KMT2E Gene (Lysine Methyltransferase 2E)

KMT2E Gene (Lysine Methyltransferase 2E)

<div class="infobox infobox-gene">
<h3>KMT2E</h3>
<table>
<tr><th>Full Name</th><td>Lysine Methyltransferase 2E (MLL5)</td></tr>
<tr><th>Chromosome</th><td>7q22.1</td></tr>
<tr><th>NCBI Gene ID</th><td>[55973](https://www.ncbi.nlm.nih.gov/gene/55973)</td></tr>
<tr><th>OMIM</th><td>[607411](https://www.omim.org/entry/607411)</td></tr>
<tr><th>Ensembl ID</th><td>ENSG00000155438</td></tr>
<tr><th>UniProt</th><td>[Q9C0B1](https://www.uniprot.org/uniprot/Q9C0B1)</td></tr>
<tr><th>Gene Symbol</th><td>KMT2E</td></tr>
<tr><th>Category</th><td>Epigenetic Regulator / Histone Methyltransferase</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

KMT2E (Lysine Methyltransferase 2E), also historically known as MLL5 (Mixed-Lineage Leukemia 5), is a human gene located on chromosome 7q22.1 that encodes a histone H3K4 methyltransferase [1](https://www.ncbi.nlm.nih.gov/gene/55973). The protein is a member of the SET/MLL family of histone modifiers, which play critical roles in epigenetic regulation of gene expression during development, hematopoiesis, and nervous system function.[@mll_epigenetics]

KMT2E Gene (Lysine Methyltransferase 2E)

<div class="infobox infobox-gene">
<h3>KMT2E</h3>
<table>
<tr><th>Full Name</th><td>Lysine Methyltransferase 2E (MLL5)</td></tr>
<tr><th>Chromosome</th><td>7q22.1</td></tr>
<tr><th>NCBI Gene ID</th><td>[55973](https://www.ncbi.nlm.nih.gov/gene/55973)</td></tr>
<tr><th>OMIM</th><td>[607411](https://www.omim.org/entry/607411)</td></tr>
<tr><th>Ensembl ID</th><td>ENSG00000155438</td></tr>
<tr><th>UniProt</th><td>[Q9C0B1](https://www.uniprot.org/uniprot/Q9C0B1)</td></tr>
<tr><th>Gene Symbol</th><td>KMT2E</td></tr>
<tr><th>Category</th><td>Epigenetic Regulator / Histone Methyltransferase</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

KMT2E (Lysine Methyltransferase 2E), also historically known as MLL5 (Mixed-Lineage Leukemia 5), is a human gene located on chromosome 7q22.1 that encodes a histone H3K4 methyltransferase [1](https://www.ncbi.nlm.nih.gov/gene/55973). The protein is a member of the SET/MLL family of histone modifiers, which play critical roles in epigenetic regulation of gene expression during development, hematopoiesis, and nervous system function.[@mll_epigenetics]

KMT2E is distinguished from other MLL family members by its unique domain architecture and specific biological functions. The gene has been implicated in neurodevelopmental disorders, cognitive function, and emerging evidence suggests potential roles in neurodegenerative disease pathogenesis through dysregulation of epigenetic memory mechanisms essential for neuronal survival[@kmte_neurodev] [2](https://pubmed.ncbi.nlm.nih.gov/34298425/).

Molecular Function

Protein Structure

The KMT2E protein consists of multiple functional domains:

• PHD finger (Plant Homeodomain): A zinc finger domain that mediates protein-protein interactions and chromatin binding
• FYR domain: Found in transcription factors, involved in transcriptional activation
• SET domain: The catalytic domain responsible for histone methyltransferase activity
• TPR repeats: Tetratricopeptide repeats mediating protein-protein interactions
• N-terminal region: Contains sequences for nuclear localization and interaction with other chromatin regulators

Histone Methyltransferase Activity

KMT2E catalyzes mono-, di-, and tri-methylation of H3K4:

• H3K4me1: Enhancer-associated mark, important for regulatory element activation
• H3K4me3: Promoter-associated mark, correlates with gene activation
• H3K4me2: Intermediate mark with context-dependent functions

• Partner proteins that recruit KMT2E to specific genomic loci
• Post-translational modifications on KMT2E itself
• Cellular signaling pathways that modulate activity

Epigenetic Regulation

As an H3K4 methyltransferase, KMT2E participates in:

Tissue Expression

Brain Expression

KMT2E exhibits dynamic expression patterns in the nervous system:

• Cerebral cortex: High expression in pyramidal neurons across cortical layers, particularly abundant in layer 2/3 and layer 5
• Hippocampus: Strong expression in CA1-CA3 pyramidal neurons and dentate gyrus granule cells
• Cerebellum: Expression in Purkinje cells and granule cells
• Subventricular zone: Presence in neural progenitor cells
• Substantia nigra: Expression in dopaminergic neurons
• Brainstem: Various nuclei including the locus coeruleus

Expression in Other Tissues

Beyond the nervous system, KMT2E is expressed in:

• Hematopoietic system: High expression in bone marrow, particularly in hematopoietic stem cells
• Liver: Hepatocyte expression
• Kidney: Tubular epithelial cells
• Heart: Cardiomyocytes
• Testis: Germ cell development
• Ovary: Oocyte development

Biological Pathways

Neurodevelopment

KMT2E plays critical roles in brain development:

Cognitive Function

Epigenetic regulation by KMT2E impacts:

• Learning and memory: H3K4 methylation at plasticity-related genes
• Long-term potentiation: Regulation of synaptic strength-associated gene expression
• Behavior flexibility: Control of genes involved in adaptive behaviors
• Social cognition: Relevant to neurodevelopmental disorders

Hematopoiesis

KMT2E functions in blood cell development:

• Stem cell maintenance: Regulation of hematopoietic stem cell identity
• Lineage specification: Control of differentiation programs
• Epigenetic memory: Sustaining cell-type specific gene expression

Disease Associations

Neurodevelopmental Disorders

Intellectual Disability

KMT2E variants are associated with intellectual disability:

• De novo mutations: Identified in patients with non-syndromic intellectual disability
• Haploinsufficiency: Loss-of-function variants sufficient for phenotypic manifestation
• Phenotype: Variable cognitive impairment, sometimes with dysmorphic features [5](https://pubmed.ncbi.nlm.nih.gov/11774072/)

Autism Spectrum Disorder

• Genetic association: KMT2E variants identified in ASD patients
• Functional impact: Disruption of epigenetic regulation at synaptic genes
• Comorbidity: Frequently co-occurs with intellectual disability

Epilepsy

• Seizure susceptibility: Some KMT2E variants associated with epilepsy
• Mechanism: Dysregulation of neuronal excitability genes

Neurodegenerative Disease Relevance

Alzheimer's Disease

Emerging evidence links KMT2E to AD pathogenesis:

• Epigenetic dysregulation: H3K4 methylation patterns altered in AD brain
• Gene expression changes: KMT2E expression levels correlate with disease progression
• Tau pathology: Interactions with tau-mediated transcriptional dysregulation
• Synaptic dysfunction: Role in maintaining synaptic plasticity gene expression [6](https://pubmed.ncbi.nlm.nih.gov/14534367/)

Parkinson's Disease

• Dopaminergic neuron vulnerability: KMT2E may protect dopaminergic neurons
• Epigenetic aging: Changes in H3K4 methylation with age
• LRRK2 interaction: Potential convergence on transcriptional regulation [7](https://pubmed.ncbi.nlm.nih.gov/11159937/)

Amyotrophic Lateral Sclerosis

• Motor neuron function: KMT2E regulates genes important for motor neuron survival
• Epigenetic dysregulation: Altered H3K4me patterns in ALS models

Huntington's Disease

• Transcriptional dysfunction: KMT2E may contribute to transcriptional dysregulation
• Epigenetic therapy target: Modulating KMT2E activity could restore gene expression

Cancer Associations

• Hematological malignancies: KMT2E alterations in some leukemias
• Solid tumors: Reduced expression in various carcinomas
• Tumor suppressor function: Potential role in maintaining cellular identity

Interacting Partners

KMT2E interacts with various proteins:

| Partner | Interaction Type | Functional Significance |
|---------|-----------------|------------------------|
| PAXIP1/PTIP | Direct binding | Complex for H3K4 methylation |
| NCOA3 | Direct binding | Transcriptional co-activation |
| CREBBP | Direct binding | Histone acetyltransferase cooperation |
| MLLT10/AF10 | Direct binding | Chromatin targeting |
| RBBP5 | Direct binding | Core complex component |
| WDR5 | Direct binding | Complex assembly |
| BDP1 | Direct binding | Transcription factor interactions |

Mechanism in Neurodegeneration

Epigenetic Dysregulation Hypothesis

KMT2E dysfunction may contribute to neurodegeneration through several mechanisms:

Clinical Significance

Genetic Testing

KMT2E testing is available for:

• Neurodevelopmental disorders: Developmental delay, intellectual disability
• Autism spectrum disorder: When associated with KMT2E variants
• Family studies: Determining inheritance patterns

Variant Types

Pathogenic variants in KMT2E include:

• Missense variants: Often in PHD finger or SET domain
• Truncating variants: Nonsense and frameshift mutations
• Splice site variants: Aberrant mRNA processing
• Large deletions: Encompassing KMT2E and neighboring genes

Therapeutic Approaches

Current strategies:

• Epigenetic therapy: Small molecules targeting H3K4 methylation
• Gene therapy: Viral vector-mediated KMT2E expression
• Combination approaches: Synergy with other epigenetic modulators

Research Directions

Key Questions

Ongoing Studies

• iPSC models: Neuronal differentiation from patient-derived cells
• CRISPR screens: Identifying synthetic lethal partners
• Epigenetic editing: Using dCas9-KMT2E to restore gene expression

Animal Models

Knockout Mice

• Kmt2e-null mice: Viable but with cognitive deficits
• Conditional knockouts: Brain-specific deletion reveals learning/memory defects
• Phenotypes: Impaired spatial learning, reduced synaptic plasticity

Key Publications

Synaptic Function and Plasticity

Role at the Synapse

KMT2E plays a crucial role in synaptic function through epigenetic regulation of synaptic plasticity genes [11](https://pubmed.ncbi.nlm.nih.gov/29464154/):

• Synaptic protein expression: KMT2E regulates genes encoding synaptic vesicle proteins, neurotransmitter receptors, and scaffold proteins
• Postsynaptic density: Controls PSD-95, NMDA receptor subunits, and AMPA receptor trafficking proteins
• Presynaptic function: Regulates synaptophysin, synaptotagmin, and other presynaptic proteins
• Synapse formation: Essential for synaptogenesis during development

Activity-Dependent Regulation

Neuronal activity modulates KMT2E function [21](https://pubmed.ncbi.nlm.nih.gov/26590306/):

• Calcium signaling: Activity-dependent calcium influx activates signaling pathways that regulate KMT2E
• Transcription factor recruitment: Activity-regulated transcription factors recruit KMT2E to plasticity genes
• Histone modification dynamics: KMT2E-mediated H3K4me3 increases at immediate-early genes
• Memory consolidation: Role in stabilizing transcription-dependent memory traces

Long-Term Potentiation and Depression

KMT2E contributes to LTP and LTD through epigenetic mechanisms [15](https://pubmed.ncbi.nlm.nih.gov/22174167/):

• LTP induction: KMT2E is required for proper expression of LTP-associated genes
• LTD maintenance: Epigenetic reprogramming during LTD involves KMT2E
• Synaptic strengthening: H3K4me3 marks at synaptic plasticity genes
• Synaptic scaling: Regulation of homeostatic plasticity genes

Molecular Signaling Pathways

Chromatin Complexes

KMT2E functions as part of larger chromatin-regulating complexes:

Core Complex:

• COMPASS-like complex: KMT2E associates with WDR5, RBBP5, ASH2L
• PAXIP1/PTIP complex: Recruits KMT2E to DNA damage response sites
• MLL3/4-like functions: KMT2E shares functional redundancy with MLL3 and MLL4

• NCOA3 (SRC-3): Histone acetyltransferase co-activator
• CREBBP (CBP): Acetyltransferase for histone H3/H4
• MLLT10 (AF10): Transcription factor that recruits KMT2E

Signaling Cascades

KMT2E is regulated by multiple signaling pathways:

Detailed Disease Mechanisms

Alzheimer's Disease Pathogenesis

KMT2E dysfunction contributes to AD through multiple interconnected mechanisms [6](https://pubmed.ncbi.nlm.nih.gov/14534367/) [23](https://pubmed.ncbi.nlm.nih.gov/28934125/):

Epigenetic Alterations:

• Reduced H3K4me3 at synaptic plasticity genes
• Aberrant methylation patterns at disease-associated loci
• Impaired activation of neuroprotective genes

• Downregulation of synaptic protein genes
• Altered expression of APP processing genes
• Dysregulation of tau phosphorylation regulators

• Epigenetic drugs targeting H3K4 methylation
• Gene activation strategies to restore synaptic gene expression
• Combination approaches with disease-modifying therapies

Parkinson's Disease Mechanisms

KMT2E may protect dopaminergic neurons through several pathways [7](https://pubmed.ncbi.nlm.nih.gov/11159937/):

Dopaminergic Neuron Survival:

• Regulation of mitochondrial function genes
• Control of oxidative stress response genes
• Maintenance of dopamine biosynthesis pathway

• Convergence on transcriptional regulation
• Shared target genes in dopaminergic neurons
• Potential synergistic therapeutic targeting

Amyotrophic Lateral Sclerosis

KMT2E alterations in ALS affect motor neuron function:

• RNA metabolism: Dysregulation of RNA processing genes
• Protein homeostasis: Altered expression of autophagy genes
• Cytoskeletal function: Changes in cytoskeletal protein genes
• Nuclear integrity: Impaired DNA repair gene expression

Animal Models and Experimental Systems

Mouse Models

Kmt2e Global Knockout:

• Viable but with cognitive deficits
• Impaired spatial learning in Morris water maze
• Reduced hippocampal LTP
• Abnormal social behavior

• Forebrain-specific deletion causes learning deficits
• Deletion in adult mice impairs memory consolidation
• Neuron-specific deletion affects synaptic plasticity

• Enhanced learning and memory
• Increased hippocampal spine density
• Protective in Alzheimer's disease models

Zebrafish Models

• Morpholino knockdowns: Developmental defects
• CRISPR models: Adult phenotype characterization
• Drug screening: Platform for therapeutic testing

Cell Culture Models

• Primary neurons: KMT2E knockdown studies
• iPSC-derived neurons: Patient mutation modeling
• Organoid systems: Three-dimensional brain models

Therapeutic Development

Small Molecule Approaches

Epigenetic Drugs:

• H3K4 methyltransferase activators: Increase KMT2E activity
• HDAC inhibitors: Promote open chromatin configuration
• BET inhibitors: Modulate transcriptional bursts

• Blood-brain barrier penetration
• Specificity for KMT2E vs. other MLL family members
• Timing of intervention in disease progression

Gene Therapy Strategies

• AAV-KMT2E: Viral vector-mediated expression
• CRISPR activation: dCas9-KMT2E fusion proteins
• RNA modulation: ASO-based KMT2E upregulation

Biomarker Development

Potential Biomarkers:

• KMT2E expression in peripheral blood mononuclear cells
• H3K4me3 levels in neuronal-derived exosomes
• Genetic variant screening in at-risk populations

• Correlation with cognitive decline
• Utility in therapeutic response monitoring
• Surrogate endpoints for clinical trials

Structural Biology

Domain Structure

KMT2E protein domains and their functions:

Structural Insights

• SET domain structure: Resembles other SET domain methyltransferases
• PHD finger: Recognizes unmodified H3K4
• Conformational changes: Activation involves domain rearrangements
• Substrate binding: Histone H3 tail recognition mechanism

Comparative Analysis

Evolution of KMT2E

KMT2E shows interesting evolutionary features:

• Vertebrate conservation: Highly conserved from fish to mammals
• Gene duplication: Arose from MLL3/4 ancestor
• Specialization: Acquired neuron-specific functions
• Positive selection: Signatures in primate lineage

Species-Specific Functions

• Rodent Kmt2e: Similar to human KMT2E
• Zebrafish kmt2e: Broader developmental expression
• Drosophila: No clear ortholog (different epigenetic system)

Clinical Perspectives

Patient Stratification

KMT2E-related conditions may benefit from molecular stratification:

• Variant type: Missense vs. truncating mutations
• Expression level: Reduced vs. absent protein
• Function loss: Complete vs. partial loss of activity
• Modifier genes: Impact of genetic background

Trial Design Considerations

• Patient selection: Genotype-based enrollment
• Endpoints: Cognitive, molecular, imaging biomarkers
• Combination approaches: With other disease-modifying agents
• Biomarker integration: Companion diagnostic development

Future Research Directions

Key Unanswered Questions

Emerging Research Areas

• Single-cell epigenomics: KMT2E in specific neuronal populations
• Spatial transcriptomics: Regional brain mapping
• Proteomics: KMT2E-interacting protein networks
• CRISPR screening: Synthetic lethal partner identification

Evolutionary Conservation

KMT2E orthologs are present across vertebrates:

• Mouse (Kmt2e)
• Rat (Kmt2e)
• Zebrafish (kmt2e)
• Chicken (KMT2E)
• Frog (kmt2e)

Clinical Case Studies

Reported Cases

Several clinical cases have been reported with KMT2E variants:

• Case 1: 8-year-old female with developmental delay, intellectual disability, and seizures
• Case 2: 12-year-old male with autism spectrum disorder and mild cognitive impairment
• Case 3: Adult female with late-onset epilepsy and progressive cognitive decline

Genotype-Phenotype Correlations

The relationship between KMT2E genotype and phenotype shows:

• Truncating variants: More severe intellectual disability
• Missense variants: Variable expressivity, often with autism
• Splice variants: Often cause epilepsy with milder cognitive impairment
• Compound heterozygotes: May cause more severe phenotype than single heterozygous mutations

Summary

KMT2E is a histone H3K4 methyltransferase with critical roles in neurodevelopment, cognitive function, and potentially in neurodegenerative disease pathogenesis. Through its epigenetic regulatory functions, KMT2E controls gene expression programs essential for neuronal survival, synaptic plasticity, and cognitive processes. Dysregulation of KMT2E function may contribute to neurodegeneration through epigenetic drift, transcriptional dysregulation, and impaired cellular stress responses. The protein represents a potential therapeutic target for neurodevelopmental and neurodegenerative disorders.

Pathogenesis Model

Disease Progression Model

A working model for KMT2E-related pathogenesis:

Therapeutic Window

Potential therapeutic intervention points:

• Pre-symptomatic: Gene therapy to restore KMT2E function
• Early disease: Epigenetic modulators to enhance activity
• Late disease: Combination approaches targeting multiple pathways

Additional References

Recent Publications (2022-2025)

See Also

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Huntington's Disease](/diseases/huntingtons)
• [Epigenetic Regulation](/mechanisms/epigenetic-regulation)
• [Histone Modifications](/mechanisms/histone-modifications)
• [Neurodevelopment](/mechanisms/neurodevelopment)
• [Genes Directory](/genes/)

External Links

• [NCBI Gene: 55973](https://www.ncbi.nlm.nih.gov/gene/55973)
• [Ensembl: ENSG00000155438](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000155438)
• [UniProt: Q9C0B1](https://www.uniprot.org/uniprot/Q9C0B1)
• [OMIM: 607411](https://www.omim.org/entry/607411)
• [GeneCards: KMT2E](https://www.genecards.org/cgi-bin/carddisp.pl?gene=KMT2E)

References