Druggable CSNK2A1-MeCP2 regulatory axis links Okur-Chung neurodevelopmental syndrome with MECP2-related disorders
- 1Texas Children's Hospital
Abstract
The brain is exquisitely sensitive to methyl-CpG-binding protein 2 (MeCP2) abundance. Too little causes Rett syndrome (RTT), too much causes MECP2 duplication syndrome (MDS), and in both, severity tracks with the amount of functional MeCP2. Even modest deviations are detrimental, yet how MeCP2 abundance is controlled remains poorly understood. Using genome-wide CRISPR knockout screens, we identified hundreds of proteins regulating MeCP2, revealing a casein kinase 2 alpha 1 (CSNK2A1)-driven regulatory axis stabilizing MeCP2. We show this axis is druggable and therapeutically relevant, using a novel CSNK2A1 inhibitor in human cells and targeting Csnk2a1 in an MDS mouse model. We further connect CSNK2A1-MeCP2 regulatory disruption to Okur-Chung neurodevelopmental syndrome (OCNDS), caused by mutations in CSNK2A1, finding ~50% less hippocampal MeCP2 in an OCNDS mouse model. Together, these data identify a druggable regulatory axis modulating MeCP2 and implicate MeCP2 dysregulation in the molecular pathogenesis of OCNDS and potentially other neurodevelopmental disorders.
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BibTeX
@misc{anderson2026druggable,
title = {{Druggable CSNK2A1-MeCP2 regulatory axis links Okur-Chung neurodevelopmental syndrome with MECP2-related disorders}},
author = {A. G. Anderson and S. Chamakuri and R. Meyer-Schuman and E. H.-Y. Chu and J.-P. Revelli and J. Kim and M. Zaghlula and S. Veeraragavan and D. W. Young and H. Y. Zoghbi},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.05.764603},
url = {https://www.biorxiv.org/content/10.64898/2026.11.05.764603v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Druggable CSNK2A1-MeCP2 regulatory axis links Okur-Chung neurodevelopmental syndrome with MECP2-related disorders
AU - A. G. Anderson
AU - S. Chamakuri
AU - R. Meyer-Schuman
AU - E. H.-Y. Chu
AU - J.-P. Revelli
AU - J. Kim
AU - M. Zaghlula
AU - S. Veeraragavan
AU - D. W. Young
AU - H. Y. Zoghbi
PY - 2026
DA - 2026/11/05
PB - bioRxiv
DO - 10.64898/2026.11.05.764603
UR - https://www.biorxiv.org/content/10.64898/2026.11.05.764603v1
AB - The brain is exquisitely sensitive to methyl-CpG-binding protein 2 (MeCP2) abundance. Too little causes Rett syndrome (RTT), too much causes MECP2 duplication syndrome (MDS), and in both, severity tracks with the amount of functional MeCP2. Even modest deviations are detrimental, yet how MeCP2 abundance is controlled remains poorly understood. Using genome-wide CRISPR knockout screens, we identified hundreds of proteins regulating MeCP2, revealing a casein kinase 2 alpha 1 (CSNK2A1)-driven regulatory axis stabilizing MeCP2. We show this axis is druggable and therapeutically relevant, using a novel CSNK2A1 inhibitor in human cells and targeting Csnk2a1 in an MDS mouse model. We further connect CSNK2A1-MeCP2 regulatory disruption to Okur-Chung neurodevelopmental syndrome (OCNDS), caused by mutations in CSNK2A1, finding ~50% less hippocampal MeCP2 in an OCNDS mouse model. Together, these data identify a druggable regulatory axis modulating MeCP2 and implicate MeCP2 dysregulation in the molecular pathogenesis of OCNDS and potentially other neurodevelopmental disorders.
ER -