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| Full Name | SET Domain Containing 2 |
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| Symbol | SETD2 |
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| Chromosomal Location | 9p21.3 |
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| NCBI Gene ID | [29072](https://www.ncbi.nlm.nih.gov/gene/29072) |
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| OMIM | [612054](https://www.omim.org/entry/612054) |
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| Ensembl ID | ENSG00000161547 |
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| UniProt ID | [Q9C0B1](https://www.uniprot.org/uniprot/Q9C0B1) |
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| Associated Diseases | Sotos syndrome, autism, cancer, neurodevelopmental disorders |
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SETD2 (SET Domain Containing 2) is a histone H3 lysine 36 trimethyltransferase (H3K36me3 writer). It is the only enzyme known to catalyze H3K36me3, a mark associated with transcriptional elongation, DNA mismatch repair, and alternative splicing. SETD2 is a conserved nuclear protein essential for normal development and cellular function.
In the nervous system, SETD2 and H3K36me3 play critical roles in neuronal development, synaptic plasticity, and memory formation. SETD2 is one of the most frequently mutated chromatin modifiers in cancer, and germline mutations cause Luscan-Lumish syndrome, a neurodevelopmental disorder. Recent research suggests SETD2 dysfunction may contribute to neurodegenerative processes.
SETD2 is a histone H3K36 trimethyltransferase that plays essential roles in transcription elongation, RNA splicing, and DNA mismatch repair. It is the sole enzyme responsible for H3K36me3 in mammals.
- H3K36 Trimethylation: Catalyzes H3K36me3, a mark of transcriptionally active genes
- Transcriptional Elongation: Facilitates RNA polymerase II processivity
- RNA Splicing: Regulates alternative splicing through interaction with splicing factors
- DNA Repair: Involved in mismatch repair and homologous recombination
¶ Protein Domains
- SET Domain: Catalytic methyltransferase domain
- AWS Domain: Associated with SET domain
- SRI Domain: Set2-Rpb1 Interacting domain
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Sotos Syndrome
- Haploinsufficiency of SETD2 causes Sotos syndrome
- Characterized by overgrowth, macrocephaly, intellectual disability
- ~10% of Sotos syndrome cases due to SETD2 mutations
- References: Tatton-Brown et al., 2011
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Autism Spectrum Disorder
- De novo SETD2 mutations identified in ASD patients
- Affects synaptic function and connectivity
- References: Iossifov et al., 2014
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Intellectual Disability
- Severe intellectual disability in null mutations
- Variable phenotype in missense mutations
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Alzheimer's Disease
- SETD2 expression reduced in AD brain
- H3K36me3 levels decrease with age and AD progression
- May affect amyloid processing genes
- References: Zhang et al., 2021
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Huntington's Disease
- Altered H3K36 methylation in HD models
- Transcriptional dysfunction linked to SETD2 loss
- References: Acharya et al., 2019
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Cancer
- Tumor suppressor - frequently mutated in clear cell renal cell carcinoma
- Mutations in various cancers
- Nuclear: Colocalizes with RNA Pol II
- Chromatin: Enriched at gene bodies of actively transcribed genes
- Epigenetic Modulators: H3K36 methyltransferase modulators in development
- Gene Therapy: Potential for neurodevelopmental disorders
- Combination Approaches: With other epigenetic therapies
- Essential gene - complete loss lethal
- Therapeutic window needed