Expanding the MECP2 network using comparative genomics reveals potential therapeutic targets for Rett syndrome

摘要: Inactivating mutations in the Methyl-CpG Binding Protein 2 (MECP2) gene are main cause of Rett syndrome (RTT). Despite extensive research into MECP2 function, no treatments for RTT currently available. Here we use an evolutionary genomics approach to construct unbiased network, using 1,028 eukaryotic genomes prioritize proteins with strong co-evolutionary signatures MECP2. Focusing on targeted by FDA approved drugs led three promising candidates, two which were previously linked function (IRAK, KEAP1) and one that was not (EPOR). We show each these compounds has ability rescue different phenotypes inactivation cultured human neural cell types, appear act Nuclear Factor Kappa B (NF-{kappa}B) signaling inflammation. This study highlights potential comparative accelerate drug discovery, yields new avenues treatment RTT. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/431162v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@a2a404org.highwire.dtl.DTLVardef@1be2f0borg.highwire.dtl.DTLVardef@102a413org.highwire.dtl.DTLVardef@6203eb_HPS_FORMAT_FIGEXP M_FIG C_FIG