ZFHX2

Summary

ZFHX2 (zinc finger homeobox 2, HGNC:20152) is a protein-coding gene on chromosome 14q11.2, encoding Zinc finger homeobox protein 2 (Q9C0A1). Transcriptional regulator that is critical for the regulation of pain perception and processing of noxious stimuli.

Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Involved in regulation of sensory perception of pain. Located in nucleus. Implicated in Marsili syndrome.

Source: NCBI Gene 85446 — RefSeq curated summary.

At a glance

• Gene–disease (curated): indifference to pain, congenital, autosomal dominant (Limited, GenCC)
• Clinical variants (ClinVar): 20 total
• Phenotypes (HPO): 10
• MANE Select transcript: NM_033400

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20152
Approved symbol	ZFHX2
Name	zinc finger homeobox 2
Location	14q11.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1762, KIAA1056, ZFH-5
Ensembl gene	ENSG00000136367
Ensembl biotype	protein_coding
OMIM	617828
Entrez	85446

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000412565, ENST00000419474, ENST00000555334, ENST00000606808

RefSeq mRNA: 1 — MANE Select: NM_033400 NM_033400

CCDS: CCDS55907

Canonical transcript exons

ENST00000419474 — 10 exons

Exon	Start	End
ENSE00001269869	23523203	23526679
ENSE00001493371	23532567	23533084
ENSE00001493372	23533285	23535374
ENSE00001627418	23526847	23526973
ENSE00001655044	23520857	23522941
ENSE00001657514	23529710	23529768
ENSE00001730956	23530120	23530194
ENSE00001741306	23527604	23527804
ENSE00001747806	23531481	23531721
ENSE00002454304	23551343	23551765

Expression profiles

Bgee: expression breadth ubiquitous, 166 present calls, max score 93.40.

FANTOM5 (CAGE): breadth broad, TPM avg 2.1746 / max 60.6110, expressed in 834 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
142485	1.0367	467
142487	0.8675	405
142484	0.2353	122
142483	0.0268	11
142486	0.0083	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	93.40	gold quality
sperm	CL:0000019	83.86	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.22	gold quality
left testis	UBERON:0004533	80.55	gold quality
right testis	UBERON:0004534	80.15	gold quality
lateral nuclear group of thalamus	UBERON:0002736	78.87	silver quality
testis	UBERON:0000473	78.83	gold quality
cerebellar vermis	UBERON:0004720	78.69	gold quality
substantia nigra pars reticulata	UBERON:0001966	77.87	gold quality
sural nerve	UBERON:0015488	77.75	gold quality
right hemisphere of cerebellum	UBERON:0014890	77.01	gold quality
substantia nigra pars compacta	UBERON:0001965	76.36	gold quality
cerebellar hemisphere	UBERON:0002245	76.31	gold quality
cerebellar cortex	UBERON:0002129	76.30	gold quality
cortical plate	UBERON:0005343	76.22	gold quality
right frontal lobe	UBERON:0002810	75.88	gold quality
cerebellum	UBERON:0002037	75.86	gold quality
primary visual cortex	UBERON:0002436	75.81	gold quality
right uterine tube	UBERON:0001302	75.36	gold quality
kidney epithelium	UBERON:0004819	75.27	gold quality
upper arm skin	UBERON:0004263	75.23	gold quality
ganglionic eminence	UBERON:0004023	75.17	gold quality
anterior cingulate cortex	UBERON:0009835	74.85	gold quality
occipital lobe	UBERON:0002021	74.75	gold quality
lateral globus pallidus	UBERON:0002476	74.53	gold quality
adenohypophysis	UBERON:0002196	74.07	gold quality
Brodmann (1909) area 9	UBERON:0013540	74.06	gold quality
pituitary gland	UBERON:0000007	73.77	gold quality
prefrontal cortex	UBERON:0000451	73.60	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	73.55	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.54
E-GEOD-109979	no	50.92

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
PSEN1
TFAP2A

Literature-anchored findings (GeneRIF, showing 1)

• this study demonstrate that a A novel human pain insensitivity disorder caused by a point mutation in ZFHX2. (PMID:29253101)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	zfhx3a	ENSDARG00000073944
mus_musculus	Zfhx2	ENSMUSG00000040721
rattus_norvegicus	Zfhx2	ENSRNOG00000025634
drosophila_melanogaster	zfh2	FBGN0004607
caenorhabditis_elegans	zfh-2	WBGENE00022518

Paralogs (20): FHL1 (ENSG00000022267), LMO3 (ENSG00000048540), LHX5 (ENSG00000089116), ZFHX4 (ENSG00000091656), LHX2 (ENSG00000106689), LHX6 (ENSG00000106852), LHX3 (ENSG00000107187), LHX4 (ENSG00000121454), LMO2 (ENSG00000135363), LMX1B (ENSG00000136944), ZFHX3 (ENSG00000140836), LMO4 (ENSG00000143013), LHX9 (ENSG00000143355), CRIP3 (ENSG00000146215), LHX8 (ENSG00000162624), LMX1A (ENSG00000162761), LMO1 (ENSG00000166407), CRIP2 (ENSG00000182809), CRIP1 (ENSG00000213145), LHX1 (ENSG00000273706)

Protein

Protein identifiers

Zinc finger homeobox protein 2 — Q9C0A1 (reviewed: Q9C0A1)

Alternative names: Zinc finger homeodomain protein 2

All UniProt accessions (4): A0A2P1H683, C9JSX6, Q9C0A1, G3V3N5

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional regulator that is critical for the regulation of pain perception and processing of noxious stimuli.

Subcellular location. Nucleus.

Disease relevance. Marsili syndrome (MARSIS) [MIM:147430] An autosomal dominant disorder characterized by congenital pain insensitivity. Painless cutaneous thermal burns and bone fractures are present in affected individuals. Corneal reflex is absent, sweating is decreased or absent. Patients have normal cognitive abilities, and display no evidence of distal weakness. The disease may be caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9C0A1-1	1	yes
Q9C0A1-2	2

RefSeq proteins (1): NP_207646* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR003604	Matrin/U1-like-C_Znf_C2H2	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR013087	Znf_C2H2_type	Domain
IPR017970	Homeobox_CS	Conserved_site
IPR036236	Znf_C2H2_sf	Homologous_superfamily
IPR051968	ZnFinger_Homeobox_TR	Family

Pfam: PF00046, PF24056

UniProt features (58 total): compositionally biased region 20, region of interest 17, zinc finger region 12, DNA-binding region 3, splice variant 2, sequence conflict 2, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9C0A1-F1	47.92	0.06

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 123 (showing top): GOBP_BEHAVIOR, GOBP_ADULT_BEHAVIOR, GOBP_NEUROGENESIS, ACTGCAG_MIR173P, GOBP_SENSORY_PERCEPTION_OF_PAIN, GOBP_REGULATION_OF_NEURON_DIFFERENTIATION, MODULE_285, MODULE_301, MODULE_99, GOBP_REGULATION_OF_SENSORY_PERCEPTION, GOBP_REGULATION_OF_NERVOUS_SYSTEM_PROCESS, GOBP_REGULATION_OF_SYSTEM_PROCESS, GOBP_SENSORY_PERCEPTION, MODULE_188, GOMF_SEQUENCE_SPECIFIC_DNA_BINDING

GO Biological Process (5): regulation of transcription by RNA polymerase II (GO:0006357), adult behavior (GO:0030534), regulation of neuron differentiation (GO:0045664), regulation of sensory perception of pain (GO:0051930), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (7): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), zinc ion binding (GO:0008270), nucleic acid binding (GO:0003676), DNA binding (GO:0003677), protein binding (GO:0005515), metal ion binding (GO:0046872)

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
binding	2
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
behavior	1
neuron differentiation	1
regulation of cell differentiation	1
sensory perception of pain	1
regulation of sensory perception	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
transition metal ion binding	1
nucleic acid binding	1
cation binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

658 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZFHX2	INPP5K	Q9BT40	424
ZFHX2	TSHZ2	Q9NRE2	423
ZFHX2	TSHZ3	Q63HK5	418
ZFHX2	LGALS4	P56470	417
ZFHX2	RPH3AL	Q9UNE2	412
ZFHX2	EXOSC9	Q06265	408
ZFHX2	OPRM1	P35372	398
ZFHX2	TSHZ1	Q6ZSZ6	396
ZFHX2	MYB	P10242	393
ZFHX2	ZBTB8A	Q96BR9	372
ZFHX2	PRDM12	Q9H4Q4	368
ZFHX2	POU2F2	P09086	361
ZFHX2	RERE	Q9P2R6	356
ZFHX2	ZBTB26	Q9HCK0	353
ZFHX2	ZNF777	Q9ULD5	351

IntAct

20 interactions, top by confidence:

A	B	Type	Score
ZFHX2		psi-mi:“MI:0915”(physical association)	0.560
GPR37	ZFHX2	psi-mi:“MI:0915”(physical association)	0.560
GRN	ZFHX2	psi-mi:“MI:0915”(physical association)	0.560
MAPT	ZFHX2	psi-mi:“MI:0915”(physical association)	0.560
ZFHX2	MAPT	psi-mi:“MI:0915”(physical association)	0.560
ZFHX2	PMP22	psi-mi:“MI:0915”(physical association)	0.560
PTK2B	ARHGAP10	psi-mi:“MI:0914”(association)	0.350

BioGRID (25): ZFHX2 (Affinity Capture-RNA), ZFHX2 (Two-hybrid), ADAMTSL4 (Two-hybrid), CYSRT1 (Two-hybrid), KRTAP3-1 (Two-hybrid), ZFHX2 (Affinity Capture-MS), ZFHX2 (Proximity Label-MS), KIF5B (Cross-Linking-MS (XL-MS)), ZFHX2 (Affinity Capture-MS), ZFHX2 (Proximity Label-MS), ZFHX2 (Proximity Label-MS), ZFHX2 (Proximity Label-MS), ZFHX2 (Proximity Label-MS), ZFHX2 (Proximity Label-MS), ZFHX2 (Proximity Label-MS)

ESM2 similar proteins: A2A5E6, A5PK23, A6NKF2, A6PWV5, B0K011, E9Q6W4, O02786, O95402, P09086, P13297, P55198, Q00196, Q08DS3, Q0VDQ9, Q29013, Q2NKI2, Q2VL80, Q2VL82, Q2VL83, Q2VL85, Q2VL86, Q569K4, Q5XI28, Q62255, Q66K41, Q6AXX3, Q6PBT9, Q86V15, Q8BXJ8, Q8IVH2, Q8K4J6, Q8TAX0, Q8VD12, Q8VDL9, Q8WUU4, Q92766, Q969V6, Q96PM9, Q9BXA9, Q9BZE0

Diamond homologs: A0A1L8FFY5, A0A1W2PPF3, A0JNI8, A1L0Z1, A1L2U9, A2PZF9, B0XS89, B1WAZ8, B1WBU4, G5EBU4, G5EC36, G5EE86, G5EEA1, O60315, O62836, O73590, P08048, P09088, P10925, P17010, P17012, P20154, P20662, P20912, P28166, P29674, P31362, P31363, P34764, P34765, P36197, P36198, P36200, P37137, P37275, P42571, P48742, P49335, P50458, P52739

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	7
Likely benign	8
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1878 predictions. Top by Δscore:

Variant	Effect	Δscore
14:23522941:CCTAG:C	acceptor_loss	1.0000
14:23526675:GCCTT:G	acceptor_gain	1.0000
14:23526676:CCTTC:C	acceptor_gain	1.0000
14:23526677:CTT:C	acceptor_gain	1.0000
14:23526678:TT:T	acceptor_gain	1.0000
14:23526680:C:CC	acceptor_gain	1.0000
14:23527602:A:AC	donor_gain	1.0000
14:23527603:C:CC	donor_gain	1.0000
14:23527603:CTA:C	donor_gain	1.0000
14:23522937:CGGGC:C	acceptor_gain	0.9900
14:23522942:C:CC	acceptor_gain	0.9900
14:23522950:G:C	acceptor_gain	0.9900
14:23526676:CCTT:C	acceptor_loss	0.9900
14:23526677:CTTCT:C	acceptor_gain	0.9900
14:23526678:TTCTA:T	acceptor_loss	0.9900
14:23526679:TCTAG:T	acceptor_loss	0.9900
14:23526680:C:CG	acceptor_loss	0.9900
14:23526681:T:A	acceptor_loss	0.9900
14:23526842:CTTAC:C	donor_loss	0.9900
14:23526844:TA:T	donor_loss	0.9900
14:23526845:AC:A	donor_loss	0.9900
14:23526846:C:A	donor_loss	0.9900
14:23526846:CCTG:C	donor_gain	0.9900
14:23526974:C:CA	acceptor_loss	0.9900
14:23527600:TCAC:T	donor_gain	0.9900
14:23529689:C:A	donor_gain	0.9900
14:23529769:C:CC	acceptor_gain	0.9900
14:23530111:AAAAC:A	donor_loss	0.9900
14:23530112:AAACT:A	donor_loss	0.9900
14:23530113:AACTC:A	donor_loss	0.9900

AlphaMissense

16584 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:23523421:A:G	L2174P	1.000
14:23523596:C:G	A2116P	1.000
14:23523597:A:C	N2115K	1.000
14:23523597:A:T	N2115K	1.000
14:23523599:T:C	N2115D	1.000
14:23523603:G:C	F2113L	1.000
14:23523603:G:T	F2113L	1.000
14:23523604:A:G	F2113S	1.000
14:23523605:A:G	F2113L	1.000
14:23523606:C:A	W2112C	1.000
14:23523606:C:G	W2112C	1.000
14:23523608:A:G	W2112R	1.000
14:23523608:A:T	W2112R	1.000
14:23523610:A:T	V2111D	1.000
14:23523619:A:T	V2108D	1.000
14:23523631:A:G	L2104P	1.000
14:23523646:C:A	G2099V	1.000
14:23523646:C:T	G2099E	1.000
14:23523647:C:G	G2099R	1.000
14:23523647:C:T	G2099R	1.000
14:23523657:A:C	C2095W	1.000
14:23523659:A:G	C2095R	1.000
14:23523673:G:T	P2090H	1.000
14:23523695:A:G	C2083R	1.000
14:23523712:A:G	L2077P	1.000
14:23523727:A:G	M2072T	1.000
14:23523736:C:A	R2069M	1.000
14:23524221:A:C	N1907K	1.000
14:23524221:A:T	N1907K	1.000
14:23524222:T:A	N1907I	1.000

dbSNP variants (sampled 300 via entrez): RS1000070652 (14:23521059 A>G), RS1000308389 (14:23526376 C>T), RS1000375875 (14:23550211 T>C), RS1000420254 (14:23520965 T>C), RS1000476809 (14:23550969 C>T), RS1000481365 (14:23532123 C>T), RS1000546550 (14:23524446 C>T), RS1000577393 (14:23556646 A>G,T), RS1000718292 (14:23530530 G>A), RS1000813340 (14:23530774 T>C), RS1000917911 (14:23524768 A>C), RS1000924271 (14:23545325 T>G), RS1000960209 (14:23537277 C>T), RS1001047550 (14:23539109 C>T), RS1001051872 (14:23550676 G>A)

Disease associations

OMIM: gene MIM:617828 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
indifference to pain, congenital, autosomal dominant	Limited	Autosomal dominant

Mondo (1): (MONDO:0007828)

Orphanet (0):

HPO phenotypes

10 total (10 of 10 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000559	Corneal scarring
HP:0000632	Lacrimation abnormality
HP:0000966	Hypohidrosis
HP:0001954	Recurrent fever
HP:0002315	Headache
HP:0002661	Painless fractures due to injury
HP:0007021	Pain insensitivity
HP:0008000	Decreased corneal reflex
HP:0010829	Impaired temperature sensation

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

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

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
propionaldehyde	increases methylation	1
nonanal	increases methylation	1
n-hexanal	increases methylation	1
butyraldehyde	increases methylation	1
benzo(e)pyrene	increases methylation	1
butylbenzyl phthalate	increases expression	1
ferrous chloride	decreases expression	1
caprylic aldehyde	increases methylation	1
pentanal	increases methylation	1
heptanal	increases methylation	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Methapyrilene	increases methylation	1
Phthalic Acids	increases methylation	1
Plant Extracts	decreases expression, affects cotreatment	1
Tobacco Smoke Pollution	decreases expression	1
Tunicamycin	decreases expression	1
Urethane	increases expression	1
Aflatoxin B1	decreases methylation	1
Asbestos, Crocidolite	decreases expression	1
Copper Sulfate	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_XV94	HEK293 eGFP-ZFHX2	Transformed cell line	Female

Clinical trials (associated diseases)

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