The main objective of the GENDEV team is to decipher the genetic causes of neurodevelopmental disorders through the conduct of integrative and translational projects.
The team comprises several clinicians who give access to a wide range of neurogenetic disorders and a broad recruitment of well characterized patients through National Reference Centres for rare diseases, as well as molecular geneticists/biologists and bioinformaticians.
The presence of these complementary skills allows to develop ambitious projects that aim at elucidating underlying pathophysiological mechanisms.
- To identify rare disease genetic basis: cohorts, family-based studies, linkage analysis, array CGH, next-generation sequencing (panel of genes, exome, whole genome)
- To study gene function, effects of mutations and pathophysiological mechanisms: human cellular and zebrafish animal models, molecular and biochemical approaches for gene expression analysis (qRT-PCR, RNAseq…), protein expression and interaction/complex formation (IP, WB…)
- We also use data (transcriptomes…) from human or zebrafish public databases.
The two main projects of the team concern a rare Mendelian disease, the Taybi-Linder syndrome (TALS or microcephalic osteodysplastic primordial dwarfism type 1) and a plurifactorial disease, Idiopathic Scoliosis (IS). Causal genes for these conditions were identified by P. Edery and coll. in 2011 and 2015 respectively.
TALS is a very rare and severe autosomal recessive disorder characterized by syndromic brain malformations including severe neuronal migration defects, very short stature with bone anomalies, and early unexplained death (< 3 years old).
The causative gene, RNU4ATAC, was the first non-coding gene responsible for a monogenic disorder. U4atac snRNA is a component of the minor spliceosome involved in the removal of <1% of introns, the so-called U12-type introns (~850 introns located in 700 genes). We aim to understand why RNU4ATAC mutations lead to neuronal growth and migration defects, and investigate fine mechanisms of U12-type intron splicing in cells derived from controls, patients and in zebrafish models.
IS is defined as a 3D torsion of the spine in the absence of obvious underlying anatomical or physiological defect. It affects as much as 3% of the teenagers worldwide, with the most severe forms necessitating invasive surgical correction. The first penetrant mutations identified in IS families are located in a gene, POC5, involved in the maturation of the centrioles that form the cilium base.
Our goal is to identify new causal genes in our cohort of human families with IS and test their function in zebrafish, a favoured model to study IS. In parallel, we investigate pathogenic mechanisms of IS by studying in vitro and in vivo the impact of POC5 variants on the protein function. Ultimately, we want to take advantage of the zebrafish POC5 model to conduct a chemical drug screen to start investigating a therapeutic approach.
Sylvie Mazoyer - email@example.com