Abstract: This invention relates generally to methods for treating, preventing and/or ameliorating symptoms of disorders characterized with aberrant RAS/MAPK signaling (e.g., Kabuki Syndrome). This invention further relates to methods and compositions for treating such disorders with pharmaceutical compositions capable of one or more of inhibiting aberrant RAS/MAPK signaling, inhibiting MEK hyperactivation related to RAS/MAPK signaling, inhibiting aberrant kmt2d, kmd6a, RAP1A, and/or RAP1B activity and/or expression related to RAS/MAPK signaling, preventing diminished RAF1 inhibition of RAP1A or RAP1B activity within RAS/C MAPK signaling, preventing or ameliorating symptoms of disorders characterized with aberrant RAS/MAPK signaling.

Abstract: The present disclosure provides methods of screening and compositions and methods for treating ciliopathy diseases. Methods are provided for screening for molecules to treat ciliopathy disorders by measuring the activity of ubiquitin-proteasome system (UPS)-mediated protein degradation in the presence and the absence of a candidate molecule, wherein an increase of the activity in the presence of the candidate molecule identifies the molecule as a potential therapeutic. The methods provided also include measuring the activity of a ubiquitin peptidase or a Zic family member 1 (ZIC1) gene product, in the presence and absence of a candidate molecule, wherein a decrease in activity in the presence of the molecule identifies it as a potential therapeutic.