Rett Syndrome Mutation MeCP2 T158A Disrupts DNA Binding, Protein Stability and ERP Responses

Overview

Journal Nat Neurosci

Date 2011 Nov 29

PMID 22119903

Citations 115

Authors

Darren Goffin

Megan Allen

Le Zhang

Maria Amorim

I-Ting Judy Wang

Arith-Ruth S Reyes

Amy Mercado-Berton

Caroline Ong

Sonia Cohen

Linda Hu

Julie A Blendy

Gregory C Carlson

Steve J Siegel

Michael E Greenberg

Zhaolan Zhou

Affiliations

Soon will be listed here.

Abstract

Mutations in the MECP2 gene cause the autism spectrum disorder Rett syndrome (RTT). One of the most common MeCP2 mutations associated with RTT occurs at threonine 158, converting it to methionine (T158M) or alanine (T158A). To understand the role of T158 mutations in the pathogenesis of RTT, we generated knockin mice that recapitulate the MeCP2 T158A mutation. We found a causal role for T158A mutation in the development of RTT-like phenotypes, including developmental regression, motor dysfunction, and learning and memory deficits. These phenotypes resemble those present in Mecp2 null mice and manifest through a reduction in MeCP2 binding to methylated DNA and a decrease in MeCP2 protein stability. The age-dependent development of event-related neuronal responses was disrupted by MeCP2 mutation, suggesting that impaired neuronal circuitry underlies the pathogenesis of RTT and that assessment of event-related potentials (ERPs) may serve as a biomarker for RTT and treatment evaluation.

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