ZIC2: A Key Regulator in Neural Development and Holoprosencephaly
Comprehensive genomic and functional analysis of ZIC2, a zinc finger transcription factor critical for forebrain patterning.
Gene Information Card
| Symbol | ZIC2 |
|---|---|
| Full Name | Zic family member 2 |
| Gene Type | protein-coding |
| Chromosomal Location | 13q32.3 |
| NCBI Gene ID | 7546 ncbi.nlm.nih.gov/gene/7546 |
| Ensembl ID | ENSG00000143355 |
| UniProt ID | O95409 |
| OMIM ID | 603073 |
| HGNC ID | 12873 |
| Aliases | HPE5, Zic2 |
Description
ZIC2 encodes a zinc finger transcription factor of the ZIC family, essential for early neural development, particularly the formation of the forebrain and midline structures. It acts as a transcriptional repressor or activator depending on context, regulating genes involved in cell proliferation, differentiation, and patterning. Mutations in ZIC2 are a major cause of holoprosencephaly type 5 (HPE5), a severe brain malformation characterized by incomplete separation of the cerebral hemispheres.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Holoprosencephaly 5 (HPE5) | Loss-of-function mutations (nonsense, frameshift, deletions) impair ZIC2 DNA-binding or nuclear localization, disrupting forebrain patterning. | ClinVar, OMIM |
| Holoprosencephaly (non-syndromic) | Heterozygous pathogenic variants, including missense and truncating mutations, reduce ZIC2 activity, leading to variable expressivity. | ClinVar, NCBI |
| Microform holoprosencephaly | Mild mutations or hypomorphic alleles cause subtle midline defects such as single central incisor or hypotelorism. | OMIM, ClinVar |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 12.5 | Medium |
| Cerebellum | 8.2 | Low |
| Testis | 3.1 | Low |
| Spinal cord | 6.7 | Low |
| Retina | 4.5 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| SH-SY5Y (neuroblastoma) | 15.3 | Neuronal model; high expression |
| U-87 MG (glioblastoma) | 9.8 | Moderate expression |
| HEK293 (embryonic kidney) | 2.1 | Low endogenous expression |
| HepG2 (hepatocellular carcinoma) | 1.5 | Very low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1195C>T (p.Arg399*) | Nonsense | <0.01% | Premature stop; loss of C-terminal zinc fingers; loss of function |
| c.1462_1463del (p.Leu488Valfs*12) | Frameshift | <0.01% | Truncated protein; loss of DNA-binding; loss of function |
| c.1033G>A (p.Gly345Arg) | Missense | <0.01% | Disrupts zinc finger structure; reduced transcriptional activity |
| c.1321C>T (p.Arg441Trp) | Missense | <0.01% | Impaired nuclear localization; dominant negative effect |
Mutation functional classification
Loss of Function (LOF)
Nonsense, frameshift, and splice-site mutations that truncate the protein or disrupt zinc finger domains, leading to haploinsufficiency in holoprosencephaly.
Gain of Function (GOF)
Not reported for ZIC2; no activating mutations documented in cancer or developmental disorders.
Dominant Negative (DN)
Missense mutations (e.g., p.Arg441Trp) that retain dimerization but impair DNA binding or nuclear localization, interfering with wild-type ZIC2 function.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Hedgehog signaling pathway (regulation of Gli transcription factors)
• Neural crest differentiation
• Forebrain development (midline patterning)
Protein Summary
ZIC2 is a 532-amino acid protein containing five C2H2-type zinc finger domains that mediate sequence-specific DNA binding. It localizes to the nucleus and functions as a transcription factor, often repressing target genes involved in neural differentiation. The protein interacts with GLI proteins to modulate Hedgehog signaling. Structural integrity of the zinc finger region is critical; mutations in this domain are common in HPE5.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| ZIC2 Knockout HEK293 Cell Line | EDJ-KQ6027 | Human | 7546 | Details Get a Quote |
| ZIC2 Knockout HCT 116 Cell Line | EDJ-KQ28367 | Human | 7546 | Details Get a Quote |
| ZIC2 Knockout A-549 Cell Line | EDJ-KQ29650 | Human | 7546 | Details Get a Quote |
| ZIC2 Knockout HeLa Cell Line | EDJ-KQ29652 | Human | 7546 | Details Get a Quote |
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