Description de la soumission d'un avis
Developmental and Epileptic Encephalopathies (DEE) are rare genetic diseases. They are characterized by the early onset of epileptic seizures, sometimes starting as early as the first day of life, which are resistant to antiepileptic treatments. The prognosis is severe, with a high mortality rate in the first few years of life, or progression to severe multiple disabilities. No prenatal or postnatal signs can predict the onset of this disease before the first epileptic manifestations. To date, there is no curative treatment for patients. At the molecular level, the KCNQ2 gene is most frequently involved in early-onset forms. KCNQ2 encodes a subunit of a tetrameric voltage-gated potassium channel mediating the M current. Dominant-negative loss-of-function (LoF) variants of the KCNQ2 gene are responsible for these DEE, while gain-of-function (GoF) variants cause intellectual disability (ID) of varying severity. Surprisingly, genetic variants causing haplo-insufficiency (nonsense variants, frameshifts, deletions) are responsible for a benign form of familial neonatal epilepsy (BFNE). Given the wide range of variants observed, and the difficulty of carrying out functional tests, it seems appropriate to develop a strategy that can be adapted to every situation. Currently, two main approaches are used to specifically target and degrade a messenger RNA (mRNA): double-stranded RNA-mediated interference (RNAi) and antisense oligonucleotides (ASO). These approaches have demonstrated their therapeutic potential, notably in mouse models of epilepsy linked to defects in the SCN2A, SCN8A and DNM1 genes.
The aim of this project is to develop a therapeutic strategy aimed at inactivating the mutant allele of the KCNQ2 gene. The hypothesis is that it could be possible to transform the prognosis of patients from a severe form to a benign form.
To achieve this goal, the Human Neurogenetics team at the Marseille Medical Genetics Center (MMG – Inserm Unit 1251) has developed its own study models, and can rely on additional expertise from a wide network of collaborators.
We are looking for an enthusiastic M2 candidate with a neurosciences or molecular/human genetics background.
He/she must be interested in epilepsy, genetic diseases and pre-clinical research, and keen to interact with the other members of the team to perform collaborative work.
Located at the heart of the third largest European university hospital center, Marseille Medical Genetics (MMG) boasts a triple mission: decipher the mechanisms involved in genetic diseases, open new diagnostic and therapeutic pathways and improve the quality of life of patients affected by these rare diseases. From the genetics of rare diseases to developmental biology, from epigenetics to genome dynamics and from bioinformatics to systems biology, MMG explores all facets of the discipline through a translational approach that focuses on the patient.