GO:0021544), olfactory bulb development (GO:0021772), neuron fate commitment (GO:0048663), generation of neurons (GO:0048699)

GO Molecular Function (4): DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700)

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
anatomical structure morphogenesis	2
forebrain regionalization	2
telencephalon development	2
neuron fate commitment	2
regulation of DNA-templated transcription	2
cellular anatomical structure	2
respiratory gaseous exchange by respiratory system	1
regulation of respiratory system process	1
nervous system process	1
cell surface receptor signaling pathway	1
cell differentiation in spinal cord	1
dorsal spinal cord development	1
central nervous system neuron differentiation	1
hindbrain development	1
dorsal/ventral pattern formation	1
olfactory bulb development	1
forebrain neuron differentiation	1
regionalization	1
cell migration	1
regulation of cell motility	1
Notch signaling pathway	1
regulation of Notch signaling pathway	1
positive regulation of signal transduction	1
cell fate specification	1
positive regulation of glial cell differentiation	1
oligodendrocyte differentiation	1
regulation of oligodendrocyte differentiation	1
forebrain development	1
brain morphogenesis	1
subpallium development	1
neuron differentiation	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
transcription by RNA polymerase II	1
multicellular organism development	1
multicellular organismal process	1
nervous system development	1
system development	1
central nervous system development	1

Protein interactions and networks

STRING

776 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GSX2	ASCL1	P50553	684
GSX2	FOXG1	P55315	662
GSX2	TBR1	Q16650	628
GSX2	LHX6	Q9UPM6	625
GSX2	SP8	Q8IXZ3	621
GSX2	NEUROG2	Q9H2A3	611
GSX2	OLIG2	Q13516	595
GSX2	SHH	Q15465	564
GSX2	BCL11B	Q9C0K0	556
GSX2	MEIS2	O14770	543
GSX2	PPP1R1B	Q9UD71	541
GSX2	CALB2	P22676	525
GSX2	LHX8	Q68G74	512
GSX2	EOMES	O95936	499
GSX2	HES6	Q96HZ4	491

IntAct

3 interactions, top by confidence:

A	B	Type	Score
GSX2	ABL1	psi-mi:“MI:0915”(physical association)	0.400
GSX2	RNF4	psi-mi:“MI:0914”(association)	0.350

BioGRID (7): KLHL8 (Affinity Capture-MS), RNF4 (Affinity Capture-MS), C11orf31 (Affinity Capture-MS), GSX2 (Affinity Capture-Western), GSX2 (Affinity Capture-Western), SHH (Affinity Capture-Western), GLI1 (Affinity Capture-Western)

ESM2 similar proteins: B0W1V2, B0X9H6, B3DM47, B4H4H5, B5DLV1, E7FDX5, G5EC89, O15266, O22300, O35317, O35984, O73673, O76762, O77215, O93366, P05527, P10035, P10181, P22809, P23459, P29552, P39021, P40424, P40425, P40426, P41778, P49925, P53772, P53773, P56224, Q05007, Q05192, Q07961, Q1KKY1, Q1KL13, Q24648, Q27355, Q28ZA9, Q4V5A3, Q4VYR7

Diamond homologs: A9ZPC9, F1R2J1, O02491, O42370, O43365, O60479, O93353, O93528, P02831, P02836, P05527, P09015, P09065, P09066, P09075, P09076, P09089, P09090, P09145, P09532, P10105, P14150, P15858, P17487, P19622, P20009, P20269, P23397, P27609, P27610, P31316, P31533, P31534, P31535, P31536, P31537, P31538, P34326, P34684, P42580

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	37
Likely benign	6
Benign	7

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
57309	GRCh38/hg38 4q12(chr4:51870025-55102392)x1	Pathogenic

SpliceAI

440 predictions. Top by Δscore:

Variant	Effect	Δscore
4:54101572:C:A	acceptor_gain	1.0000
4:54101581:GGA:G	acceptor_gain	1.0000
4:54100994:G:GT	donor_gain	0.9900
4:54101569:C:CA	acceptor_gain	0.9900
4:54101573:G:A	acceptor_gain	0.9900
4:54101577:CGCA:C	acceptor_loss	0.9900
4:54101578:GCA:G	acceptor_loss	0.9900
4:54101579:CAGG:C	acceptor_gain	0.9900
4:54101580:A:AG	acceptor_gain	0.9900
4:54101580:A:G	acceptor_loss	0.9900
4:54101580:AGGA:A	acceptor_gain	0.9900
4:54101580:AGGAG:A	acceptor_gain	0.9900
4:54101581:G:GG	acceptor_gain	0.9900
4:54101581:GGAG:G	acceptor_gain	0.9900
4:54101581:GGAGG:G	acceptor_gain	0.9900
4:54101577:C:CA	acceptor_gain	0.9800
4:54101580:AG:A	acceptor_gain	0.9800
4:54101581:GG:G	acceptor_gain	0.9800
4:54102122:G:GT	donor_gain	0.9800
4:54102126:T:G	donor_gain	0.9800
4:54101580:A:T	acceptor_loss	0.9700
4:54100471:A:AG	donor_gain	0.9600
4:54100917:GG:G	donor_gain	0.9600
4:54100918:GG:G	donor_gain	0.9600
4:54101108:GCCTG:G	donor_gain	0.9600
4:54102046:G:GT	donor_gain	0.9600
4:54100915:ATGGG:A	donor_loss	0.9500
4:54100916:TGGGT:T	donor_loss	0.9500
4:54100917:GGGTA:G	donor_loss	0.9500
4:54100919:G:A	donor_loss	0.9500

AlphaMissense

1969 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:54101624:G:C	R206T	1.000
4:54101624:G:T	R206M	1.000
4:54101625:G:C	R206S	1.000
4:54101625:G:T	R206S	1.000
4:54101632:T:A	F209I	1.000
4:54101632:T:C	F209L	1.000
4:54101632:T:G	F209V	1.000
4:54101633:T:C	F209S	1.000
4:54101633:T:G	F209C	1.000
4:54101634:C:A	F209L	1.000
4:54101634:C:G	F209L	1.000
4:54101646:A:C	Q213H	1.000
4:54101646:A:T	Q213H	1.000
4:54101648:T:A	L214H	1.000
4:54101648:T:C	L214P	1.000
4:54101651:T:C	L215P	1.000
4:54101657:T:A	L217Q	1.000
4:54101657:T:C	L217P	1.000
4:54101657:T:G	L217R	1.000
4:54101660:A:T	E218V	1.000
4:54101661:G:C	E218D	1.000
4:54101661:G:T	E218D	1.000
4:54101668:T:A	F221I	1.000
4:54101668:T:C	F221L	1.000
4:54101668:T:G	F221V	1.000
4:54101669:T:C	F221S	1.000
4:54101669:T:G	F221C	1.000
4:54101670:C:A	F221L	1.000
4:54101670:C:G	F221L	1.000
4:54101683:T:C	Y226H	1.000

dbSNP variants (sampled 300 via entrez): RS1000102491 (4:54102767 G>A), RS1000162520 (4:54099966 A>C,G), RS1000452885 (4:54102520 T>C), RS1000830511 (4:54098183 A>T), RS1002166620 (4:54101331 G>C,T), RS1003433221 (4:54100201 G>C,T), RS1003504568 (4:54102869 CTTCT>C), RS1003964952 (4:54100194 C>G), RS1005052943 (4:54098713 C>A,G), RS1005073765 (4:54099531 A>C), RS1006008654 (4:54102068 G>A), RS1006369061 (4:54101844 G>A), RS1006663111 (4:54098684 G>A,C), RS1008093986 (4:54100706 G>A,C), RS1010150612 (4:54102512 G>A)

Disease associations

OMIM: gene MIM:616253 | disease phenotypes: MIM:618646

GenCC curated gene-disease

Disease	Classification	Inheritance
diencephalic-mesencephalic junction dysplasia syndrome 2	Moderate	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
diencephalic-mesencephalic junction dysplasia syndrome 2	Limited	AR

Mondo (1): diencephalic-mesencephalic junction dysplasia syndrome 2 (MONDO:0020762)

Orphanet (0):

HPO phenotypes

11 total (11 of 11 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001332	Dystonia
HP:0001344	Absent speech
HP:0002134	Abnormal basal ganglia morphology
HP:0002510	Spastic tetraplegia
HP:0002540	Inability to walk
HP:0003577	Congenital onset
HP:0008872	Feeding difficulties in infancy
HP:0011344	Severe global developmental delay
HP:0012695	Decreased thalamic volume
HP:0040326	Hypoplasia of the olfactory bulb

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST002479_6	Lupus nephritis in systemic lupus erythematosus	5.000000e-07
GCST004639_30	Prudent dietary pattern	6.000000e-06
GCST006976_71	Macular thickness	8.000000e-10
GCST009462_28	Optic disc size	1.000000e-10
GCST009723_25	Vertical cup-disc ratio (adjusted for vertical disc diameter)	2.000000e-13
GCST009724_36	Vertical cup-disc ratio (multi-trait analysis)	1.000000e-15
GCST009724_37	Vertical cup-disc ratio (multi-trait analysis)	1.000000e-14
GCST011769_13	Schizophrenia	2.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008111	diet measurement
EFO:0006939	cup-to-disc ratio measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

8 total (human), top 8 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation	1
terbufos	increases methylation	1
CGP 52608	affects binding, increases reaction	1
Benzo(a)pyrene	decreases methylation	1
Fonofos	increases methylation	1
Parathion	increases methylation	1
Valproic Acid	decreases methylation	1
Aflatoxin B1	decreases methylation	1

Clinical trials (associated diseases)

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