The role of the MeCP2 binding partner LEGDF in the Rett syndrome and MECP2 duplication syndrome.

Rett syndrome (RTT) is a progressive neurodevelopmental disorder without effective treatment that predominantly affects girls. It occurs in 1 of 10 000-15 000 women and is a major cause of intellectual disability. Two independent studies recently evidenced a direct interaction between the transcriptional co-activator lens epithelium-derived growth factor p75 (LEDGF/p75) and methyl-CpG-binding protein 2 (MeCP2). Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene are responsible for over 90% of classic RTT cases. More recently, Dr. Van Esch and her team at the KU Leuven showed that increased dosage of MeCP2 also leads to a severe neurodevelopmental disorder in boys, a disease designated as the MECP2 duplication syndrome (MECP2dup). Since MeCP2 is a major player in the Rett syndrome and since LEDGF/p75 and its interactome are the main research focus of the host lab since 2002, I will investigate in this PhD project the possible role of LEDGF/p75 in Rett syndrome. For this novel research line my promoter teams up with Dr. Van Esch, geneticist and expert in Rett Syndrome and Dr. V. Baekelandt, neurobiologist, both from KU Leuven. I will investigate the interaction between both proteins in vitro, in an iPSC model and in mouse brain. The project may validate LEDGF as drug target for Rett Syndrome.