KMT2D — Lysine Methyltransferase 2D

KMT2D — Lysine Methyltransferase 2D

<div class="infobox infobox-gene">
<div class="infobox-header">KMT2D</div>
<table> [@wu2017]
<tr><th>Full Name</th><td>Lysine Methyltransferase 2D</td></tr>
<tr><th>Symbol</th><td>KMT2D (formerly MLL4)</td></tr>
<tr><th>Chromosomal Location</th><td>12q13.12</td></tr>
<tr><th>NCBI Gene ID</th><td>[8085](https://www.ncbi.nlm.nih.gov/gene/8085)</td></tr>
<tr><th>OMIM</th><td>[607532](https://www.omim.org/entry/607532)</td></tr>
<tr><th>Ensembl ID</th><td>ENSG00000167525</td></tr>
<tr><th>UniProt ID</th><td>[O14686](https://www.uniprot.org/uniprot/O14686)</td></tr>
<tr><th>Associated Diseases</th><td>Kabuki syndrome, neurodevelopmental disorders, cancer</td></tr>
</table>
</div>

Overview

KMT2D — Lysine Methyltransferase 2D

<div class="infobox infobox-gene">
<div class="infobox-header">KMT2D</div>
<table> [@wu2017]
<tr><th>Full Name</th><td>Lysine Methyltransferase 2D</td></tr>
<tr><th>Symbol</th><td>KMT2D (formerly MLL4)</td></tr>
<tr><th>Chromosomal Location</th><td>12q13.12</td></tr>
<tr><th>NCBI Gene ID</th><td>[8085](https://www.ncbi.nlm.nih.gov/gene/8085)</td></tr>
<tr><th>OMIM</th><td>[607532](https://www.omim.org/entry/607532)</td></tr>
<tr><th>Ensembl ID</th><td>ENSG00000167525</td></tr>
<tr><th>UniProt ID</th><td>[O14686](https://www.uniprot.org/uniprot/O14686)</td></tr>
<tr><th>Associated Diseases</th><td>Kabuki syndrome, neurodevelopmental disorders, cancer</td></tr>
</table>
</div>

Overview

KMT2D (also known as MLL4 - Mixed Lineage Leukemia 4) is a histone H3 lysine 4 methyltransferase that functions as part of the COMPASS-like complex. It is a large nuclear protein closely related to KMT2C (MLL3) and is essential for transcriptional activation through H3K4 monomethylation (H3K4me1) at enhancer regions. KMT2D is critical for development, tissue-specific gene expression, and cellular differentiation.

In the nervous system, KMT2D regulates genes important for neuronal function, brain development, and synaptic plasticity. Germline mutations in KMT2D cause Kabuki syndrome, a neurodevelopmental disorder characterized by distinctive facial features, intellectual disability, and various systemic manifestations. Research suggests KMT2D may also play roles in neurodegenerative disease pathogenesis.

Function

KMT2D (also known as MLL4) is a histone H3K4 monomethyltransferase that functions as a transcriptional coactivator. It is highly expressed in the brain and plays crucial roles in neurodevelopment and synaptic function.

Enzymatic Activity

• H3K4 Methylation: Catalyzes H3K4me1 at enhancer regions
• Enhancer Activation: Essential for enhancer activation and super-enhancer function
• Transcriptional Regulation: Activates gene expression through chromatin modification

Protein Domains

• SET Domain: Catalytic methyltransferase domain
• PHD Finger Domains: Chromatin reading for substrate recognition
• FYR Domains: Regulatory domains
• AT Hooks: DNA-binding motifs

Disease Associations

Neurodevelopmental Disorders

• Primary cause: Heterozygous loss-of-function mutations in KMT2D
• Characteristic facial features, intellectual disability, skeletal anomalies
• ~60% of Kabuki syndrome cases caused by KMT2D mutations
• References: [Kuroki et al., 2001](https://doi.org/10.1086/324125), [Ng et al., 2010](https://doi.org/10.1038/ng.646)

• KMT2D mutations identified in ASD patients
• Affects synaptic gene expression
• References: [Ishida et al., 2019](https://doi.org/10.1038/s41398-019-0488-4)

• Variable severity depending on mutation type
• Often accompanied by developmental delay
• References: [Baptista et al., 2015](https://doi.org/10.1016/j.ejmg.2015.04.010)

Neurodegeneration

• Dysregulated KMT2D in AD brain [@chen2019]
• May contribute to transcriptional dysfunction
• Genetic variants may influence AD risk [@liu2020]

• Altered H3K4 methylation patterns in PD substantia nigra [@wang2020]
• KMT2D dysregulation affects dopaminergic neuron survival
• Therapeutic target potential

• Altered H3K4 methylation patterns [@xu2020]
• Potential therapeutic target

• KMT2D regulates inflammatory gene expression [@zhang2020b]
• Epigenetic modulation of neuroinflammation

• KMT2D expression declines with age [@wang2019b]
• Contributes to age-related cognitive decline

Molecular Mechanisms

Enhancer Function

• Catalyzes H3K4me1 at enhancer regions
• Regulates cell-type specific gene expression
• Maintains transcriptional memory [@choi2019]

Synaptic Plasticity

• Regulates synaptic gene expression
• Important for learning and memory
• Dysfunction leads to cognitive deficits [@song2020]

Neurogenesis

• Regulates neural stem cell function
• Affects neuronal differentiation
• Critical for brain development

Mitochondrial Function

• Regulates genes involved in mitochondrial dynamics
• Affects neuronal energy metabolism

DNA Damage Response

• Maintains genomic stability
• Important for neuronal survival

Expression

Brain Expression

• Cerebral [Cortex](/brain-regions/cortex): High expression in excitatory [neurons](/entities/neurons)
• [Hippocampus](/brain-regions/hippocampus): Strong expression in CA1 pyramidal cells
• Cerebellum: Moderate expression in Purkinje cells
• Developmental: Highest expression during embryonic brain development [@lee2020]
• Aging: Expression declines with age [@wang2019b]
• Allen Brain Atlas: [KMT2D expression data](https://human.brain-map.org/)

Cellular Localization

• Nuclear: Colocalizes with active chromatin marks
• Enhancer Regions: Enriched at enhancer and super-enhancer regions

Therapeutic Targeting

Therapeutic Approaches

• Histone Methyltransferase Inhibitors: Research ongoing for MLL4 inhibitors [@yang2020b]
• Epigenetic Combination Therapy: Potential with [HDAC](/entities/hdac-enzymes) or DNMT inhibitors
• Gene Therapy: Future potential for Kabuki syndrome
• Small Molecule Activators: Being developed to restore KMT2D function

Research Directions

• Understanding genotype-phenotype correlation
• Developing targeted therapies for Kabuki syndrome
• Exploring KMT2D as therapeutic target in AD and PD

See Also

• MLL4 Protein
• [Kabuki Syndrome](/diseases/kabuki-syndrome)
• [H3K4 Methylation Pathway](/genes/th)
• [Epigenetic Mechanisms in Neurodegeneration](/content/mechanisms)

External Links

• [NCBI Gene](https://www.ncbi.nlm.nih.gov/gene/)
• [UniProt](https://www.uniprot.org/)
• [OMIM](https://www.omim.org/)
• [GeneCards](https://www.genecards.org/)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving KMT2D — Lysine Methyltransferase 2D discovered through SciDEX knowledge graph analysis: