Related Experiment Video
Updated: May 9, 2026

Identification and Classification of Position-specific GABAA Receptor Subunit Missense Variants for Their Role In Hippocampal Pyramidal Neurons
Published on: June 6, 2025
Variants in KLHL15, encoding a regulator of protein ubiquitination, linked to focal epilepsy with neurodevelopmental
Si-Qi Zhang1, Zhi-Hong Lao2, Wen-Hui Liu1
1Department of Neurology, The First Affiliated Hospital of Jinan University, 613 West Huangpu Ave, Guangzhou 510630, China.
Purpose:
KLHL15 encodes Kelch-like protein 15, an adapter for the Cullin3 (CUL3) E3 ubiquitin ligase complex. CUL3 variants are linked to developmental disorders and epilepsy. However, the association between KLHL15 variants and epilepsy is unclear. This study aimed to explore the association of KLHL15 with epilepsy.
Methods:
Exome sequencing was performed in patients with non-acquired focal epilepsy. Pathogenic variants' effects were assessed via protein modeling. Single-cell analysis of KLHL15 expression was performed to explore neurodevelopmental mechanisms. Its interacting proteins were analyzed via network diffusion analysis to explore functional links with epilepsy and neurodevelopmental disorders (NDDs).
Results:
KLHL15 missense variants were identified in four unrelated focal epilepsy cases with NDDs. These variants, absent in gnomAD, were predicted to alter protein stability. The observed genotype-phenotype associations suggest that variants within the domain may be implicated in epilepsy and neurodevelopmental disorders. Spatiotemporal analysis showed KLHL15 was highly expressed in the developing brain. Single-cell sequencing of organoids and adult brain demonstrated predominant expression in excitatory neurons across developmental stages. Functional enrichment revealed KLHL15 as a central component of the ubiquitin-proteasome pathway and Cullin-based E3 complexes. Network diffusion analysis confirmed functional links to epilepsy with NDDs genes.
Conclusion:
KLHL15 variants are correlated with focal epilepsy with NDDs. The observed domain variants contribute to elucidating genotype-phenotype relationships. The spatiotemporal expression profiles and functional network provide crucial insights into the pathogenic mechanisms of KLHL15 variants.
More Related Videos
06:41In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
08:22A Novel Strategy Combining Array-CGH, Whole-exome Sequencing and In Utero Electroporation in Rodents to Identify Causative Genes for Brain Malformations
Published on: December 1, 2017
Related Concept Videos
Cytoskeletal Linker Proteins - Plakins
Covalently Linked Protein Regulators
These groups modify specific amino acids in a protein.
Covalently Linked Protein Regulators
These groups modify specific amino acids in a protein.
Protein Complexes with Interchangeable Parts
The SCF ubiquitin ligase is a protein complex of five individual proteins. This complex attaches ubiquitin to other target proteins to mark them for degradation. In order to...
Antiepileptic Drugs: Modulators of Neurotransmitter Release Mediated by SV2A Protein
SV2A is a transmembrane glycoprotein located predominantly in the brain, modulating the release of neurotransmitters for neuronal communication. Both levetiracetam and brivaracetam exhibit a high affinity for...
Alternative RNA Splicing
There are five types of alternative RNA splicing that vary in the ways the pre-mRNA segments are removed or retained in the mature mRNA. The first...