A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome

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

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100 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1013-1020
Number of pages8
JournalNature genetics
Volume45
Issue number9
DOIs
StatePublished - Sep 1 2013

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ASJC Scopus subject areas

  • Genetics

Cite this

Buchovecky, C. M., Turley, S. D., Brown, H. M., Kyle, S. M., McDonald, J. G., Liu, B., Pieper, A. A., Huang, W., Katz, D. M., Russell, D. W., Shendure, J., & Justice, M. J. (2013). A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome. Nature genetics, 45(9), 1013-1020. https://doi.org/10.1038/ng.2714