Reference:
Charlotte Kilstrup-Nielsen
Abstract:
Rett syndrome (RTT) is a severe pediatric neurological disorder that, because of its incidence, represents the most common genetic cause of severe intellectual disability in girls worldwide. Several RTT variants have been described ranging from milder forms with a later age of onset to conditions with very early severe epileptic manifestations. Mutations in the transcriptional repressor MeCP2 (methyl CpG-binding protein 2) are found in the majority of patients with classic RTT whereas CDKL5 (cyclin-dependent kinase-like 5) is associated with the early-onset seizure variant. Clinical, genetic and biological data suggest a functional relationship between CDKL5 and MeCP2 leading to hypothesize that common biological networks are disrupted when either gene is mutated. To determine the degree of molecular overlap between MeCP2 and CDKL5, we have by a combined RNA-seq and bioinformatics approach identified a list of genes that are deregulated in hippocampal neurons devoid of either protein. The project is aimed at validating genes belonging to common molecular networks and performing functional studies to understand their relevance for RTT onset. Even though functional assays will be specifically tailored to the single genes, depletion or overexpression of the identified genes in primary neurons and in the neo-cortex of electroporated mouse embryos will permit verifying if their gain or loss of function mimics the loss of CDKL5 and/or MeCP2. Whenever possible, the student will also investigate if chemical compounds might be able to modulate the identified target genes.
PROJECT DETAILS
beginning: 2014.
end: 2015.
Country of research: Italy
Counry of funding source: United States
Funding organization: International Rett Syndrome Foundation and International Foundation for CDKL5
Financing: PRIVATE FUNDERS – 148 000 €