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Is precision medicine relevant for Rett syndrome?

Rett mice models

We provide a full set of behavioral tests demonstrating that the generated novel knockin mouse, carrying a human mutation causing Rett syndrome, is characterized by a very severe phenotype largely overlapping with the vastly used null model. We then characterize at the molecular level why this mutation is pathogenic. Interestingly, we find that the molecular phenotypes associated with the mutant protein become overt only in mature neurons/brains. Indeed, we prove that the mutation impairs the ability of Mecp2 to acquire a tight binding to chromatin, therefore, affecting the architectural functions usually exerted by Mecp2 on the chromatin structure of mature neurons. In line with these molecular phenotypes, we show that the chromatin of the mature knockin brain is globally more accessible and transcribable compared to the WT, a phenotype that is not present in the immature brain. Vice versa, and in contrast with the general perception, the Mecp2 null brain chromatin structure is more condensed and less competent for transcription. These results well fit with most gene expression profiling studies performed so far, that unexpectedly revealed a general decrement of transcription in the Mecp2 null brain. 

By discussing our data, we suggest that, in spite of overlapping RTT-like symptoms, different mouse models of Mecp2 might display largely different molecular phenotypes, a novel perspective for the field. Furthermore, while our results reinforce our previous publications demonstrating that Mecp2 functions change with brain maturation, they challenge the general perception of the impact of Mecp2 mutations on neuronal chromatin architecture.

These studies strongly suggest that the Mecp2 null mouse might not be the best model for the study of Rett syndrome.  Indeed, when Mecp2 is absent, its functions are replaced by compensatory mechanisms that might mask and confound the consequences of its loss. Notably, these mechanisms might occur any time a knockout model of a relevant gene is generated. Eventually, by comparing the molecular and behavioral consequences of other Mecp2 mutations, we suggest that the field should investigate whether treatment of MECP2 related disorders has to consider precision medicine.


A Novel Mecp2Y120D Knock-in Model Displays Similar Behavioral Traits But Distinct Molecular Features Compared to the Mecp2-Null Mouse Implying Precision Medicine for the Treatment of Rett Syndrome.
Mol Neurobiol. 2018 Nov 6. doi: 10.1007/s12035-018-1412-2. 


Prof. Nicoletta Landsberger

Dr.ssa Angelisa Frasca
Dip. di Biotecnologie Mediche e Medicina Traslazionale
Università degli Studi di Milano
Via F.lli Cervi, 93
20090 Segrate (MI)

18 November 2018
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