Project title: Molecular characterization of two severe forms of Intellectual Disability with microcephaly, associated with mutations in PQBP1 and DYRK1A
Thesis advisor: Amélie Piton
Intellectual disability is the leading cause of genetic counselling in France and obtaining an accurate and early diagnosis is essential. This project has improved the molecular diagnosis of intellectual disability associated with mutations in the DYRK1A, PQBP1 and NLGN3 genes. In parallel, the study allowed the identification of interactors of DYRK1A and PQBP1 in a model of neural progenitors and the cellular mechanisms that are deregulated when DYRK1A and PQBP1 are inactivated. This knowledge is important to better understand the pathological mechanisms involved in these neurodevelopmental disorders.
Project title: Characterization of a novel spontaneous mutation in the Kcc2 gene in mouse: a new model of developmental brain disorder
Thesis advisor: Barbara Bardoni
Co-advisor: Enzo Lalli
Developmental Brain Disorders (DBDs) encompass a highly heterogeneous group of disorders that manifest through cognitive, motor, neurobehavioral, neuroanatomical and neurophysiological aberrations. Using diverse models DBDs, this project 1) contributed to the definition of the role of cAMP and cGMP in the pathophysiology of Fragile X syndrome, 2) generated a CRISPR-Cas9 cell line with a point mutation in a novel factor involved in childhood onset schizophrenia, and 3) identified and characterised the first spontaneous mutation in the Kcc2 gene in mouse which recapitulate the phenotype of patients with the same mutation, e.g. spontaneous tonic-clonic seizures and cognitive deficit. This model will help understand the pathophysiology of this disease and will be key for the set-up of preclinical trials.