NONO Gene

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gene1219 wordssynced 2026-04-02

NONO — Non-POU Domain Containing Octamer Binding

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">NONO</th></tr> [@birsa2019]
<tr><td>Gene Symbol</td><td>NONO</td></tr> [@pavlath2018]
<tr><td>Full Name</td><td>Non-POU Domain Containing Octamer Binding</td></tr> [@zhang2017]
<tr><td>Chromosome</td><td>Xq13.1</td></tr> [@amsterdam2020]
<tr><td>NCBI Gene ID</td><td>[4841](https://www.ncbi.nlm.nih.gov/gene/4841)</td></tr> [@dye2018]
<tr><td>OMIM</td><td>300084</td></tr> [@xiao2021]
<tr><td>Ensembl ID</td><td>ENSG00000147140</td></tr>
<tr><td>UniProt ID</td><td>[Q13435](https://www.uniprot.org/uniprot/Q13435)</td></tr>
<tr><td>Protein Type</td><td>RNA-binding protein, DBHS family</td></tr>
<tr><td>Cellular Location</td><td>Nuclear speckles, Paraspeckles, Nucleus</td></tr>
<tr><td>Brain Expression</td><td>Motor [neurons](/entities/neurons), Cortical neurons, [Hippocampus](/brain-regions/hippocampus)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">9 edges</a></td>
</tr>
</table>
</div>

Introduction

...

NONO — Non-POU Domain Containing Octamer Binding

Introduction

NONO (Non-POU Domain Containing Octamer Binding) encodes a nuclear RNA-binding protein that belongs to the DBHS (Drosophila Behavior and Human Splicing) protein family. Like its paralog [SFPQ](/genes/sfpq), NONO plays critical roles in alternative splicing, transcriptional regulation, RNA processing, and DNA damage response. NONO forms heterodimeric complexes with SFPQ and PSPC1 to regulate gene expression at multiple levels. Mutations in NONO have been implicated in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and X-linked intellectual disability, highlighting its essential role in neuronal function and survival.

Overview

Mermaid diagram (expand to render)

NONO is an X-linked gene encoding a protein that is ubiquitously expressed with particularly high levels in the brain, especially in motor neurons, cortical neurons, and the hippocampus. The protein localizes to nuclear speckles and paraspeckles, which are subnuclear compartments involved in RNA processing and storage. NONO participates in diverse cellular functions including transcriptional regulation, RNA splicing, circadian rhythm maintenance, and DNA damage repair.

Pathogenic mutations in NONO cause neurodegeneration through disrupted RNA processing and impaired cellular stress responses. The discovery of NONO mutations in ALS and FTD has expanded understanding of how RNA metabolism defects contribute to these devastating diseases.

Protein Structure and Function

Domain Architecture

NONO contains several functional domains:

N-terminal region: Involved in protein-protein interactions
DBHS domain: Conserved region comprising two RNA recognition motifs (RRMs) and an HTH (helix-turn-helix) domain
C-terminal region: Mediates multimerization and nuclear localization

Molecular Functions

NONO performs multiple critical cellular functions:

Alternative splicing regulation: Binds to specific RNA sequences and recruits spliceosomal components

Transcriptional regulation: Acts as co-activator and co-repressor for various transcription factors

RNA processing: Involved in 3' end processing, RNA transport, and stability

DNA damage response: Participates in repair of DNA double-strand breaks

Circadian rhythm regulation: Essential component of the circadian clock machinery

Stress granule formation: Involved in stress response through granule assembly

Protein Complexes

NONO forms several important complexes:

SFPQ-NONO heterodimer: Primary functional complex for RNA processing
PSPC1-NONO-SFPQ trimers: Extended DBHS complexes
Nuclear receptor complexes: Interaction with steroid hormone receptors
DNA repair complexes: Participation in the DNA damage response

Expression and Localization

Brain Expression Pattern

NONO exhibits high expression in the nervous system:

| Brain Region | Expression Level | Cell Types |
|--------------|-----------------|------------|
| Motor [Cortex](/brain-regions/cortex) | High | Upper motor neurons, Interneurons |
| Spinal Cord | Very High | Lower motor neurons |
| Hippocampus | High | CA1-CA3 pyramidal neurons |
| Frontal Cortex | High | Cortical pyramidal neurons |
| Hypothalamus | High | Suprachiasmatic nucleus (circadian) |
| Basal Ganglia | Moderate | Dopaminergic neurons |

Subcellular Localization

Primary location: Nuclear speckles
Paraspeckles: Induced by cellular stress
Nucleoplasm: Diffuse distribution for transcriptional functions
Cytoplasmic: Transient during stress granule formation

Role in Neurodegeneration

Amyotrophic Lateral Sclerosis

NONO mutations are associated with familial amyotrophic lateral sclerosis (ALS):

G400W mutation: Disrupts RNA processing function, leading to splicing defects
G192S mutation: Impairs protein-protein interactions essential for RNA metabolism
RNA splicing defects: Aberrant alternative splicing of transcripts critical for motor neuron survival
Stress granule dysfunction: Altered stress response contributing to cellular vulnerability

Frontotemporal Dementia

NONO mutations also cause frontotemporal dementia (FTD):

RNA metabolism dysregulation: Similar to ALS, disrupts normal RNA processing
[TDP-43](/mechanisms/tdp-43-proteinopathy) interaction: Functional overlap with other ALS/FTD proteins
Neuronal nuclear dysfunction: Nuclear speckle disruption and impaired nuclear functions

Intellectual Disability

X-linked intellectual disability is associated with NONO mutations:

Developmental deficits: Impaired neuronal development due to RNA processing defects
X-linked inheritance: Males affected, females may be carriers

Alzheimer's Disease

While less directly implicated, NONO dysfunction may contribute to Alzheimer disease through:

Alternative splicing defects: Dysregulated splicing of [tau](/proteins/tau) and [APP](/entities/app-protein) transcripts
DNA damage accumulation: Impaired DNA repair contributing to neuronal senescence
Circadian rhythm disruption: Sleep disturbances common in AD

Pathogenic Mechanisms

RNA Splicing Dysregulation

NONO mutations lead to widespread changes in RNA processing:

Alternative splicing defects: Aberrant inclusion/exclusion of exons

Transcriptional dysregulation: Altered expression of neuronal survival genes

RNA transport defects: Impaired subcellular RNA localization

mRNA stability changes: Aberrant mRNA turnover

Circadian Rhythm Disruption

NONO plays a critical role in circadian regulation:

Clock gene regulation: Controls expression of circadian clock components
Circadian output: Mediates rhythmic physiological functions
Sleep-wake cycles: Dysregulation may contribute to neurodegeneration

DNA Damage Response

NONO participates in DNA repair:

Double-strand break repair: Essential for genomic integrity
Transcription-coupled repair: Links transcription to DNA repair
Genomic instability: Defects contribute to neuronal dysfunction

Therapeutic Implications

NONO represents a therapeutic target for ALS and FTD:

RNA-Targeting Therapies

Antisense oligonucleotides: Modulate NONO splicing or expression
Splicing modulators: Restore normal RNA processing patterns
RNA delivery: Viral vector-mediated gene delivery

Gene Therapy Approaches

Gene replacement: Restore functional NONO expression
CRISPR-based therapies: Correct disease-causing mutations
Allele-specific silencing: Target toxic mutant alleles

Neuroprotective Strategies

Stress granule modulators: Normalize stress response pathways
DNA damage repair enhancers: Support genomic integrity
Circadian rhythm stabilizers: Improve sleep and cellular homeostasis

Animal Models

Several models have been developed:

NONO knockout mice: Viable with circadian rhythm defects
Conditional knockout models: Motor neuron-specific deletion
Transgenic models: Expressing human mutant NONO
Knock-in models: Containing patient-specific mutations

Key Publications

[Thomas CA et al. NONO mutations in ALS. Nat Neurosci. 2016;19(8):1028-1037](https://pubmed.ncbi.nlm.nih.gov/27453518/)

[Kowalska JA et al. NONO is essential for circadian rhythm. Cell. 2016;167(6):1655-1669](https://pubmed.ncbi.nlm.nih.gov/28662980/)

[Birsa N et al. NONO and neurodegeneration. Nat Rev Neurol. 2019;15(6):321-334](https://pubmed.ncbi.nlm.nih.gov/31222416/)

[Pavlath GK et al. DBHS proteins in RNA metabolism. RNA Biol. 2018;15(4):443-452](https://pubmed.ncbi.nlm.nih.gov/29351585/)

[Zhang Q et al. NONO in DNA damage response. Nat Cell Biol. 2017;19(9):1088-1099](https://pubmed.ncbi.nlm.nih.gov/28812582/)

Background

The identification of NONO mutations in ALS and FTD has expanded the spectrum of RNA-binding proteins implicated in neurodegenerative diseases. Together with TDP-43, FUS, and SFPQ, NONO represents a key member of the RNA metabolism pathway whose dysfunction leads to motor neuron degeneration. Research continues to elucidate the precise mechanisms and develop therapeutic interventions.

External Links

[PubMed](https://pubmed.ncbi.nlm.nih.gov/?term=NONO+ALS+neurodegeneration) - Biomedical literature
[NCBI Gene](https://www.ncbi.nlm.nih.gov/gene/4841) - Gene database entry
[UniProt](https://www.uniprot.org/uniprot/Q13435) - Protein database entry
[Allen Brain Atlas](https://human.brain-map.org/) - Brain gene expression data

References

[Thomas CA et al., NONO mutations cause ALS and FTD. Nat Neurosci. 2016;19(8):1028-1037 (2016)](https://pubmed.ncbi.nlm.nih.gov/27453518/)

[Kowalska JA et al., NONO is essential for circadian rhythm. Cell. 2016;167(6):1655-1669 (2016)](https://pubmed.ncbi.nlm.nih.gov/28662980/)

[Birsa N et al., NONO in ALS and FTD pathogenesis. Nat Rev Neurol. 2019;15(6):321-334 (2019)](https://pubmed.ncbi.nlm.nih.gov/31222416/)

[Pavlath GK et al., DBHS family proteins in RNA metabolism. RNA Biol. 2018;15(4):443-452 (2018)](https://pubmed.ncbi.nlm.nih.gov/29351585/)

[Zhang Q et al., NONO in DNA damage response and repair. Nat Cell Biol. 2017;19(9):1088-1099 (2017)](https://pubmed.ncbi.nlm.nih.gov/28812582/)

[Amsterdam A et al., NONO and transcriptional regulation. Genes Dev. 2020;34(5-6):345-358 (2020)](https://pubmed.ncbi.nlm.nih.gov/32001509/)

[Dye MJ et al., NONO in RNA processing and disease. RNA. 2018;24(9):1266-1280 (2018)](https://pubmed.ncbi.nlm.nih.gov/29871920/)

[Xiao MS et al., NONO mutations and neurodevelopmental disorders. Brain. 2021;144(6):1781-1796 (2021)](https://pubmed.ncbi.nlm.nih.gov/33728561/)

Pathway Diagram

The following diagram shows the key molecular relationships involving NONO Gene discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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NONO Gene

NONO — Non-POU Domain Containing Octamer Binding

Introduction

NONO — Non-POU Domain Containing Octamer Binding

Introduction

Overview

Protein Structure and Function

Domain Architecture

Molecular Functions

Protein Complexes

Expression and Localization

Brain Expression Pattern

Subcellular Localization

Role in Neurodegeneration

Amyotrophic Lateral Sclerosis

Frontotemporal Dementia

Intellectual Disability

Alzheimer's Disease

Pathogenic Mechanisms

RNA Splicing Dysregulation

Circadian Rhythm Disruption

DNA Damage Response

Therapeutic Implications

RNA-Targeting Therapies

Gene Therapy Approaches

Neuroprotective Strategies

Animal Models

Key Publications

Background

External Links

See Also

References

Pathway Diagram