Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/86762
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Type: Journal article
Title: A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome
Author: Buchovecky, C.
Turley, S.
Brown, H.
Kyle, S.
McDonald, J.
Liu, B.
Pieper, A.
Huang, W.
Katz, D.
Russell, D.
Shendure, J.
Justice, M.
Citation: Nature Genetics, 2013; 45(9):1013-1022
Publisher: Nature Publishing Group
Issue Date: 2013
ISSN: 1061-4036
1546-1718
Statement of
Responsibility: 
Christie M Buchovecky, Stephen D Turley, Hannah M Brown, Stephanie M Kyle, Jeffrey G McDonald, Benny Liu, Andrew A Pieper, Wenhui Huang, David M Katz, David W Russell, Jay Shendure & Monica J Justice
Abstract: Mutations in MECP2, encoding methyl CpG-binding protein 2, cause Rett syndrome, the most severe autism spectrum disorder. Re-expressing Mecp2 in symptomatic Mecp2-null mice markedly improves function and longevity, providing hope that therapeutic intervention is possible in humans. To identify pathways in disease pathology for therapeutic intervention, we carried out a dominant N-ethyl-N-nitrosourea (ENU) mutagenesis suppressor screen in Mecp2-null mice and isolated five suppressors that ameliorate the symptoms of Mecp2 loss. We show that a stop codon mutation in Sqle, encoding squalene epoxidase, a rate-limiting enzyme in cholesterol biosynthesis, underlies suppression in one line. Subsequently, we also show that lipid metabolism is perturbed in the brains and livers of Mecp2-null male mice. Consistently, statin drugs improve systemic perturbations of lipid metabolism, alleviate motor symptoms and confer increased longevity in Mecp2 mutant mice. Our genetic screen therefore points to cholesterol homeostasis as a potential target for the treatment of patients with Rett syndrome.
Keywords: Animals; Mice, Knockout; Mice; Rett Syndrome; Disease Models, Animal; Cholesterol; Codon, Terminator; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Chromosome Mapping; Behavior, Animal; Mutation; Quantitative Trait Loci; Female; Male; Methyl-CpG-Binding Protein 2
Rights: © 2013, Nature America Inc. All rights reserved.
RMID: 0020131124
DOI: 10.1038/ng.2714
Appears in Collections:Paediatrics publications

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