ZIC4

Summary

ZIC4 (Zic family zinc finger 4, HGNC:20393) is a protein-coding gene on chromosome 3q24, encoding Zinc finger protein ZIC 4 (Q8N9L1). Binds to DNA.

This gene encodes a member of the ZIC family of C2H2-type zinc finger proteins. Members of this family are important during development, and have been associated with X-linked visceral heterotaxy and holoprosencephaly type 5. This gene is closely linked to the gene encoding zinc finger protein of the cerebellum 1, a related family member on chromosome 3. Heterozygous deletion of these linked genes is involved in Dandy-Walker malformation, which is a congenital cerebellar malformation. Multiple transcript variants have been identified for this gene.

Source: NCBI Gene 84107 — RefSeq curated summary.

At a glance

• GWAS associations: 21
• Clinical variants (ClinVar): 164 total
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_032153

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20393
Approved symbol	ZIC4
Name	Zic family zinc finger 4
Location	3q24
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000174963
Ensembl biotype	protein_coding
OMIM	608948
Entrez	84107

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 9 protein_coding, 6 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000383075, ENST00000425731, ENST00000462748, ENST00000463250, ENST00000463850, ENST00000464144, ENST00000464502, ENST00000472749, ENST00000473123, ENST00000475502, ENST00000480015, ENST00000484399, ENST00000484586, ENST00000491672, ENST00000493664, ENST00000494569, ENST00000525172

RefSeq mRNA: 4 — MANE Select: NM_032153 NM_001168378, NM_001168379, NM_001243256, NM_032153

CCDS: CCDS43160, CCDS54652, CCDS54653, CCDS58857

Canonical transcript exons

ENST00000383075 — 5 exons

Exon	Start	End
ENSE00001908480	147406363	147406543
ENSE00001911301	147386046	147388859
ENSE00003600537	147390931	147391246
ENSE00003629720	147402728	147402812
ENSE00003790026	147395852	147396469

Expression profiles

Bgee: expression breadth ubiquitous, 115 present calls, max score 97.64.

FANTOM5 (CAGE): breadth broad, TPM avg 2.4951 / max 629.3577, expressed in 398 samples.

FANTOM5 promoters (18 alternative TSS)

Promoter ID	TPM avg	Samples expressed
44971	0.5263	100
44956	0.3885	218
44961	0.3459	92
44964	0.3393	82
44957	0.1697	79
44965	0.1340	62
44972	0.1174	46
44969	0.0967	33
44966	0.0803	36
44955	0.0667	24

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar hemisphere	UBERON:0002245	97.64	gold quality
cerebellar cortex	UBERON:0002129	97.54	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.96	gold quality
cerebellum	UBERON:0002037	95.54	gold quality
cerebellar vermis	UBERON:0004720	81.16	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	76.23	gold quality
nucleus accumbens	UBERON:0001882	73.92	gold quality
right frontal lobe	UBERON:0002810	73.62	gold quality
spinal cord	UBERON:0002240	72.73	gold quality
hypothalamus	UBERON:0001898	72.27	gold quality
cingulate cortex	UBERON:0003027	70.70	gold quality
anterior cingulate cortex	UBERON:0009835	70.70	gold quality
putamen	UBERON:0001874	69.78	gold quality
prefrontal cortex	UBERON:0000451	69.68	gold quality
caudate nucleus	UBERON:0001873	69.65	gold quality
Brodmann (1909) area 9	UBERON:0013540	69.54	gold quality
right lobe of liver	UBERON:0001114	68.48	gold quality
colonic epithelium	UBERON:0000397	68.21	gold quality
gastrocnemius	UBERON:0001388	67.82	gold quality
muscle of leg	UBERON:0001383	67.81	gold quality
calcaneal tendon	UBERON:0003701	67.06	gold quality
hindlimb stylopod muscle	UBERON:0004252	66.57	gold quality
brain	UBERON:0000955	66.42	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	65.91	gold quality
neocortex	UBERON:0001950	65.62	gold quality
frontal cortex	UBERON:0001870	65.44	gold quality
diaphragm	UBERON:0001103	65.15	gold quality
corpus callosum	UBERON:0002336	65.12	gold quality
telencephalon	UBERON:0001893	64.08	gold quality
pancreatic ductal cell	CL:0002079	64.03	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.91

Regulation

Is transcription factor: yes

JASPAR motifs

Motif	Name	Family
MA0751.1	ZIC4	More than 3 adjacent zinc fingers
MA0751.2	ZIC4	More than 3 adjacent zinc fingers

JASPAR matrix evidence (PMIDs): PMID:19443739

miRNA regulators (miRDB)

136 targeting ZIC4, 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-3646	100.00	73.56	5283
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 8)

• Through physical mapping of 3q2 interstitial deletions in several individuals with Dandy-Walker malformation (DWM), we defined the first critical region associated with DWM, encompassing two adjacent Zinc finger in cerebellum genes, ZIC1 and ZIC4. (PMID:15338008)
• Dandy-Walker malformation associated with heterozygous ZIC1 and ZIC4 deletion. (PMID:21204220)
• ZIC4 CPG island methylation predicts progression in bladder cancer. (PMID:22284968)
• The rate of methylation of ZIC1, ZIC4, HHIP, and DACT2 in tumors was very high, while methylation of CXXC4 was low to moderate in OSCC and LSCC. (PMID:27553089)
• Epigenetic silencing of ZIC4 contributes to cancer progression in hepatocellular carcinoma. (PMID:33097694)
• Transcriptional expression of ZICs as an independent indicator of survival in gliomas. (PMID:34475426)
• Common Variants Near ZIC1 and ZIC4 in Autopsy-Confirmed Multiple System Atrophy. (PMID:35997131)
• Epigenetic silencing of ZIC4 unveils a potential tumor suppressor role in pediatric choroid plexus carcinoma. (PMID:39266576)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	zic4	ENSDARG00000031307
mus_musculus	Zic4	ENSMUSG00000036972
rattus_norvegicus	Zic4	ENSRNOG00000014871

Paralogs (14): ZIC2 (ENSG00000043355), ZXDC (ENSG00000070476), GLI2 (ENSG00000074047), GLI3 (ENSG00000106571), GLIS3 (ENSG00000107249), GLI1 (ENSG00000111087), GLIS2 (ENSG00000126603), AEBP2 (ENSG00000139154), ZIC5 (ENSG00000139800), ZIC1 (ENSG00000152977), ZIC3 (ENSG00000156925), GLIS1 (ENSG00000174332), ZXDA (ENSG00000198205), ZXDB (ENSG00000198455)

Protein

Protein identifiers

Zinc finger protein ZIC 4 — Q8N9L1 (reviewed: Q8N9L1)

Alternative names: Zinc finger protein of the cerebellum 4

All UniProt accessions (4): Q8N9L1, C9J6T3, C9JD04, C9JZU7

UniProt curated annotations — full annotation on UniProt →

Function. Binds to DNA.

Subcellular location. Nucleus.

Miscellaneous. May be due to an intron retention.

Similarity. Belongs to the GLI C2H2-type zinc-finger protein family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q8N9L1-1	1	yes
Q8N9L1-2	2
Q8N9L1-3	3
Q8N9L1-4	4
Q8N9L1-5	5

RefSeq proteins (4): NP_001161850, NP_001161851, NP_001230185, NP_115529* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013087	Znf_C2H2_type	Domain
IPR036236	Znf_C2H2_sf	Homologous_superfamily
IPR041643	Znf_ZIC	Domain
IPR043359	GLI-like	Family
IPR056436	Znf-C2H2_ZIC1-5/GLI1-3-like	Domain

Pfam: PF00096, PF18366, PF23561

UniProt features (16 total): zinc finger region 5, splice variant 5, sequence conflict 2, region of interest 2, chain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N9L1-F1	64.20	0.08

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 205 (showing top): CREL_01, RRAGTTGT_UNKNOWN, chr3q24, TAATAAT_MIR126, BENPORATH_ES_WITH_H3K27ME3, AAGTCCA_MIR422B_MIR422A, CMYB_01, AREB6_01, RACCACAR_AML_Q6, TGACCTY_ERR1_Q2, CHX10_01, GGGTGGRR_PAX4_03, AAAYRNCTG_UNKNOWN, CEBPB_01, COUP_01

GO Biological Process (2): regulation of transcription by RNA polymerase II (GO:0006357), central nervous system development (GO:0007417)

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), DNA binding (GO:0003677), zinc ion binding (GO:0008270), sequence-specific double-stranded DNA binding (GO:1990837), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), metal ion binding (GO:0046872)

GO Cellular Component (1): 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
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
nervous system development	1
system development	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
transition metal ion binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
transcription cis-regulatory region binding	1
cation binding	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1334 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZIC4	PNMA2	Q9UL42	813
ZIC4	AMPH	P49418	806
ZIC4	DNER	Q8NFT8	780
ZIC4	LGI1	O95970	777
ZIC4	DPYSL5	Q9BPU6	765
ZIC4	RCVRN	P35243	763
ZIC4	FOXL2	P58012	753
ZIC4	SOX1	O00570	734
ZIC4	ZPR1	O75312	733
ZIC4	BIN1	O00499	728
ZIC4	GAD2	Q05329	720
ZIC4	CNTNAP2	Q9UHC6	715
ZIC4	DPP10	Q8N608	714
ZIC4	DPP6	P42658	697
ZIC4	IGLON5	A6NGN9	686

IntAct

4 interactions, top by confidence:

A	B	Type	Score
CCDC93	VPS26C	psi-mi:“MI:0914”(association)	0.350
TP53BP1	PSMD14	psi-mi:“MI:2364”(proximity)	0.270
ZNF598	ZIC4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (2): ZIC4 (Affinity Capture-MS), ZIC4 (Affinity Capture-RNA)

ESM2 similar proteins: A0PJY2, A1YPR0, A2A935, B0K011, B0X9H6, B7ZRU9, O13089, O15090, O15156, O75626, O88939, O93567, O95365, P14404, P25932, P41183, P56260, Q03112, Q08DS3, Q0IHB8, Q1L8W0, Q2VWH6, Q32NK7, Q3T135, Q5XJQ7, Q60636, Q64321, Q6AY34, Q6DBW0, Q6F2E4, Q802Y8, Q8I7Z8, Q8K083, Q8N9L1, Q8NAP8, Q8TBJ5, Q8VCZ7, Q8VDL9, Q98T94, Q99PV8

Diamond homologs: A0A5K4F1D0, A0JC51, A4FV57, O57311, O60481, O73689, O95409, P08151, P10070, P10071, P19538, P34708, P39768, P46684, P47806, P55878, P55879, Q0VGT2, Q15915, Q17308, Q5IS56, Q61467, Q61602, Q62520, Q62521, Q6DJQ6, Q6GR30, Q6XP49, Q6ZN18, Q7JNM3, Q7K0S9, Q7SXV2, Q7TQ40, Q8JJC0, Q8K1M4, Q8N9L1, Q8NBF1, Q8NEA6, Q8SV95, Q8VDL9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	105
Likely benign	43
Benign	9

Top pathogenic / likely-pathogenic (0)

SpliceAI

1364 predictions. Top by Δscore:

Variant	Effect	Δscore
3:147388556:C:CT	acceptor_gain	1.0000
3:147388857:CAT:C	acceptor_gain	1.0000
3:147388860:C:CC	acceptor_gain	1.0000
3:147388860:C:CG	acceptor_loss	1.0000
3:147388861:T:G	acceptor_loss	1.0000
3:147402722:ACTT:A	donor_loss	1.0000
3:147402723:CTT:C	donor_loss	1.0000
3:147402724:TTAC:T	donor_loss	1.0000
3:147402725:TA:T	donor_loss	1.0000
3:147402726:A:AC	donor_gain	1.0000
3:147402726:A:C	donor_loss	1.0000
3:147402727:C:CA	donor_loss	1.0000
3:147402727:C:CC	donor_gain	1.0000
3:147402727:CTTGA:C	donor_gain	1.0000
3:147402729:TG:T	donor_gain	1.0000
3:147388557:G:T	acceptor_gain	0.9900
3:147388855:GACAT:G	acceptor_gain	0.9900
3:147388856:ACAT:A	acceptor_gain	0.9900
3:147388857:CATC:C	acceptor_gain	0.9900
3:147388858:AT:A	acceptor_gain	0.9900
3:147388867:A:T	acceptor_gain	0.9900
3:147388870:C:CT	acceptor_gain	0.9900
3:147396469:CCT:C	acceptor_loss	0.9900
3:147396471:T:G	acceptor_loss	0.9900
3:147402721:AACTT:A	donor_loss	0.9900
3:147402722:A:C	donor_gain	0.9900
3:147402727:CTTG:C	donor_gain	0.9900
3:147402812:CCTG:C	acceptor_loss	0.9900
3:147402813:C:CC	acceptor_gain	0.9900
3:147402813:CT:C	acceptor_loss	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000113616 (3:147393642 T>C), RS1000203267 (3:147394113 T>G), RS1000269588 (3:147398935 A>G), RS1000337144 (3:147393855 G>A), RS1000496189 (3:147405775 C>A), RS1000756555 (3:147399909 G>C), RS1000870277 (3:147400273 C>T), RS1001037990 (3:147389899 C>T), RS1001068378 (3:147394845 C>A), RS1001167831 (3:147403218 G>C), RS1001325034 (3:147402990 C>T), RS1001418325 (3:147398368 G>A,C,T), RS1001590754 (3:147404098 T>A,G), RS1002006069 (3:147392833 A>G), RS1002170336 (3:147404375 C>A,T)

Disease associations

OMIM: gene MIM:608948 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

21 associations (top):

Study	Trait	p-value
GCST003833_16	Adult asthma	4.000000e-06
GCST007323_10	Risk-taking tendency (4-domain principal component model)	6.000000e-09
GCST007323_53	Risk-taking tendency (4-domain principal component model)	5.000000e-08
GCST007326_85	Number of sexual partners	5.000000e-08
GCST007326_87	Number of sexual partners	1.000000e-13
GCST007335_12	Age at first sexual intercourse	2.000000e-09
GCST008710_1	Parietal lobe volume	4.000000e-10
GCST010699_2	Brain morphology (min-P)	3.000000e-11
GCST010701_124	Cortical surface area (MOSTest)	7.000000e-11
GCST010702_73	Subcortical volume (MOSTest)	2.000000e-11
GCST010703_88	Brain morphology (MOSTest)	5.000000e-87
GCST011616_13	Cortical volume	3.000000e-23
GCST011616_36	Cortical volume	5.000000e-18
GCST011616_38	Cortical volume	3.000000e-17
GCST011617_23	Cortical surface area	3.000000e-46
GCST011617_29	Cortical surface area	1.000000e-45
GCST011617_41	Cortical surface area	2.000000e-26
GCST011743_35	HDL cholesterol levels in HIV infection	8.000000e-06
GCST90000047_60	Age at first sexual intercourse	2.000000e-09
GCST90010427_7	Left–right brain asymmetry	1.000000e-09
GCST90093325_7	Language functional connectivity	8.000000e-21

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0008579	risk-taking behaviour
EFO:0009749	age at first sexual intercourse measurement
EFO:0004346	neuroimaging measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0007797	language measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression	2
Valproic Acid	affects expression, increases expression	2
ethyl-p-hydroxybenzoate	decreases expression	1
sodium arsenite	affects methylation	1
S-(1,2-dichlorovinyl)cysteine	decreases expression, decreases reaction	1
CGP 52608	affects binding, increases reaction	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Lipopolysaccharides	decreases reaction, decreases expression	1
Rotenone	decreases expression	1
Silver	decreases expression	1
Cyclosporine	decreases methylation	1
Aflatoxin B1	decreases methylation	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

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