Rett Syndrome and MECP2 Duplication Syndrome: Disorders of MeCP2 Dosage

Rett syndrome (RTT) is a neurodevelopmental disorder caused predominantly by loss-of-function mutations in the gene ( ), which encodes the MeCP2 protein. RTT is a -related disorder, along with duplication syndrome (MDS), caused by gain-of-function duplications of . Nearly two decades of research hav...

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Bibliographic Details
Published in:Neuropsychiatric disease and treatment 2022-01, Vol.18, p.2813-2835
Main Authors: Collins, Bridget E, Neul, Jeffrey L
Format: Article
Language:English
Subjects:
Causes of
Children & youth
Cognitive ability
Convulsions & seizures
Disability
disease modeling
dna methylation
Drug development
epigenetics
Females
Gene mutations
Genetic aspects
Genetic disorders
Genomes
Genotypes
Males
MeCP2 protein
Medical research
Medicine, Experimental
Methyl-CpG binding protein
Mutation
Nervous system diseases
Neurodevelopmental disorders
Pediatrics
Phenotypes
Rett syndrome
Review
Skills
therapeutics
X chromosomes
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Description
Summary:Rett syndrome (RTT) is a neurodevelopmental disorder caused predominantly by loss-of-function mutations in the gene ( ), which encodes the MeCP2 protein. RTT is a -related disorder, along with duplication syndrome (MDS), caused by gain-of-function duplications of . Nearly two decades of research have advanced our knowledge of MeCP2 function in health and disease. The following review will discuss MeCP2 protein function and its dysregulation in the -related disorders RTT and MDS. This will include a discussion of the genetic underpinnings of these disorders, specifically how sporadic X-chromosome mutations arise and manifest in specific populations. We will then review current diagnostic guidelines and clinical manifestations of RTT and MDS. Next, we will delve into MeCP2 biology, describing the dual landscapes of methylated DNA and its reader MeCP2 across the neuronal genome as well as the function of MeCP2 as a transcriptional modulator. Following this, we will outline common mutations and genotype-phenotype correlations in both diseases, with particular focus on mutations associated with relatively mild disease in RTT. We will also summarize decades of disease modeling and resulting molecular, synaptic, and behavioral phenotypes associated with RTT and MDS. Finally, we list several therapeutics in the development pipeline for RTT and MDS and available evidence of their safety and efficacy.
ISSN:1176-6328
1178-2021
1178-2021
DOI:10.2147/NDT.S371483