Small molecule inhibition of RAS/MAPK signaling ameliorates developmental pathologies of Kabuki Syndrome

Scientific Reports
I-Chun TsaiNicholas Katsanis

Abstract

Kabuki Syndrome (KS) is a rare disorder characterized by distinctive facial features, short stature, skeletal abnormalities, and neurodevelopmental deficits. Previously, we showed that loss of function of RAP1A, a RAF1 regulator, can activate the RAS/MAPK pathway and cause KS, an observation recapitulated in other genetic models of the disorder. These data suggested that suppression of this signaling cascade might be of therapeutic benefit for some features of KS. To pursue this possibility, we performed a focused small molecule screen of a series of RAS/MAPK pathway inhibitors, where we tested their ability to rescue disease-relevant phenotypes in a zebrafish model of the most common KS locus, kmt2d. Consistent with a pathway-driven screening paradigm, two of 27 compounds showed reproducible rescue of early developmental pathologies. Further analyses showed that one compound, desmethyl-Dabrafenib (dmDf), induced no overt pathologies in zebrafish embryos but could rescue MEK hyperactivation in vivo and, concomitantly, structural KS-relevant phenotypes in all KS zebrafish models (kmt2d, kmd6a and rap1). Mass spectrometry quantitation suggested that a 100 nM dose resulted in sub-nanomolar exposure of this inhibitor and was suffic...Continue Reading

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Citations

Sep 4, 2019·PLoS Biology·Maria de Los Angeles SerranoH Joseph Yost
Sep 15, 2020·Birth Defects Research·Michael A GarlandChengji J Zhou
Dec 23, 2020·Genesis : the Journal of Genetics and Development·Janina Schwenty-LaraAnnette Borchers
Jan 1, 2021·Frontiers in Oncology·Flora CimminoMario Capasso
Mar 20, 2021·Molecular Therapy. Methods & Clinical Development·Li ZhangHans Tomas Bjornsson

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Methods Mentioned

BETA
GTPases
genotyping
PCR
electrophoresis
Protein Assay

Software Mentioned

Image J
NIS Elements
ImageJ

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