NOVA2 — NOVA Alternative Splicing Regulator 2

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NOVA2 — NOVA Alternative Splicing Regulator 2

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NOVA2 — NOVA Alternative Splicing Regulator 2

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">NOVA2 — NOVA Alternative Splicing Regulator 2</th>
</tr>
<tr> [@raj2018]
<td class="label">Symbol</td> [@bhatt2020]
<td><strong>NOVA2</strong></td> [@licatalosi2008]
</tr>
<tr>
<td class="label">Full Name</td>
<td>NOVA Alternative Splicing Regulator 2 (Neuro-Oncological Ventral Antigen 2)</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>19p13.3</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/4858" target="_blank">4858</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000104967" target="_blank">ENSG00000104967</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/601991" target="_blank">601991</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9UNW9" target="_blank">Q9UNW9</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Huntington's Disease](/diseases/huntingtons-disease), [Epilepsy](/diseases/epilepsy)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>[Neurons](/entities/neurons) (neocortex, hippocampus), Vascular endothelium</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">2 edges</a></td>
</tr>
</table>

...

NOVA2 — NOVA Alternative Splicing Regulator 2

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">NOVA2 — NOVA Alternative Splicing Regulator 2</th>
</tr>
<tr> [@raj2018]
<td class="label">Symbol</td> [@bhatt2020]
<td><strong>NOVA2</strong></td> [@licatalosi2008]
</tr>
<tr>
<td class="label">Full Name</td>
<td>NOVA Alternative Splicing Regulator 2 (Neuro-Oncological Ventral Antigen 2)</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>19p13.3</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/4858" target="_blank">4858</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000104967" target="_blank">ENSG00000104967</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/601991" target="_blank">601991</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9UNW9" target="_blank">Q9UNW9</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Huntington's Disease](/diseases/huntingtons-disease), [Epilepsy](/diseases/epilepsy)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>[Neurons](/entities/neurons) (neocortex, hippocampus), Vascular endothelium</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">2 edges</a></td>
</tr>
</table>

NOVA2 — NOVA Alternative Splicing Regulator 2

Overview

Mermaid diagram (expand to render)

NOVA2 (NOVA Alternative Splicing Regulator 2), also known as Neuro-Oncological Ventral Antigen 2, encodes a neuron-specific KH-type RNA-binding protein on chromosome 19p13.3 that functions as a master regulator of alternative splicing in the forebrain and [cortex](/brain-regions/cortex). NOVA2 is the paralog of [NOVA1](/genes/nova1), and together these two proteins constitute the NOVA family, which governs the most extensively characterized neuron-specific splicing regulatory network in mammals["@ule2006"].

While [NOVA1](/genes/nova1) predominates in the hindbrain and spinal cord, NOVA2 is the dominant NOVA family member in the cerebral cortex and [hippocampus](/brain-regions/hippocampus), making it especially relevant to higher cognitive functions and cortical neurodegenerative diseases such as [Alzheimer's disease](/diseases/alzheimers-disease). NOVA2 regulates the splicing, polyadenylation, and localization of hundreds of neuronal pre-mRNAs, with targets highly enriched for synaptic and axon guidance molecules["@saito2016"].

Gene Structure and Protein Products

Genomic Organization

The NOVA2 gene is located on chromosome 19p13.3, spanning approximately 79 kb with 8 exons. Despite divergent genomic locations, NOVA1 and NOVA2 share ~75% amino acid identity, particularly within their KH RNA-binding domains[@yang1998].

Protein Structure

The NOVA2 protein (492 amino acids) contains three KH (K-Homology) RNA-binding domains:

KH1, KH2, KH3 domains: Each adopts a βααββα fold; KH3 is the primary RNA-recognition domain, directly contacting YCAY tetranucleotide motifs with high specificity
Linker regions: Flexible regions between KH domains that contribute to multivalent RNA binding
Nuclear/cytoplasmic shuttling signals: Enable activity-dependent redistribution between nucleus and dendrites

Functional Differences from NOVA1

Despite structural similarity, NOVA2 has distinct properties:

Regional specificity: NOVA2 predominates in cortex/hippocampus; NOVA1 in hindbrain/spinal cord
Target preferences: While sharing many targets, NOVA2 uniquely regulates cortical axon guidance molecules and excitatory synapse components
Developmental timing: NOVA2 expression peaks later in development, coinciding with cortical maturation

Function

Cortical Splicing Regulation

NOVA2 is the primary splicing regulator in cortical and hippocampal neurons:

Target scope: CLIP-seq studies identify ~1,400 NOVA2 binding sites in mouse brain, regulating ~500 alternative splicing events
Positional splicing code: Like NOVA1, binding downstream of an exon promotes inclusion; upstream binding promotes skipping
Cooperative binding: Multiple NOVA2 molecules bind clustered YCAY elements, creating switch-like regulation of target exons[@ule2006]

Key Cortical Splicing Targets

NOVA2 regulates transcripts essential for cortical circuit formation and function:

| Target | Regulated Event | Functional Impact |
|--------|----------------|-------------------|
| [DCC](/genes/dcc) (Netrin receptor) | Exon 17 | Axon midline crossing in cortex |
| [Dab1](/genes/dab1) (Reelin pathway) | Exon 7b/7c | Cortical layer positioning |
| [GRIN1](/genes/grin1) (NR1) | Exon 5 | [NMDA receptor](/entities/nmda-receptor) properties at cortical synapses |
| [NRXN1](/genes/nrxn1) (Neurexin-1) | SS4 | Excitatory vs inhibitory synapse specification |
| [NLGN1](/genes/nlgn1) (Neuroligin-1) | Splice site B | Excitatory synapse development |
| [Robo2](genes/ROBO2) | Alternative exons | Cortical axon guidance |
| [SLIT2](genes/SLIT2) | Multiple exons | Cortical neuron migration |

Cortical Development

NOVA2 is essential for proper cortical wiring:

Axon guidance: Nova2 knockout mice show severe cortical axon pathfinding defects, including failure of commissural crossing and aberrant corticospinal tract projections[@saito2016]
Cortical lamination: NOVA2 regulates Dab1 splicing, which is critical for Reelin-dependent neuronal migration and layer formation
Synaptogenesis: Alternative splicing of neurexin and neuroligin genes by NOVA2 specifies excitatory/inhibitory synapse identity
Dendritic development: NOVA2 targets include cytoskeletal regulators that control dendritic arborization

Vascular Development

Uniquely among neuronal splicing factors, NOVA2 is also expressed in vascular endothelium:

Regulates alternative splicing of adhesion molecules in endothelial cells
Controls angiogenesis during brain vascular development
Endothelial NOVA2 loss disrupts [blood-brain barrier](/entities/blood-brain-barrier) formation[@giampietro2015]

Alternative Polyadenylation

Beyond splicing, NOVA2 regulates 3' end processing:

Controls alternative polyadenylation site selection for hundreds of neuronal transcripts
Affects mRNA stability, localization, and translation through 3' UTR length changes
3' UTR regulation by NOVA2 is particularly important for dendritic mRNA targeting

Disease Associations

Alzheimer's Disease

NOVA2 dysfunction is increasingly linked to [Alzheimer's disease](/diseases/alzheimers-disease):

Expression decline: NOVA2 protein levels decrease in the cortex and hippocampus of AD patients, correlating with Braak stage and cognitive decline[@raj2018]
Splicing alterations: Hundreds of NOVA2-dependent exons show altered inclusion in AD cortex, affecting synaptic proteins, glutamate receptors, and cell adhesion molecules
[Tau](/proteins/tau) connection: NOVA2 may contribute to [MAPT](/genes/mapt) exon 10 splicing regulation in the cortex; loss of NOVA2 could contribute to tau isoform imbalance
Synaptic loss correlation: NOVA2-regulated splicing changes correlate with synaptic density loss, a major driver of cognitive decline in AD
Amyloid toxicity: [Aβ](/proteins/amyloid-beta) oligomers can downregulate NOVA2 expression through translational repression, creating a feed-forward cycle of splicing dysfunction

Huntington's Disease

In [Huntington's disease](/diseases/huntington-disease):

NOVA2-dependent splicing events are disrupted in the caudate and cortex of HD patients
Mutant [huntingtin](/proteins/huntingtin) protein sequesters NOVA2 in nuclear inclusions
Striatal medium spiny neurons show particularly severe NOVA2 target mis-splicing

Epilepsy

NOVA2 variants have been identified in patients with focal epilepsy
NOVA2 conditional knockout mice develop spontaneous seizures
Loss of NOVA2-dependent GABA and glutamate receptor splicing disrupts excitatory/inhibitory balance in cortical circuits
NOVA2 regulates splicing of [SCN1A](/genes/scn1a) and [SCN8A](/genes/scn8a) sodium channel transcripts, which are major epilepsy genes[@bhatt2020]

Autism Spectrum Disorder

NOVA2 target exons overlap significantly with autism-associated splicing changes
Cortical circuit miswiring due to NOVA2 dysfunction may contribute to ASD features
NOVA2 regulates splicing of multiple high-confidence ASD risk genes ([NRXN1](/genes/nrxn1), [SHANK3](/genes/shank3), [NLGN1](/genes/nlgn1))

Expression

Brain Distribution

NOVA2 shows a complementary pattern to NOVA1:

Cerebral cortex: Highest expression; all cortical layers, particularly layers II/III and V
Hippocampus: Strong expression in CA1–CA3 pyramidal neurons and dentate gyrus granule cells
Striatum: Moderate expression in medium spiny neurons
Amygdala: Moderate expression
Olfactory bulb: Moderate expression
Thalamus: Low-moderate expression
Cerebellum: Minimal (NOVA1 predominates)
Brainstem/spinal cord: Minimal (NOVA1 predominates)

Cell Type Specificity

Primarily expressed in excitatory pyramidal neurons
Lower expression in inhibitory interneurons (where NOVA1 may have greater relative contribution)
Endothelial expression (unique among neuronal splicing factors)
Not expressed in glia

Developmental Trajectory

Expression begins at ~E13.5 in mouse cortex, coinciding with the onset of cortical neurogenesis
Increases throughout postnatal development, peaking in young adulthood
Gradual decline with aging, potentially contributing to age-related splicing changes

Therapeutic Implications

RNA-Targeted Therapies

Antisense oligonucleotides (ASOs): Correction of specific NOVA2-regulated mis-splicing events in AD could restore synaptic function without needing to rescue NOVA2 itself

Splice-switching oligonucleotides (SSOs): Targeting individual NOVA2-dependent exons in disease-relevant transcripts

NOVA2 expression restoration: Gene therapy or small molecules to maintain NOVA2 levels during aging and disease

Diagnostic Applications

NOVA2-dependent splicing signatures in CSF exosomal RNA as biomarkers for cortical neurodegeneration
Blood-based splicing biomarkers leveraging NOVA2's endothelial expression

Key Publications

[Ule et al., An RNA map predicting Nova-dependent splicing regulation (2006)](https://pubmed.ncbi.nlm.nih.gov/16998473/)

[Saito et al., NOVA2-mediated RNA regulation is required for axonal pathfinding during development (2016)](https://pubmed.ncbi.nlm.nih.gov/27185892/)

[Licatalosi et al., HITS-CLIP yields genome-wide insights into brain alternative RNA processing (2008)](https://pubmed.ncbi.nlm.nih.gov/18978215/)

External Links

[NCBI Gene: NOVA2](https://www.ncbi.nlm.nih.gov/gene/4858)
[UniProt: Q9UNW9](https://www.uniprot.org/uniprot/Q9UNW9)
[OMIM: 601991](https://omim.org/entry/601991)
[GeneCards: NOVA2](https://www.genecards.org/cgi-bin/carddisp.pl?gene=NOVA2)

References

[Ule et al., An RNA map predicting Nova-dependent splicing regulation (2006) (2006)](https://pubmed.ncbi.nlm.nih.gov/16998473/)

[Saito et al., NOVA2-mediated RNA regulation is required for axonal pathfinding during development (2016) (2016)](https://pubmed.ncbi.nlm.nih.gov/27185892/)

[Yang et al., Cloning and characterization of NOVA2, a neuron-specific RNA-binding protein (1998) (1998)](https://pubmed.ncbi.nlm.nih.gov/9560382/)

[Giampietro et al., The alternative splicing factor Nova2 regulates vascular development and lumen formation (2015) (2015)](https://pubmed.ncbi.nlm.nih.gov/26609816/)

[Unknown, Raj & Bhatt, Integrative transcriptomic analysis of the NOVA1-regulated network in Alzheimer's disease brain (2018) (2018)](https://pubmed.ncbi.nlm.nih.gov/29959142/)

[Bhatt et al., NOVA2 mutations in epileptic encephalopathy (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32503736/)

[Licatalosi et al., HITS-CLIP yields genome-wide insights into brain alternative RNA processing (2008) (2008)](https://pubmed.ncbi.nlm.nih.gov/18978215/)

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Related Entities

NOVA2

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-nova2
kg_node_id	NOVA2
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-f08effdae01d
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-nova2'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

40%

Debates

0

Incoming

8

Outgoing

9

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

NOVA2 — NOVA Alternative Splicing Regulator 2

NOVA2 — NOVA Alternative Splicing Regulator 2

NOVA2 — NOVA Alternative Splicing Regulator 2

NOVA2 — NOVA Alternative Splicing Regulator 2

Overview

Gene Structure and Protein Products

Genomic Organization

Protein Structure

Functional Differences from NOVA1

Function

Cortical Splicing Regulation

Key Cortical Splicing Targets

Cortical Development

Vascular Development

Alternative Polyadenylation

Disease Associations

Alzheimer's Disease

Huntington's Disease

Epilepsy

Autism Spectrum Disorder

Expression

Brain Distribution

Cell Type Specificity

Developmental Trajectory

Therapeutic Implications

RNA-Targeted Therapies

Diagnostic Applications

Key Publications

See Also

External Links

References

💬 Discussion