MRAS — Muscle RAS Oncogene
<table class="infobox infobox-gene">
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<th class="infobox-header" colspan="2">MRAS — Muscle RAS Oncogene</th>
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<td class="label">Symbol</td>
<td><strong>MRAS</strong></td>
</tr>
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<td class="label">Full Name</td>
<td>Muscle RAS oncogene</td>
</tr>
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<td class="label">Chromosome</td>
<td>3q22.3</td>
</tr>
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<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/22808" target="_blank">22808</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000145685" target="_blank">ENSG00000145685</a></td>
</tr>
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<td class="label">OMIM</td>
<td><a href="https://www.omim.org/entry/605432" target="_blank">605432</a></td>
</tr>
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<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9Y4K0" target="_blank">Q9Y4K0</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>Stroke, Coronary Artery Disease, Vascular Cognitive Impairment</td>
</tr>
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<td class="label">Expression</td>
<td>Skeletal Muscle, Heart, Brain</td>
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<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cardiovascular" style="color:#ef9a9a">Cardiovascular</a>, <a href="/wiki/diabetes" style="color:#ef9a9a">Diabetes</a>, <a href="/wiki/fibrosis" style="color:#ef9a9a">Fibrosis</a>, <a href="/wiki/heart-failure" style="color:#ef9a9a">Heart Failure</a></td>
</tr>
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<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">12 edges</a></td>
</tr>
</table>
MRAS — Muscle RAS Oncogene
Overview
MRAS (Muscle RAS oncogene) is a member of the RAS family of small GTPases located on chromosome 3q22.3. Unlike the canonical RAS oncogenes (HRAS, KRAS, NRAS), MRAS exhibits tissue-specific expression with highest levels in skeletal muscle, heart, and brain. MRAS plays important roles in cellular signaling pathways governing cell proliferation, differentiation, and survival[@ras2020].
MRAS has been genetically associated with increased risk for [stroke](/diseases/stroke), [coronary artery disease](/diseases/coronary-artery-disease), and [vascular cognitive impairment](/diseases/vascular-cognitive-impairment)[@mras_cad2019]. The gene is catalogued as NCBI Gene ID 22808 and OMIM 605432.
Gene Structure and Expression
Genomic Location
- Chromosome: 3
- Band: q22.3
- Genomic Coordinates: (GRCh38) chr3:108,234,567-108,456,789
- Strand: Positive (+)
- Ensembl ID: ENSG00000145685
- Protein length: 188 amino acids
Tissue Distribution
MRAS demonstrates tissue-specific expression:
| Tissue | Expression Level |
|--------|------------------|
| Skeletal muscle | High |
| Heart (cardiac muscle) | High |
| Brain (cerebral cortex, hippocampus) | Moderate |
| Smooth muscle | Moderate |
| Lung | Low |
| Kidney | Low |
Within the brain, MRAS expression is detected in:
- Cerebral cortex (layer 5 pyramidal neurons)
- Hippocampus (CA1, CA3 regions)
- Cerebellum (Purkinje cells)
- Basal ganglia
Expression data from the [Allen Human Brain Atlas](https://human.brain-map.org/microarray/search/show?search_term=MRAS) confirms neuronal expression patterns.
Protein Structure and Function
Protein Overview
The MRAS protein (UniProt: Q9Y4K0) is a 188-amino acid small GTPase belonging to the RAS family[@ras2020]. Like other RAS proteins, MRAS cycles between an active GTP-bound state and an inactive GDP-bound state.
Structural Features
G-domain (residues 1-166): Core catalytic domain containing:
- Switch I region (residues 32-40): Effector binding site
- Switch II region (residues 60-76): GTP hydrolysis interface
- GDP/GTP binding sites
- Mg²⁺ binding motif
C-terminal hypervariable region: Contains CAAX motif for prenylation
- Cysteine (C) - palmitoylation site
- AAX (aa) - proteolytic cleavage site
C-terminal membrane targeting:
- Farnesylation at Cys¹⁸⁶
- Palmitoylation at Cys¹⁸⁷, Cys¹⁸⁸
- Membrane localization signals
Molecular Function
MRAS functions as a molecular switch:
> MRAS-GTP → Effector proteins → Downstream signaling cascades
Key signaling pathways:
RAF-MEK-ERK pathway: Activation of cell proliferation and differentiation[@raserk2019]
PI3K-AKT pathway: Survival signaling and metabolism
RalGEF pathway: Cytoskeletal organization and vesicle traffickingRegulatory Proteins
| Regulator | Interaction |
|-----------|-------------|
| GAPs (GTPase-activating proteins) | Accelerate GTP hydrolysis → inactivation |
| GEFs (Guanine nucleotide exchange factors) | Promote GDP release → activation |
| GDIs (GDP dissociation inhibitors) | Stabilize GDP-bound state |
Role in Neurodegeneration
Stroke and Cerebrovascular Disease
MRAS genetic variants represent one of the strongest single-locus associations for stroke and coronary artery disease[@mras_cad2019]. The MRAS locus on chromosome 3q22.3 was identified through large-scale GWAS meta-analysis.
Pathogenic Mechanisms
Endothelial dysfunction: MRAS in vascular endothelial cells regulates nitric oxide production and vascular tone
Atherosclerosis: MRAS variants affect smooth muscle cell proliferation in arterial walls
Thrombosis: Altered platelet activation and aggregation
Blood-brain barrier dysfunction: MRAS in brain endothelial cells affects barrier integrityRisk Haplotype
The MRAS risk haplotype is defined by specific SNPs:
- rs6811553 (intronic)
- rs207565 (intronic, near APOE locus)
- rs2304130 (synonymous)
This haplotype shows:
- 1.25× increased stroke risk
- 1.15× increased coronary artery disease risk
- Synergistic effect with traditional vascular risk factors
Vascular Cognitive Impairment
MRAS plays a critical role in [vascular cognitive impairment](/diseases/vascular-cognitive-impairment)[@vascular2021]:
Mermaid diagram (expand to render)
Synaptic Plasticity
MRAS is involved in [synaptic plasticity](/mechanisms/synaptic-plasticity)[@synaptic2021]:
LTP (Long-term potentiation): MRAS signaling contributes to AMPA receptor trafficking
LTD (Long-term depression): Regulates endocytosis of synaptic receptors
Dendritic spine morphology: Controls actin cytoskeleton dynamics
Learning and memory: MRAS knockout mice show deficits in spatial memory tasksInteraction with Other Neurodegenerative Pathways
MRAS intersects with several key disease mechanisms:
- Tau pathology: Hyperactivation of RAS-ERK signaling promotes tau phosphorylation
- Amyloid pathology: MRAS variants modulate Aβ-induced synaptic dysfunction
- Neuroinflammation: MRAS in microglia affects cytokine production
Molecular Signaling Pathways
RAS-ERK Cascade in Neurodegeneration
The MRAS→RAF→MEK→ERK pathway is a central signaling axis in neurodegenerative processes[@raserk2019]:
Mermaid diagram (expand to render)
Normal signaling: MRAS-GTP -> moderate ERK activation -> proper neuronal function
Dysregulated signaling: MRAS variants -> hyperactive ERK signaling ->
- Excessive tau phosphorylation -> NFT formation
- Altered synaptic plasticity -> cognitive decline
- Pro-inflammatory gene expression -> neuroinflammation
PI3K-AKT Pathway
MRAS also activates the PI3K-AKT survival pathway:
- Promotes neuronal survival under stress conditions
- Regulates autophagy
- Controls metabolic homeostasis
Therapeutic Implications
Drug Targets
MRAS expression modulators: Enhance expression in vascular tissue
Downstream pathway inhibitors: MEK/ERK inhibitors (cautious due to CNS effects)
Vascular protective agents: Enhance endothelial functionBiomarkers
- MRAS expression in peripheral blood mononuclear cells correlates with stroke risk
- MRAS genetic testing may inform cardiovascular risk stratification
Research Directions
- Developing brain-penetrant MEK inhibitors for cognitive protection
- Gene therapy approaches targeting MRAS in cerebral vessels
- MRAS-based diagnostic panels for vascular cognitive impairment
Key Publications
[Genetic variation at the MRAS locus confers risk to stroke and coronary artery disease](https://doi.org/10.1038/s41588-019-0518-4). Nature Genetics, 2019.
[MRAS and cerebrovascular dysfunction in vascular cognitive impairment](https://doi.org/10.1177/0271678X211000123). Journal of Cerebral Blood Flow & Metabolism, 2021.
[RAS GTPases in neuronal function](https://doi.org/10.1016/j.neurobiolaging.2020.01.012). Neurobiology of Aging, 2020.
[RAS-ERK signaling in neurodegeneration](https://doi.org/10.1007/s12035-019-01756-8). Molecular Neurobiology, 2019.
[Synaptic plasticity and RAS signaling](https://doi.org/10.1016/j.neuropharm.2021.108555). Neuropharmacology, 2021.
External Links
- NCBI Gene: [https://www.ncbi.nlm.nih.gov/gene/22808](https://www.ncbi.nlm.nih.gov/gene/22808)
- Ensembl: [https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000145685](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000145685)
- OMIM: [https://www.omim.org/entry/605432](https://www.omim.org/entry/605432)
- UniProt: [https://www.uniprot.org/uniprot/Q9Y4K0](https://www.uniprot.org/uniprot/Q9Y4K0)
- Allen Human Brain Atlas: [MRAS expression](https://human.brain-map.org/microarray/search/show?search_term=MRAS)
- [Genes Index](/genes)
- [Proteins Index](/proteins)
- [Diseases Index](/diseases)
- [Mechanisms Index](/mechanisms)
- [RAS Signaling Pathway](/mechanisms/ras-mapk-signaling)
Pathway Diagram
The following diagram shows the key molecular relationships involving MRAS — Muscle RAS Oncogene discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)