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Developmental dysfunction in a preclinical model of Kcnq2 developmental and epileptic encephalopathy
Miaomiao Mao1, Nikola Jancovski1, Yafit Kushner1
1The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3052, Australia.
Insights
This study characterizes a KCNQ2 variant (K556E) linked to developmental and epileptic encephalopathy (DEE). A novel KCNQ2 DEE mouse model reveals neuronal hyperexcitability and developmental pathway dysregulation, offering insights for future therapies.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Developmental and epileptic encephalopathies (DEE) are severe neurodevelopmental disorders with limited treatment options.
- Genetic variants, particularly in KCNQ2, are a major cause of DEE.
- KCNQ2 encodes the KV7.2 potassium channel, crucial for neuronal excitability.
Purpose of the Study:
- To characterize the KCNQ2 K556E variant found in a DEE patient.
- To develop and analyze a novel Kcnq2 DEE mouse model.
Main Methods:
- Heterologous expression of wild-type and mutant KCNQ2 in CHO cells.
- Patch clamp recordings to assess channel biophysical properties.
- Generation and characterization of a Kcnq2 knock-in mouse model (K557E) using behavioral, electrophysiological, and transcriptome analyses.
Main Results:
- The K556E variant showed mild loss of function when co-expressed with KCNQ3.
- The Kcnq2 DEE mouse model exhibited reduced survival, increased seizure susceptibility, and neuronal hyperexcitability.
- Retigabine (a KV7 channel opener) ameliorated seizure sensitivity and neuronal hyperexcitability.
- Transcriptome analysis indicated dysregulation of early developmental processes.
Conclusions:
- A novel Kcnq2 DEE mouse model was successfully developed, recapitulating key disease aspects.
- Electrophysiological and transcriptome data provide mechanistic insights into KCNQ2 DEE.
- Findings can inform future therapeutic strategies for KCNQ2-related DEE.
Background:
Developmental and epileptic encephalopathies (DEE) are rare but severe neurodevelopmental disorders characterised by early-onset seizures often combined with developmental delay, behavioural and cognitive deficits. Treatment for DEEs is currently limited to seizure control and provides no benefits to the patients' developmental and cognitive outcomes. Genetic variants are the most common cause of DEE with KCNQ2 being one of the most frequently identified disease-causing genes. KCNQ2 encodes a voltage-gated potassium channel KV7.2 widely expressed in the central nervous system and critically involved in the regulation of neuronal excitability. In this study, we aimed to characterise a KCNQ2 variant (K556E) found in a female patient with DEE using a heterologous expression system and a knock-in mouse model.
Methods:
Wild-type KCNQ2 or K556E variant were expressed in Chinese Hamster Ovary (CHO) cells (with or without KCNQ3) and their biophysical properties assessed using patch clamp recordings. We further engineered a new Kcnq2 DEE mouse model (K557E) based on the K556E variant and characterised it using behavioural, electrophysiological, and transcriptome analysis.
Results:
A mild loss of function was observed only when the mutant channel was co-expressed with KCNQ3 in the heterologous system. The heterozygous knock-in mice showed a reduced survival rate and increased susceptibility to induced seizures. Electrophysiology recordings in brain slices revealed a hyperexcitable phenotype for cortical layer 2/3 pyramidal neurons with retigabine (KV7 channel opener) able to rescue both the increased sensitivity to chemically-induced seizures in vivo and neuronal excitability ex vivo. Whole-brain RNA sequencing revealed numerous differentially expressed genes and biological pathways pointing at dysregulation of early developmental processes.
Conclusions:
Our study reports on a novel Kcnq2 DEE mouse model recapitulating aspects of the disease phenotype with the electrophysiological and transcriptome analysis providing insights into KCNQ2 DEE mechanisms that can be leveraged for future therapy development.
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