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ANR funded project

Une nouvelle représentation du vivant (DS0401)
Edition 2014


Early epileptic encephalopathies caused by KCNQ2 mutations : from cellular physiology to therapeutic approaches.

To understand and treat early onset epileptic encephalopathies caused by KCNQ2 mutations.
Early onset epileptic encephalopathies are severe, intractable, and occur sporadically (thus preventing prenatal diagnosis). Multiple pathological mechanisms are possible and it is necessary to understand their pathophysiology in order to develop treatments for patients.

Neonatal epilepsies can severely impact cognitive development.
Early onset epileptic encephalopathies are a group of rare and severe diseases of brain development accompanied by recurrent and intractable epileptic seizures. The most common genetic cause is the presence of a mutation in the KCNQ2 gene. This gene encodes a potassium channel subunit. The project combines expertise in electrophysiology, genetics, cell biology and study of behavior. It aims to understand the consequences of mutations for neurons and neuronal networks, to model these abnormalities in cell and animal models and to use these models to develop new treatments.

Study of neuronal excitability in normal and pathological conditions.
The project is conducted in different cell types. We grow non-excitable cells that we force to express abnormal or normal channels to study their behavior. Secondly, we develop induced pluripotent stem cells from patients fibroblast samples to transform these cells into neurons and to have disease-related human neurons, that can be studied. The final level of study is that of an animal model (mouse) in which we have reproduced the disease through targeted genetic manipulations. These different models are studied at the molecular, cellular and behavioral levels.


We have described two new mechanisms causing these severe epilepsies. The first is an abnormal location of potassium channels in neurons, the second a current increase due to the presence of the mutation (though we thought only decreased current densities existed).
We produced a new animal model for the most severe form of early onset epileptic encephalopathy. It is a mouse in which the KCNQ2 gene has been modified to match the most severe known mutation in patients (the KCNQ2 gene is highly conserved between mouse and human). This model will be studied starting summer of 2016.
We also built cellular models that will allow us to test different therapeutic approaches (iPS cells and stable cell lines).


The results we will obtain by studying human neurons derived from induced pluripotent stem cells and studying the mouse model should enable us to understand, for the first time, what happens in the human and mouse neurons carrying a mutation in the gene KCNQ2. The results that will be obtained will guide the search for new therapies.

Scientific outputs and patents

Two articles have been published by our consortium through this project. The first describes a new mechanism for epilepsy caused by mutations of the KCNQ2 gene. We were the first to show that certain mutations relocate potassium channel abnormally inside neurons. The channel can no longer fulfill its normal role and causes electrical abnormalities (Abidi et al. Neurobiology of Disease, 2015, 80. 80-92). The second article of our consortium describes the characteristics of a mutation in the KCNQ2 gene that increases the current instead of decreasing it, which has direct consequences for potential therapeutic approaches (Devaux et al. Epilepsia, 2016 in press).


CRN2M Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille

GMGF Génétique Médicale et Génomique Fonctionnelle

INMED Institut de Neurobiologie de la Méditerranée

ANR grant: 364 928 euros
Beginning and duration: octobre 2014 - 36 mois

Submission abstract

Brain development is an extremely complex process that depends on genetically determined factors and on the electrical activity of the brain. These activities arise from the third trimester of pregnancy and play an important role in the construction of cortical maps. Many studies have shown that fundamental changes in patterns of brain activity could ultimately lead to neurological dysfunction. Nearly 50 % of children with intellectual disability have epilepsy, and one of the fundamental questions is to determine the role of epileptic seizures in the cognitive impairment. Our consortium is particularly interested by Early Onset Epileptic Encephalopathies (EOEE), a group of rare devastating epileptic syndromes of infancy imposing an enormous socio-economic burden on families and society. They are characterized by epileptic activity that consists of frequent seizures and/or major interictal paroxysmal activity accompanied by rapid deterioration of brain function with progressive disturbance of cognitive, sensory or motor functions. EOEE show a high degree of variability, both in terms of electro-clinical manifestations, contingent pathophysiological bases and etiologies. We have created a cohort of 208 EOEE patients (as 01/05/2014) for which all available medical information is collected. Patients with brain malformations or metabolic diseases, that are a known cause of EOEE, are excluded from the cohort.
There is a strong genetic basis for EOEE and the cohort is thus genetically explored. We and other laboratories found that KCNQ2 (potassium channel, voltage-gated, KQT-like subfamily, member 2) is a major gene involved in EOEE. In our cohort, to date, de novo mutations of KCNQ2 were found in 18 patients (and 6 additional mutations for which parental origin could not be determined). These findings indicate that KCNQ2 mutations are a significant cause of EOEE. This is quite unexpected because KCNQ2 mutations are traditionally described in patients with a much milder form of childhood epilepsy called benign familial neonatal seizures (BFNS). In BFNS, seizures also start at birth and stop before the end of the third month, but in contrast to severe forms of KCNQ2-related epilepsies, interictal activity is normal, as well as the cognitive outcome of most children. The fact that mutations in the same gene can give rise either to benign seizures or to dramatic epileptic outbreaks followed by intellectual disability demonstrates the importance of KCNQ2 in brain development and suggests that the resulting potassium current may be differently affected in these 2 diseases.
We propose to take advantage of the large number of mutations that we found in KCNQ2, combined with the extensive clinical information available in our cohort in order to understand the mechanisms by which KCNQ2 mutations cause epileptic encephalopathies and to set the foundation for improvement of the medical care of EOEE patients. We will use a combination of genetic, electrophysiological, biochemical and cellular analyses in vivo and in vitro in various models and cellular compartments to answer the following questions: 1- is the severity of seizures and their consequences on brain development related to the degree of potassium current inhibition and to the alterations of the level of neuronal excitability ? 2- is it possible to restore channel functionality in EOEE patients ?
Beyond the clinical and translational aspects of our project, the results obtained will improve our knowledge on the regulation of KCNQ channel, their function during brain development and synaptic plasticity. Hopefully, this project will ultimately translate into a clinical trial for KCNQ2 related EOEE patients, an objective already reached for another neurological disease by one of the partners of this project.


ANR Programme: Une nouvelle représentation du vivant (DS0401) 2014

Project ID: ANR-14-CE13-0011

Project coordinator:
Monsieur Laurent VILLARD (Génétique Médicale et Génomique Fonctionnelle)


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The project coordinator is the author of this abstract and is therefore responsible for the content of the summary. The ANR disclaims all responsibility in connection with its content.