title: A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome.
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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Christie M
authors.initials: CM
authors.lastname: Buchovecky
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Turley
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Brown
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Kyle
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: McDonald
authors.forename: Benny
authors.initials: B
authors.lastname: Liu
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Pieper
authors.forename: Wenhui
authors.initials: W
authors.lastname: Huang
authors.forename: David M
authors.initials: DM
authors.lastname: Katz
authors.forename: David W
authors.initials: DW
authors.lastname: Russell
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.forename: Monica J
authors.initials: MJ
authors.lastname: Justice
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism*; D002874:Chromosome Mapping; D018388:Codon, Terminator; D004195:Disease Models, Animal; D005260:Female; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D040641:Quantitative Trait Loci; D015518:Rett Syndrome / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality
chemical_list: D018388:Codon, Terminator; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D051783:Methyl-CpG-Binding Protein 2; D002784:Cholesterol
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