PUBLICATION
Emerging role of KDM5C in X-linked intellectual disability based on human genetic data and zebrafish models
- Authors
- Liao, B., Chen, M., Huang, Y., Shuai, M., Xu, L., He, S., Huang, H.
- ID
- ZDB-PUB-260227-23
- Date
- 2026
- Source
- Frontiers in molecular neuroscience 19: 17503111750311 (Journal)
- Registered Authors
- Keywords
- Claes-Jensen syndrome, KDM5C, X-linked intellectual disability, neuroimmunity, neuroinflammation, novel variants
- MeSH Terms
- none
- PubMed
- 41743791 Full text @ Front. Mol. Neurosci.
Citation
Liao, B., Chen, M., Huang, Y., Shuai, M., Xu, L., He, S., Huang, H. (2026) Emerging role of KDM5C in X-linked intellectual disability based on human genetic data and zebrafish models. Frontiers in molecular neuroscience. 19:17503111750311.
Abstract
Introduction Claes-Jensen syndrome is a rare X-linked syndromic neurodevelopmental disorder by pathogenic variants in lysine specific demethylase 5C (KDM5C), a lysine-specific histone demethylase.
Methods In this study, clinical evaluations were conducted in affected individuals and carrier females. X-chromosome inactivation (XCI) assays were performed to assess genotype-phenotype correlations. Functional studies evaluated variant effects on RNA transcription, protein expression, and stability. Zebrafish models were used for in vivo validation. RNA sequencing with KEGG and GO analyses identified dysregulated genes and pathways, further confirmed in zebrafish.
Results Two novel KDM5C variants NM_004187.5:c.3019del and NM_004187.5:c.782-2A>T were identified in unrelated families with X-linked ID. Affected males presented with short stature, microcephaly, language delay, and intellectual disability, while carrier females showed milder features including learning difficulties and short stature. Skewed XCI in some carriers suggested a role in phenotypic variability. Both variants impair RNA transcription, protein expression and stability. Zebrafish models recapitulated neurodevelopmental and behavioral abnormalities. Transcriptomic analyses revealed disrupted antiviral and interferon-related signaling, implicating aberrant immune activation. Pharmacologic inhibition of the Toll-like receptor pathway ameliorated mutant phenotypes, highlighting neuroinflammation as a potential therapeutic target for KDM5C-related disorders.
Conclusion These findings expand the mutational spectrum of KDM5C-associated ID and uncover a novel pathogenic mechanism between KDM5C dysfunction, protein instability, and dysregulated inflammatory signaling.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping