CE12 - Génétique, génomique et ARN

Probing the roles of AGO variants in neurodevelopmental disorders – PAgoDe

Submission summary

De novo missense variants and inframe deletions were identified as causing neurodevelopmental disorders (NDD) characterized by intellectual disability, autism, brain anomalies and epilepsy in AGO1, AGO2 and more recently in AGO3. These genes encode Argonaute proteins which are involved in small non-coding RNA based gene-silencing pathways and have additional roles in regulation of transcription and splicing. The high percentage of sequence identity between AGO proteins and their target redundancy, as well as the strong overlap at the molecular (recurrent amino acid positions mutated in the different genes) and clinical (similar clinical manifestations) levels suggest that common mechanisms might be disrupted in NDD caused by AGO mutations. The objectives of PAgoDe are to dissect the clinical and molecular basis of these genetic disorders and how they overlap. To address these questions, we will first better delineate the clinical manifestations presented by individuals, identify novel variants in these genes and search for genotype-phenotype correlations. We will then combine approaches using complementary in vitro (human neural stem cell - hNSC) with in vivo (embryonic mouse cortices, drosophila) models to study the consequences of the patients’ variants and to decipher the respective roles of AGO proteins during brain development. We will analyze how expression of the two most recurrent variants on one hand and how knock-down of AGO genes (separately and simultaneously) on the other hand will affect miRNA functioning and mRNA regulation, but also neuronal differentiation and functioning. Finally, we will try to understand the phenotypic variability found for individuals mutated for the same gene and even the same variant, by searching for any correlation between the location of variants on protein (and their effect) and the clinical severity of the phenotype. We will also search, for individuals carrying the same variant, for potential second-hit or modifiers. In conclusion, this project will help to understand the roles of AGO proteins during brain development and how alterations of their functions can lead to neurodevelopmental disorder, which might lead to the identification of potential common therapeutic targets.

Project coordination

Amélie Piton (Institut de génétique et de biologie moléculaire et cellulaire (UM 41 - UMR 7104 - UMR_S 1258))

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

IGBMC Institut de génétique et de biologie moléculaire et cellulaire (UM 41 - UMR 7104 - UMR_S 1258)
IGBMC Institut de génétique et de biologie moléculaire et cellulaire (UM 41 - UMR 7104 - UMR_S 1258)
LBD Laboratoire de Biologie du développement

Help of the ANR 546,630 euros
Beginning and duration of the scientific project: September 2023 - 36 Months

Useful links

Explorez notre base de projets financés

 

 

ANR makes available its datasets on funded projects, click here to find more.

Sign up for the latest news:
Subscribe to our newsletter