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Sci Transl Med. 2017 Aug 23;9(404). pii: eaaf7588. doi: 10.1126/scitranslmed.aaf7588.

An RNA interference screen identifies druggable regulators of MeCP2 stability.

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
2
Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA.
3
Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA.
4
Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
5
Department of Pathology, Stanford University School of Medicine, Palo Alto, CA 94305, USA.
6
Department of Pathology, University of California, San Francisco, San Francisco, CA 94158, USA.
7
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. hzoghbi@bcm.edu.
8
Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
9
Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.

Abstract

Alterations in gene dosage due to copy number variation are associated with autism spectrum disorder, intellectual disability (ID), and other psychiatric disorders. The nervous system is so acutely sensitive to the dose of methyl-CpG-binding protein 2 (MeCP2) that even a twofold change in MeCP2 protein-either increased or decreased-results in distinct disorders with overlapping features including ID, autistic behavior, and severe motor dysfunction. Rett syndrome is caused by loss-of-function mutations in MECP2, whereas duplications spanning the MECP2 locus result in MECP2 duplication syndrome (MDS), which accounts for ~1% of X-linked ID. Despite evidence from mouse models that restoring MeCP2 can reverse the course of disease, there are currently no U.S. Food and Drug Administration-approved therapies available to clinically modulate MeCP2 abundance. We used a forward genetic screen against all known human kinases and phosphatases to identify druggable regulators of MeCP2 stability. Two putative modulators of MeCP2, HIPK2 (homeodomain-interacting protein kinase 2) and PP2A (protein phosphatase 2A), were validated as stabilizers of MeCP2 in vivo. Further, pharmacological inhibition of PP2A in vivo reduced MeCP2 in the nervous system and rescued both overexpression and motor abnormalities in a mouse model of MDS. Our findings reveal potential therapeutic targets for treating disorders of altered MECP2 dosage.

PMID:
28835516
PMCID:
PMC5736385
DOI:
10.1126/scitranslmed.aaf7588
[Indexed for MEDLINE]
Free PMC Article

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