Rett-causing mutations reveal two domains critical for MeCP2 function and for toxicity in MECP2 duplication syndrome mice

Laura Dean Heckman,Huda Y Zoghbi,Maria H Chahrour

doi:10.7554/elife.02676

Abstract

Loss of function of the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2) causes the progressive neurological disorder Rett syndrome (RTT). Conversely, duplication or triplication of Xq28 causes an equally wide-ranging progressive neurological disorder, MECP2 duplication syndrome, whose features overlap somewhat with RTT. To understand which MeCP2 functions cause toxicity in the duplication syndrome, we generated mouse models expressing endogenous Mecp2 along with a RTT-causing mutation in either the methyl-CpG binding domain (MBD) or the transcriptional repression domain (TRD). We determined that both the MBD and TRD must function for doubling MeCP2 to be toxic. Mutating the MBD reproduces the null phenotype and expressing the TRD mutant produces milder RTT phenotypes, yet both mutations are harmless when expressed with endogenous Mecp2. Surprisingly, mutating the TRD is more detrimental than deleting the entire C-terminus, indicating a dominant-negative effect on MeCP2 function, likely due to the disruption of a basic cluster.

Highlights

Rett syndrome (RTT), the most common monogenic cause of intellectual disability in females, is a debilitating, progressive neurological disorder that is caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2) (Amir et al, 1999)
It binds DNA directly through its N-terminal methyl-CpG binding domain (MBD), whereas its C-terminal transcriptional repression domain (TRD) allows it to interact with corepressors such as Sin3a, HDAC1, and HDAC2
We found no difference between wild type (WT) and R111G Tg mice in any of these behaviors (Figure 2B–I), indicating that an intact MBD is necessary to elicit the toxicity seen in the duplication syndrome model

Summary

Introduction

Rett syndrome (RTT), the most common monogenic cause of intellectual disability in females, is a debilitating, progressive neurological disorder that is caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2) (Amir et al, 1999). MeCP2 was first identified over 20 years ago as a transcriptional repressor that binds to methylated CpG dinucleotides (Lewis et al, 1992; Wakefield et al, 1999; Free et al, 2001). It binds DNA directly through its N-terminal methyl-CpG binding domain (MBD), whereas its C-terminal transcriptional repression domain (TRD) allows it to interact with corepressors such as Sin3a, HDAC1, and HDAC2

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