NSD2 (Nuclear Receptor Binding SET Domain Protein 2)

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NSD2 (Nuclear Receptor Binding SET Domain Protein 2)

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NSD2 (Nuclear Receptor Binding SET Domain Protein 2)

<div class="infobox infobox-gene">
<h3>NSD2</h3>
<table> [@bergemann2005]
<tr><td><strong>Full Name</strong></td><td>Nuclear Receptor Binding SET Domain Protein 2</td></tr> [@li2009]
<tr><td><strong>Gene Symbol</strong></td><td>NSD2</td></tr> [@zollino2008]
<tr><td><strong>Aliases</strong></td><td>WHSC1, MMSET</td></tr> [@sankaran2016]
<tr><td><strong>Chromosomal Location</strong></td><td>4p16.3</td></tr> [@popovic2014]
<tr><td><strong>NCBI Gene ID</strong></td><td>[7468](https://www.ncbi.nlm.nih.gov/gene/7468)</td></tr> [@jaffe2016]
<tr><td><strong>OMIM</strong></td><td>[602952](https://omim.org/entry/602952)</td></tr> [@derar2023]
<tr><td><strong>Ensembl</strong></td><td>[ENSG00000109685](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000109685)</td></tr> [@battaglia2015]
<tr><td><strong>UniProt</strong></td><td>[O96028](https://www.uniprot.org/uniprot/O96028)</td></tr>
<tr><td><strong>Protein</strong></td><td>Histone-lysine N-methyltransferase NSD2</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>Wolf-Hirschhorn syndrome, [Alzheimer's disease](/diseases/alzheimers-disease), intellectual disability, growth retardation</td></tr>
</table>
</div>

Overview

GSK3β is a human gene. Variants in GSK3β have been implicated in Wolf-Hirschhorn Syndrome, Alzheimer's Disease, Seizure Disorders. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.

Gene Function

...

NSD2 (Nuclear Receptor Binding SET Domain Protein 2)

<div class="infobox infobox-gene">
<h3>NSD2</h3>
<table> [@bergemann2005]
<tr><td><strong>Full Name</strong></td><td>Nuclear Receptor Binding SET Domain Protein 2</td></tr> [@li2009]
<tr><td><strong>Gene Symbol</strong></td><td>NSD2</td></tr> [@zollino2008]
<tr><td><strong>Aliases</strong></td><td>WHSC1, MMSET</td></tr> [@sankaran2016]
<tr><td><strong>Chromosomal Location</strong></td><td>4p16.3</td></tr> [@popovic2014]
<tr><td><strong>NCBI Gene ID</strong></td><td>[7468](https://www.ncbi.nlm.nih.gov/gene/7468)</td></tr> [@jaffe2016]
<tr><td><strong>OMIM</strong></td><td>[602952](https://omim.org/entry/602952)</td></tr> [@derar2023]
<tr><td><strong>Ensembl</strong></td><td>[ENSG00000109685](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000109685)</td></tr> [@battaglia2015]
<tr><td><strong>UniProt</strong></td><td>[O96028](https://www.uniprot.org/uniprot/O96028)</td></tr>
<tr><td><strong>Protein</strong></td><td>Histone-lysine N-methyltransferase NSD2</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>Wolf-Hirschhorn syndrome, [Alzheimer's disease](/diseases/alzheimers-disease), intellectual disability, growth retardation</td></tr>
</table>
</div>

Overview

GSK3β is a human gene. Variants in GSK3β have been implicated in Wolf-Hirschhorn Syndrome, Alzheimer's Disease, Seizure Disorders. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.

Gene Function

NSD2 (also known as WHSC1/MMSET) encodes a histone lysine methyltransferase of the NSD family that catalyzes dimethylation of histone H3 at lysine 36 (H3K36me2). NSD2 is the primary enzyme responsible for maintaining genome-wide H3K36me2 levels, a histone mark associated with active transcription and intergenic chromatin regulation. NSD2 resides in the critical region of the 4p16.3 deletion responsible for Wolf-Hirschhorn syndrome (WHS), and its haploinsufficiency is considered the primary driver of the cognitive and developmental phenotypes in WHS.

NSD2 is a 1365-amino acid protein containing:

SET domain: The catalytic methyltransferase domain that specifically dimethylates H3K36
PWWP domain: Reads existing H3K36 methylation marks, enabling processive methylation along gene bodies
PHD fingers (4x): Recognize various histone tail modifications for chromatin context-dependent activity
HMG box: Provides non-sequence-specific DNA binding capability
AWS (associated with SET) domain: Stabilizes the SET domain catalytic fold

NSD2 regulates neural gene expression through multiple interconnected mechanisms:

Intergenic H3K36me2: NSD2 is responsible for >80% of H3K36me2 in intergenic regions, where this mark prevents aberrant PRC2-mediated H3K27me3 spreading. NSD2 loss causes redistribution of H3K27me3 across the genome, silencing neural genes
Enhancer priming: H3K36me2 at enhancers facilitates recruitment of DNMT3A, establishing [DNA methylation](/entities/dna-methylation) patterns critical for neural lineage specification
DNA damage repair: NSD2 is recruited to DNA double-strand breaks where it methylates H3K36 to facilitate recruitment of NHEJ repair factors including Ku70/Ku80 and 53BP1
Cell cycle regulation: NSD2 promotes expression of cyclin and CDK genes required for neural progenitor proliferation during brain development
Transcriptional elongation: Gene body H3K36me2 deposited by NSD2 supports productive transcriptional elongation, particularly important for the large genes that predominate in neuronal transcriptomes

Neural Expression and Brain Distribution

NSD2 is broadly expressed throughout the developing and adult brain:

Developing brain: Peak expression during mid-embryonic neurogenesis (E12-E16 in mouse), coinciding with cortical neurogenesis and migration
[Hippocampus](/brain-regions/hippocampus): Strong expression in CA1-CA3 and dentate gyrus, reflecting roles in memory-associated chromatin plasticity
Cerebral [cortex](/brain-regions/cortex): Expression across cortical layers with enrichment in deep-layer projection [neurons](/entities/neurons)
Cerebellum: Purkinje cell and granule cell expression; cerebellar hypoplasia is a feature of Wolf-Hirschhorn syndrome
Adult brain: Maintained expression with particular enrichment in neurons and oligodendrocytes

Disease Associations

Wolf-Hirschhorn Syndrome

Heterozygous deletion of the 4p16.3 region containing NSD2 causes Wolf-Hirschhorn syndrome (WHS), characterized by severe intellectual disability, seizures (>90% of patients), distinctive facial features, growth retardation, and microcephaly. NSD2 haploinsufficiency is considered the primary contributor to the neurodevelopmental phenotype, as:

Point mutations in NSD2 alone can recapitulate intellectual disability without the full WHS spectrum
NSD2 heterozygous knockout mice show learning deficits, altered dendritic arborization, and reduced hippocampal [long-term potentiation](/mechanisms/long-term-potentiation) (LTP)
H3K36me2 levels are globally reduced in WHS patient cells, causing widespread epigenomic dysregulation

Alzheimer's Disease

NSD2 has several connections to [AD](/diseases/alzheimers-disease) pathogenesis:

Epigenetic aging: Age-dependent decline in NSD2 expression contributes to progressive H3K36me2 loss, enabling PRC2-mediated silencing of neuroprotective genes
[Tau](/proteins/tau) modification: NSD2-dependent H3K36me2 regulates expression of tau kinases including [GSK3β](/genes/gsk3b) and [CDK5](/genes/cdk5); H3K36me2 loss alters the tau phosphorylation landscape
Amyloid processing: PBAF/BAF complexes interact with NSD2-methylated chromatin at the [APP](/genes/app) and [BACE1](/genes/bace1) loci; NSD2 loss may dysregulate amyloidogenic processing
Neuroinflammation: NSD2 represses inflammatory gene expression in [microglia](/cell-types/microglia-neuroinflammation) through intergenic H3K36me2; its decline permits pro-inflammatory gene activation

Seizure Disorders

>90% of WHS patients develop seizures, often refractory to treatment. NSD2 haploinsufficiency disrupts expression of ion channel genes including [SCN1A](/genes/scn1a), [KCNQ2](/genes/kcnq2), and GABA receptor subunits, providing a molecular basis for WHS-associated epilepsy.

Common Variants

| Variant | Type | Population Frequency | Clinical Significance |
|---------|------|---------------------|----------------------|
| 4p16.3 deletion | CNV | Rare (1:50,000) | Wolf-Hirschhorn syndrome |
| p.Glu1099Lys (E1099K) | Missense (gain-of-function) | Somatic | ALL, multiple myeloma |
| p.Thr1150Ala | Missense | Rare | Intellectual disability |
| rs7660520 | Intronic | 0.15 (global) | Cognitive function GWAS signal |

Therapeutic Implications

NSD2 inhibitors: Small-molecule inhibitors targeting the SET domain of NSD2 (e.g., UNC6934) are in preclinical development for NSD2-overexpressing cancers; CNS penetrance and neurological safety require careful evaluation
EZH2 inhibitors: Since NSD2 loss causes H3K27me3 expansion, EZH2/PRC2 inhibitors (tazemetostat) could potentially rescue gene silencing in NSD2-haploinsufficient neurons
[HDAC](/entities/hdac-enzymes) inhibitors: Broad chromatin-opening agents may partially compensate for NSD2-mediated accessibility loss, though selectivity remains challenging
Gene dosage therapy: For WHS, AAV-mediated NSD2 supplementation could restore H3K36me2 levels; feasibility is limited by the large NSD2 transcript (~4.1 kb CDS)
Seizure management: Understanding NSD2-dependent ion channel gene regulation may guide anticonvulsant selection in WHS patients

External Links

[NCBI Gene: NSD2](https://www.ncbi.nlm.nih.gov/gene/7468)
[GeneCards: NSD2](https://www.genecards.org/cgi-bin/carddisp.pl?gene=NSD2)
[OMIM: 602952](https://omim.org/entry/602952)
[UniProt: O96028](https://www.uniprot.org/uniprot/O96028)
[Allen Brain Atlas: NSD2](https://portal.brain-map.org/)

References

[Nimura et al., A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-Hirschhorn syndrome (2009) (2009)](https://doi.org/10.1038/nature08086)

[Kuo et al., NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming (2011) (2011)](https://doi.org/10.1016/j.molcel.2011.08.042)

[Bergemann et al., The etiology of Wolf-Hirschhorn syndrome (2005) (2005)](https://doi.org/10.1016/j.tig.2005.01.008)

[Li et al., The target of the NSD family of histone lysine methyltransferases depends on the nature of the substrate (2009) (2009)](https://doi.org/10.1074/jbc.M109.020768)

[Zollino et al., Genotype-phenotype correlations and clinical diagnostic criteria in Wolf-Hirschhorn syndrome (2008) (2008)](https://doi.org/10.1002/ajmg.a.32366)

[Sankaran et al., A PWWP domain of histone-lysine N-methyltransferase NSD2 binds to dimethylated Lys-36 of histone H3 (2016) (2016)](https://doi.org/10.1074/jbc.M116.754481)

[Popovic et al., Histone methyltransferase MMSET/NSD2 alters EZH2 binding and reprograms the myeloma epigenome (2014) (2014)](https://doi.org/10.1016/j.ccr.2014.01.006)

[Jaffe et al., Mapping DNA methylation across development, genotype, and schizophrenia in the human frontal cortex (2016) (2016)](https://doi.org/10.1038/nn.4181)

[Derar et al., NSD2 in neural development and neurodevelopmental disorders (2023) (2023)](https://doi.org/10.1002/ajmg.a.63126)

[Battaglia et al., Wolf-Hirschhorn syndrome: a review and update (2015) (2015)](https://doi.org/10.1002/ajmg.c.31449)

Pathway Diagram

The following diagram shows the key molecular relationships involving NSD2 (Nuclear Receptor Binding SET Domain Protein 2) discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

NSD2

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kg_node_id	NSD2
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-2fea2bf4f807
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-nsd2'}
_schema_version	1

📊 Evidence Profile Foundational

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Outgoing

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📗 Cite This Artifact

NSD2 (Nuclear Receptor Binding SET Domain Protein 2)

NSD2 (Nuclear Receptor Binding SET Domain Protein 2)

Overview

Gene Function

NSD2 (Nuclear Receptor Binding SET Domain Protein 2)

Overview

Gene Function

Neural Expression and Brain Distribution

Disease Associations

Wolf-Hirschhorn Syndrome

Alzheimer's Disease

Seizure Disorders

Common Variants

Therapeutic Implications

See Also

External Links

References

Pathway Diagram

💬 Discussion