Developmental Brain Disorders Laboratory
- Anne Philippe
- Valérie Malan
- Vincent Cantagrel
- Giulia Barcia
- Marlène Rio
- Karthyayani Rajamani
- Caroline Demily
- Julien Fregeac
- Alexandre Goumba
- Ekin Ucüncü
- Karine Siquier-Pernet
- Sherlina Salignac
- Nami Altin
Developmental brain disorders (DBD) encompass a highly heterogeneous group of diseases characterized by impairments in cognition, communication, behavior or motor functioning as a result of atypical brain development. This group of disease includes intellectual disability (ID), autism spectrum disorder (ASD), attention deficit hyperactivity disorder, specific learning disorder, and motor disorders. Neurodevelopmental disorders, also extends to conditions such as schizophrenia and epilepsy. Epidemiological studies show that co-occurrence of several neurological features is the rule. For example, up to 70% of individuals with ASD present with ID. Similarly, the prevalence of epilepsy in people with ID is 26%. Cerebellum developmental defects are recognized to be responsible of specific neuropsychological deficits and pediatric onset-ataxia presents often as developmental delay and intellectual disability. This phenotypic overlap is also mirrored at the genetic level. A number of studies have shown that CNVs (i.e. the 16p11.2 deletion) or genes (i.e. SHANK3, SCN2A genes) linked to ASD are also found in ID, epilepsy or schizophrenia. Taken together, these observations support the existence of common pathophysiological mechanisms for DBD which should be viewed as a continuum of developmental brain dysfunction.
Despites recent progresses, a large number of cases remain unexplained. With a combined prevalence of up to 3% of the population, DBD accounts for 10% of the total health care cost in most Western countries far more than cancer or cardiovascular diseases. Understanding the biological bases of these conditions is thus a major medical and socio-economical challenge. Our project aims to decipher the molecular defects underlying cognitive disorders and to elucidate the pathophysiological mechanisms leading to cognitive impairment.
Decipher the genetic architecture of DBD
Over the last decade and using state-of-the-art genetic and genomics technologies, our group has characterized numerous chromosomal anomalies and disease-causing mutations responsible for DBD. To evaluate the functional impact of newly identified genomic variants several complementary approaches based on yeast models, CRISPR-Cas9 genome editing system in human neural stem cells and organisms like zebrafish or mouse are used.
Our most important scientific accomplishments over the recent years include (i) The demonstration that loss of function mutations in SNX14, coding for a protein involved in intracellular trafficking, impacts lysosome and autophagosome homeostasis with consequences on cerebellum development and neurons survival; (ii) the demonstration that members of the Drosophila Behavior Human Splicing (DBHS) protein family play a key role in inhibitory synapse biology; (iii) The identification of biallelic mutations in FRRS1L as a new cause for severe ID and the demonstration of the key role of this gene in the priming step of AMPAR biogenesis and fast excitatory synaptic; (iv) The characterization of the prevalence of de novo mutation in early-onset cerebellar atrophy and the identification of a new condition resulting from CACNA1G de novo mutations.
Identify the molecular causes of developmental cerebellar disorders with ID
Cerebellar defects are well known to cause imbalance and poor coordination. However, over the last decade, clinical and neuropsychological investigations highlighted the important role of the cerebellum in the acquisition of higher-order cognitive and affective skills. A better understanding of human cerebellum development should help to understand its role in cognition. We currently use exome sequencing in patients from Necker hospital or from the Middle East to identify new genes involved in these disorders and we study the effect of the identified variants using cell, fish or mouse models.
Characterize the physiopathological mechanisms involved in the neurological symptoms caused by a defect in protein N-glycosylation
The disruption of protein N-glycosylation is responsible of a group of genetic diseases frequently associated with ID and cerebellar atrophy/hypoplasia. The reason why the central nervous system and mostly the cerebellum are especially sensitive to this defect is totally unknown. This project aim is to identify the cellular and biochemical targets involved in these diseases using a conditional knockout mouse model for the Srd5a3 gene.