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Cholesterol metabolism and Rett syndrome pathogenesis

Nature Genetics volume 45, pages 965–967 (2013)Cite this article

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Rett syndrome is caused by mutations in the gene encoding the transcriptional regulator MECP2. A new study demonstrates that cholesterol homeostasis is disrupted in Mecp2 mutant mice and suggests new therapeutic options for this disease.

Rett syndrome (RTT) is a devastating neurological disorder that is caused largely by mutations in the X-linked gene MECP2 (encoding methyl CpG-binding protein 2)1. After an initial period of normal psychomotor development, affected females experience a regression of acquired hand and language skills and develop autistic features. In addition, patients develop severe mental retardation, motor defects, stereotypical hand movements, seizures and breathing abnormalities. Most hemizygous males die perinatally. MECP2 is a nuclear protein that regulates hundreds of genes by binding to methylated DNA and recruiting various transcription factors and chromatin-remodeling proteins2,3. Although Mecp2 was the first autism spectrum disorder gene to be molecularly identified4, RTT has been difficult to target therapeutically, in part because of the broad epigenetic effects of MECP2 on gene expression. An unbiased genetic approach taken by Monica Justice and colleagues (page 1013 of this issue) demonstrates that cholesterol metabolism is perturbed in Mecp2 mutant mice, providing new therapeutic options for this complex disease5.

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Figure 1: Potential neuronal effects of perturbed cholesterol homeostasis in Mecp2 mutant mice.

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Affiliations

  1. Gabor Nagy and Susan L. Ackerman are at the Howard Hughes Medical Institute and The Jackson Laboratory, Bar Harbor, Maine, USA.

    Gabor Nagy & Susan L Ackerman

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  1. Gabor Nagy
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  2. Susan L Ackerman
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Correspondence to Susan L Ackerman.

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The authors declare no competing financial interests.

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Nagy, G., Ackerman, S. Cholesterol metabolism and Rett syndrome pathogenesis. Nat Genet 45, 965–967 (2013). https://doi.org/10.1038/ng.2738

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