KDM5C (Lysine Demethylase 5C)
<div class="infobox infobox-gene">
<h3>KDM5C</h3>
<table> [@iwase2007]
<tr><td><strong>Full Name</strong></td><td>Lysine Demethylase 5C</td></tr> [@vallianatos2018]
<tr><td><strong>Gene Symbol</strong></td><td>KDM5C</td></tr> [@poeta2013]
<tr><td><strong>Aliases</strong></td><td>JARID1C, SMCX, DXS1272E</td></tr> [@tahiliani2007]
<tr><td><strong>Chromosomal Location</strong></td><td>Xp11.22</td></tr> [@rondinelli2015]
<tr><td><strong>NCBI Gene ID</strong></td><td>[8242](https://www.ncbi.nlm.nih.gov/gene/8242)</td></tr> [@brookes2015]
<tr><td><strong>OMIM</strong></td><td>[314690](https://omim.org/entry/314690)</td></tr> [@shen2014]
<tr><td><strong>Ensembl</strong></td><td>[ENSG00000126012](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000126012)</td></tr> [@grafodatskaya2013]
<tr><td><strong>UniProt</strong></td><td>[P41229](https://www.uniprot.org/uniprot/P41229)</td></tr>
<tr><td><strong>Protein</strong></td><td>Lysine-specific demethylase 5C</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>X-linked intellectual disability (Claes-Jensen type), [Alzheimer's disease](/diseases/alzheimers-disease), autism spectrum disorder, epilepsy</td></tr>
</table>
</div>
Overview
...KDM5C (Lysine Demethylase 5C)
<div class="infobox infobox-gene">
<h3>KDM5C</h3>
<table> [@iwase2007]
<tr><td><strong>Full Name</strong></td><td>Lysine Demethylase 5C</td></tr> [@vallianatos2018]
<tr><td><strong>Gene Symbol</strong></td><td>KDM5C</td></tr> [@poeta2013]
<tr><td><strong>Aliases</strong></td><td>JARID1C, SMCX, DXS1272E</td></tr> [@tahiliani2007]
<tr><td><strong>Chromosomal Location</strong></td><td>Xp11.22</td></tr> [@rondinelli2015]
<tr><td><strong>NCBI Gene ID</strong></td><td>[8242](https://www.ncbi.nlm.nih.gov/gene/8242)</td></tr> [@brookes2015]
<tr><td><strong>OMIM</strong></td><td>[314690](https://omim.org/entry/314690)</td></tr> [@shen2014]
<tr><td><strong>Ensembl</strong></td><td>[ENSG00000126012](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000126012)</td></tr> [@grafodatskaya2013]
<tr><td><strong>UniProt</strong></td><td>[P41229](https://www.uniprot.org/uniprot/P41229)</td></tr>
<tr><td><strong>Protein</strong></td><td>Lysine-specific demethylase 5C</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>X-linked intellectual disability (Claes-Jensen type), [Alzheimer's disease](/diseases/alzheimers-disease), autism spectrum disorder, epilepsy</td></tr>
</table>
</div>
Overview
Mermaid diagram (expand to render)
KDM5B is a human gene. Variants in KDM5B have been implicated in X-Linked Intellectual Disability (Claes-Jensen Type), Alzheimer's Disease, Epilepsy. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.
Gene Function
KDM5C (formerly JARID1C or SMCX) encodes an X-linked JmjC domain-containing histone demethylase that removes di- and trimethyl marks from histone H3 lysine 4 (H3K4me2/3). Unlike its paralog [KDM5B](/genes/kdm5b) which is broadly expressed, KDM5C shows strong enrichment in brain tissue and is the most abundantly expressed KDM5 family member in [neurons](/entities/neurons). KDM5C escapes X-inactivation in females, meaning it is expressed from both X chromosomes, though with some degree of variable dosage compensation.
KDM5C is a 1560-amino acid protein containing:
- JmjN + JmjC domains: Catalytic domains for Fe(II)/2-OG-dependent oxidative demethylation of H3K4me2/3
- ARID domain: AT-rich interaction domain for DNA binding, directing KDM5C to specific genomic loci
- PHD fingers (2x): PHD1 reads H3K9me3, linking KDM5C to heterochromatin; PHD2 reads unmethylated H3K4, providing product recognition
- C5HC2 zinc finger: Mediates interactions with transcriptional co-repressors including REST/NRSF and [HDAC](/entities/hdac-enzymes) complexes
KDM5C plays essential roles in neural epigenetic regulation:
- Activity-dependent gene regulation: KDM5C is rapidly recruited to enhancers of immediate-early genes (IEGs) following neuronal activity, where it fine-tunes H3K4me3 levels to prevent excessive transcriptional responses. This "gain control" function prevents epileptiform hyperactivation
- Enhancer decommissioning: KDM5C removes H3K4me3 from deactivating enhancers, converting them to poised (H3K4me1) state. Loss of KDM5C causes persistent "ghost" enhancers that drive spurious gene expression
- REST/NRSF cooperation: KDM5C interacts with the RE1-Silencing Transcription factor ([REST](/genes/rest)) to repress neuronal genes in non-neuronal cells and to fine-tune neuronal gene dosage in mature neurons
- Dendritic development: KDM5C regulates dendritic branching and spine morphogenesis by controlling expression of cytoskeletal regulators and cell adhesion molecules
- Synaptic plasticity: KDM5C-mediated H3K4me3 demethylation at synaptic gene promoters modulates [long-term potentiation](/mechanisms/long-term-potentiation) (LTP) and long-term depression (LTD) in hippocampal neurons
Neural Expression and Brain Distribution
KDM5C shows prominent neural expression:
- [Hippocampus](/brain-regions/hippocampus): Very high expression in CA1, CA3, and dentate gyrus neurons, consistent with critical roles in memory-associated chromatin dynamics
- [Cortex](/brain-regions/cortex): Expressed across all cortical layers with enrichment in glutamatergic projection neurons
- Amygdala: High expression levels, suggesting roles in emotional memory and fear conditioning
- Cerebellum: Purkinje cell expression
- Brainstem: Expression in monoaminergic nuclei including locus coeruleus and raphe nuclei
- Expression is neuron-enriched: Single-cell data show 3-5x higher expression in neurons compared to glial cells
Disease Associations
X-Linked Intellectual Disability (Claes-Jensen Type)
Hemizygous loss-of-function mutations in KDM5C are one of the most common causes of
X-linked intellectual disability (XLID), known as Claes-Jensen type mental retardation (MRXSCJ; OMIM 300534). The clinical phenotype includes:
- Moderate to severe intellectual disability (IQ 25-50 in affected males)
- Short stature and microcephaly
- Seizures (in ~30% of cases)
- Aggressive behavior, hyperactivity
- Characteristic facial features (midface hypoplasia, prominent brow)
- Females carriers are typically unaffected due to X-inactivation skewing
Over 50 pathogenic KDM5C mutations have been identified, including missense mutations in the JmjC catalytic domain (abolishing demethylase activity), nonsense mutations, and genomic deletions. KDM5C knockout mice recapitulate the human phenotype with impaired learning, increased aggression, reduced dendritic complexity, and altered synaptic plasticity.
Alzheimer's Disease
KDM5C dysfunction contributes to [AD](/diseases/alzheimers-disease) through:
- Enhancer dysregulation: KDM5C loss of function in aging neurons leads to aberrant H3K4me3 accumulation at enhancers of inflammatory and apoptotic genes, priming neurons for damage
- Epigenetic memory: KDM5C normally resets H3K4me3 marks after activity-dependent transcription; failure of this resetting in AD neurons leads to chronic activation of stress-responsive genes
- [Tau](/proteins/tau) pathology: H3K4me3 dysregulation at the [MAPT](/genes/mapt) locus may alter tau isoform ratios, favoring 4-repeat tau that is more aggregation-prone
- X-chromosome effects: KDM5C escapes X-inactivation, and females (with two active copies) have lower AD risk than males (one copy); KDM5C dosage may partially explain the sex difference in AD incidence
Epilepsy
Approximately 30% of individuals with KDM5C mutations develop seizures, ranging from generalized tonic-clonic to absence seizures. The mechanism involves:
- Loss of KDM5C "gain control" at enhancers leads to hyperactivation of IEGs including [FOS](/genes/fos), [EGR1](/genes/egr1), and [ARC](/genes/arc)
- Reduced expression of GABA receptor subunits including [GABRA1](/genes/gabra1) and [GABRG2](/genes/gabrg2) disrupts inhibitory neurotransmission
- Altered excitatory synapse number due to dysregulated expression of synaptic adhesion molecules
Common Variants
| Variant | Type | Population Frequency | Clinical Significance |
|---------|------|---------------------|----------------------|
| p.Ala388Pro | Missense (JmjC) | Rare | Claes-Jensen XLID |
| p.Trp1288Arg | Missense (C-terminal) | Rare | Intellectual disability, seizures |
| p.Asp87Gly | Missense (N-terminal) | Rare | Mild ID, behavioral issues |
| rs5963153 | Intronic | 0.22 (global) | Cognitive ability modifier |
| p.Leu731Phe | Missense | Rare | ASD with ID |
Therapeutic Implications
- Precision medicine: KDM5C mutation-specific therapies may be developed; some missense mutations reduce but don't abolish enzymatic activity, suggesting rescue approaches
- Epigenetic rebalancing: Since KDM5C loss causes H3K4me3 accumulation, modulation of H3K4 methyltransferases (MLL/KMT2 family) could rebalance the mark. KMT2A/MLL1 inhibitors are in clinical trials for leukemia
- Enhancer therapy: Targeted silencing of aberrantly active enhancers in KDM5C-deficient neurons using CRISPRi approaches could suppress pathological gene expression
- REST pathway modulation: Since KDM5C cooperates with REST, REST-pathway enhancers could partially compensate for KDM5C loss at shared target genes
- Gene therapy: AAV-mediated KDM5C delivery to affected neurons could restore H3K4me3 homeostasis; the large transcript (~4.7 kb CDS) is near the limit of AAV packaging capacity
- AD sex-difference insight: Understanding KDM5C dosage effects could lead to sex-specific therapeutic strategies in AD
See Also
- [KDM5B](/genes/kdm5b) — JARID1B, H3K4 demethylase paralog
- [KDM6B](/genes/kdm6b) — JMJD3, H3K27 demethylase
- [KDM1A](/genes/kdm1a) — LSD1, H3K4/K9 demethylase
- [REST](/genes/rest) — RE1-silencing transcription factor
- [KMT2A](/genes/kmt2a) — MLL1, H3K4 methyltransferase
- [BRD2](/genes/brd2) — BET bromodomain, epilepsy gene
External Links
- [NCBI Gene: KDM5C](https://www.ncbi.nlm.nih.gov/gene/8242)
- [GeneCards: KDM5C](https://www.genecards.org/cgi-bin/carddisp.pl?gene=KDM5C)
- [OMIM: 314690](https://omim.org/entry/314690)
- [UniProt: P41229](https://www.uniprot.org/uniprot/P41229)
- [Allen Brain Atlas: KDM5C](https://portal.brain-map.org/)
References
[Jensen et al., Mutations in the JARID1C gene, which is involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation (2005) (2005)](https://doi.org/10.1086/427563)
[Scandaglia et al., Loss of Kdm5c causes spurious transcription and prevents the fine-tuning of activity-regulated enhancers in neurons (2017) (2017)](https://doi.org/10.1016/j.celrep.2017.05.015)
[Iwase et al., The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases (2007) (2007)](https://doi.org/10.1016/j.cell.2007.07.018)
[Vallianatos et al., Altered gene-regulatory function of KDM5C by a novel mutation associated with autism and intellectual disability (2018) (2018)](https://doi.org/10.3389/fnmol.2018.00104)
[Poeta et al., A regulatory path associated with X-linked intellectual disability and epilepsy links KDM5C to the polyalanine expansions in ARX (2013) (2013)](https://doi.org/10.1016/j.ajhg.2013.07.012)
[Tahiliani et al., The histone H3K4 demethylase SMCX links REST target genes to X-linked mental retardation (2007) (2007)](https://doi.org/10.1038/nature06092)
[Rondinelli et al., Histone demethylase JARID1C inactivation triggers genomic instability in cancer (2015) (2015)](https://doi.org/10.1172/JCI81040)
[Brookes et al., Mutations in the intellectual disability gene KDM5C reduce protein stability and demethylase activity (2015) (2015)](https://doi.org/10.1093/hmg/ddv046)
[Shen et al., Experience-dependent epigenomic reorganization in the hippocampus (2014) (2014)](https://doi.org/10.1101/lm.032904.113)
[Grafodatskaya et al., Multilocus loss of DNA methylation in individuals with mutations in the histone H3 lysine 4 demethylase KDM5C (2013) (2013)](https://doi.org/10.1186/1755-8794-6-1)