MSH6 — MutS Homolog 6

MSH6 — MutS Homolog 6

Introduction

Msh6 — Muts Homolog 6 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

<!-- Gene Infobox -->
<div class="infobox infobox-gene">
<div class="infobox-header">MSH6</div>
<div class="infobox-content">
<table>
<tr><th>Full Name</th><td>MutS Homolog 6</td></tr>
<tr><th>Synonyms</th><td>MSH6, mutS homolog 6, GTRAP</td></tr>
<tr><th>Chromosome</th><td>2p16.3</td></tr>
<tr><th>NCBI Gene ID</th><td>4433</td></tr>
<tr><th>OMIM</th><td>604928</td></tr>
<tr><th>Ensembl ID</th><td>ENSG00000182162</td></tr>
<tr><th>UniProt ID</th><td>P53271</td></tr>
<tr><th>Protein</th><td>[MSH6 Protein](/proteins/msh6-protein)</td></tr>
<tr><th>Associated Diseases</th><td>Lynch Syndrome, Alzheimer's Disease, Parkinson's Disease, ALS</td></tr>
</table>
</div>
</div>

Overview

MSH6 — MutS Homolog 6

Introduction

Msh6 — Muts Homolog 6 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

<!-- Gene Infobox -->
<div class="infobox infobox-gene">
<div class="infobox-header">MSH6</div>
<div class="infobox-content">
<table>
<tr><th>Full Name</th><td>MutS Homolog 6</td></tr>
<tr><th>Synonyms</th><td>MSH6, mutS homolog 6, GTRAP</td></tr>
<tr><th>Chromosome</th><td>2p16.3</td></tr>
<tr><th>NCBI Gene ID</th><td>4433</td></tr>
<tr><th>OMIM</th><td>604928</td></tr>
<tr><th>Ensembl ID</th><td>ENSG00000182162</td></tr>
<tr><th>UniProt ID</th><td>P53271</td></tr>
<tr><th>Protein</th><td>[MSH6 Protein](/proteins/msh6-protein)</td></tr>
<tr><th>Associated Diseases</th><td>Lynch Syndrome, Alzheimer's Disease, Parkinson's Disease, ALS</td></tr>
</table>
</div>
</div>

Overview

MSH6 (MutS Homolog 6) is a DNA mismatch repair (MMR) protein that partners with MSH2 to form the MutSalpha complex, which initiates the repair of base-base mismatches and small insertion/deletion loops. MSH6 plays a crucial role in maintaining genomic integrity in proliferating and post-mitotic cells, including [neurons](/entities/neurons). Mutations in MSH6 cause Lynch syndrome (hereditary nonpolyposis colorectal cancer), and altered MSH6 expression has been implicated in the DNA repair deficits observed in neurodegenerative diseases.

Normal Function

MSH6 forms a heterodimer with MSH2 (MutSα):

MutSα Functions

Brain-Specific Roles

• Neuronal DNA repair: Active base excision repair and MMR in post-mitotic neurons
• Somatic mutation prevention: Prevents accumulation of mutations in long-lived neurons
• Transcriptional fidelity: Maintains accuracy of gene expression

Role in Neurodegenerative Diseases

Alzheimer's Disease

MSH6 and DNA repair in AD:

• Neuronal MSH6 expression declines with age
• Accumulation of DNA mismatches in AD brain
• MSH6 protein levels reduced in AD temporal [cortex](/brain-regions/cortex)
• Impaired MMR contributes to genomic instability

Parkinson's Disease

• Dopaminergic neurons accumulate mitochondrial DNA mutations
• MSH6 may compensate for other repair deficiencies
• Oxidative stress overwhelms MMR capacity

Amyotrophic Lateral Sclerosis

• Motor neurons show DNA repair deficits
• MSH6 dysfunction may contribute to [TDP-43](/proteins/tdp-43) pathology
• DNA damage response is impaired in ALS

Therapeutic Targeting

Strategies

• Enhance MSH6 expression through transcriptional activation
• Reduce oxidative stress to decrease DNA damage burden
• Gene therapy approaches to restore MMR function

Animal Models

• Msh6 knockout mice: Viable but tumor-prone
• Conditional neuronal knockout: DNA damage accumulation
• Transgenic overexpression: Enhanced DNA repair capacity

Role in Mismatch Repair

MSH6 partners with MSH2 to form the MutSα complex, which initiates mismatch repair by recognizing base-base mismatches and small insertion/deletion loops. MSH6 contains a PCNA-interacting peptide (PIP) motif that tethers the complex to replicating DNA, ensuring repair occurs on the newly synthesized strand.

Substrate Specificity

• Primary recognition of base-base mismatches
• Sensitivity to single base substitutions
• Cooperation with MSH3 for larger loops

PCNA Interaction

• Direct binding to proliferating cell nuclear antigen
• Coordinated repair with DNA polymerase δ
• Ensures strand specificity of repair

Transcriptional Regulation

MSH6 expression is tightly regulated:

Transcriptional Control

• p53-dependent activation following DNA damage
• Regulation by E2F transcription factors
• Cell cycle-dependent expression

Epigenetic Regulation

• Promoter methylation in some cancers
• [Histone modifications](/entities/histone-modifications) affect MSH6 expression
• Post-translational modifications (phosphorylation, acetylation)

Cancer Predisposition

Lynch Syndrome

• MSH6 mutations cause Lynch syndrome
• Later onset than MSH2/MLH1 mutations
• Variable penetrance and cancer spectrum

Phenotype Characteristics

• Colorectal cancer mean age: ~60 years
• Endometrial cancer prominent
• Reduced penetrance compared to other LS genes

MSH6 Variant Classification

• Pathogenic variants: clear cancer risk
• Variants of uncertain significance (VUS): challenging interpretation
• Missense mutations: often functionally neutral

Clinical Management

Surveillance

• Colonoscopy beginning at age 25-30
• Endometrial cancer screening for women
• Upper GI endoscopy consideration

Therapeutic Approaches

• Immunotherapy for MSI-H tumors
• Aspirin chemoprevention studies
• Regular monitoring for early detection

Animal Models

| Model | Phenotype | Key Findings |
|-------|-----------|--------------|
| Msh6 knockout mice | Viable with tumors | Cancer predisposition model |
| Conditional knockout | Tissue-specific | Gastrointestinal cancers |
| Msh6 knock-in | Variable | Missense variants studied |

Disease Associations

Top DisGeNET gene-disease associations for this gene are listed below. Scores are numeric DisGeNET association scores (`score_max`) from the consolidated DisGeNET disease-gene association table; higher values indicate stronger aggregated evidence.

| Disease | DisGeNET score | Evidence sources | Supporting PMID count |
|---|---:|---|---:|
| uterine cancer | 0.224 | BeFree/CTD_human/GAD/LHGDN | 47 |
| lung cancer | 0.210 | CTD_human | 1 |
| IgA glomerulonephritis | 0.210 | CTD_human | 1 |
| breast cancer | 0.015 | BeFree/GAD | 15 |
| urinary bladder cancer | 0.010 | BeFree/GAD | 5 |

Source: DisGeNET-derived consolidated disease-gene associations (`dhimmel/disgenet`, gene symbol `MSH6`).

See Also

• [MSH2 Gene](/proteins/msh2-protein)
• [MLH1 Gene](/mlh1-gene)
• [DNA Damage Response Pathway](/mechanisms/dna-damage-response)
• [Oxidative Stress Pathway](/mechanisms/oxidative-stress-pathway)

External Links

• [NCBI Gene: MSH6](https://www.ncbi.nlm.nih.gov/gene/4433)
• [UniProt: MSH6](https://www.uniprot.org/uniprot/P53271)
• [CIViC: MSH6 variants](https://civicdb.org/variants/102)
• [PubMed Search: MSH6 neurodegeneration](https://pubmed.ncbi.nlm.nih.gov/?term=MSH6+neurodegeneration)

Background

The study of Msh6 — Muts Homolog 6 has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

References

^[1] Li GM. Cell Res. 2008;18(1):85-98. PMID: 18166976(https://pubmed.ncbi.nlm.nih.gov/18166976/)

^[2] Edelmann W, et al. Cold Spring Harb Symp Quant Biol. 2000;65:217-224. PMID: 12869748(https://pubmed.ncbi.nlm.nih.gov/12869748/)

^[3] Kruman II, et al. J Neurosci. 2004;24(33):7392-7399. PMID: 15317865(https://pubmed.ncbi.nlm.nih.gov/15317865/)

^[4] Suberbielle E, et al. Nat Neurosci. 2013;16(10):1506-1514. PMID: 24056795(https://pubmed.ncbi.nlm.nih.gov/24056795/)

^[5] Chen J, et al. J Mol Neurosci. 2020;70(12):1933-1946. PMID: 32803784(https://pubmed.ncbi.nlm.nih.gov/32803784/)

Pathway Diagram

The following diagram shows the key molecular relationships involving MSH6 — MutS Homolog 6 discovered through SciDEX knowledge graph analysis: