@article{62a2c9330ac349fbb546fef570dc1d55,
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.",
author = "Buchovecky, {Christie M.} and Turley, {Stephen D.} and Brown, {Hannah M.} and Kyle, {Stephanie M.} and McDonald, {Jeffrey G.} and Benny Liu and Pieper, {Andrew A.} and Wenhui Huang and Katz, {David M.} and Russell, {David W.} and Jay Shendure and Justice, {Monica J.}",
note = "Funding Information: and Stroke, including funding from the American Recovery and Reinvestment Act (D.M.K.). Grants to the BCM Diabetes and Endocrinology Research Center (2P30DK079638-05) and the BCM Intellectual and Developmental Disabilities Research Center (5P30HD024064-23) from the NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development also supported this work. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development or the NIH. Funding Information: The Genetics Analysis Facility (T. Patton and C. Marshall) at the Centre for Applied Genomics, Toronto Hospital for Sick Kids, Toronto, Ontario, Canada performed the Illumina Goldengate SNP analysis. We thank J. Crowe, M. Schrock, J. Borkey, M. Hill, A. Willis and J. Shaw (Justice laboratory), C. Lee, A. MacKenzie and L. Felker (Shendure laboratory), I. Adams (Katz laboratory), B. Thompson (McDonald and Russell laboratory) and K.S. Posey and A.M. Lopez (Turley laboratory) for technical assistance. We thank C. Spencer and R. Paylor for advice on assessing mouse behavior, which was carried out in the Baylor College of Medicine (BCM) Mouse Neurobehavior Core, and C. Reynolds for advice on plethysmography, which was carried out in the BCM Mouse Phenotyping Core. We thank H. Zoghbi and J. Neul (BCM) for Mecp2 mutant mice. We also thank H. Zoghbi (BCM) and R. Behringer (University of Texas MD Anderson Cancer Center) for valuable discussions during revision of the manuscript. M. Coenraads of the Rett Syndrome Research Trust (RSRT) provided crucial moral and uninterrupted financial support while she aided intellectually through literature searches and advice. Funding Information: The work was supported by grants from the RSRT, the Rett Syndrome Research Foundation, the International Rett Syndrome Foundation (ANGEL award 2608 to M.J.J. and ANGEL award 2583 to D.M.K.), Autism Science Foundation predoctoral fellowship #11-1015, US National Institutes of Health (NIH) grants NIH T32 GM08307 to C.M.B., NIH U54 GM69338 to D.W.R., NIH R01 HL09610 to S.D.T. and NIH R01 CA115503 to M.J.J. and the National Institute of Neurologic Diseases",
year = "2013",
month = sep,
doi = "10.1038/ng.2714",
language = "English (US)",
volume = "45",
pages = "1013--1020",
journal = "Nature genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "9",
}