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https://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. |
DOI: | 10.1038/ng.2714 |
Published version: | http://dx.doi.org/10.1038/ng.2714 |
Appears in Collections: | Aurora harvest 7 Paediatrics publications |
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