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Please use this identifier to cite or link to this item: http://hdl.handle.net/10277/701

Authors: Gandaglia, Anna
Title: Phenotypic and molecular consequences of a pathogenic mutation in MeCP2: characterization of a novel mouse model.
Abstract: Rett syndrome (RTT) is a devastating genetic disease that affects predominantly girls. It is characterized by a host of neurological symptoms of variable severity and it is primarily caused by sporadic mutations in the X-linked Methyl-CpG binding protein 2 (MECP2) gene. Over the years, different mouse models mutated in Mecp2 – well recapitulating the human disorder – have been instrumental for understanding some aspects of RTT pathogenesis and of MeCP2 biological activities. This protein appears as a multifunctional molecule involved in many different processes, such as transcriptional regulation and chromatin compaction. However, several aspects regarding MeCP2 and the consequences of its alterations need further deeper investigation. In particular, new interest is rising on the post-translational modifications found along the protein, which are hypothesized to regulate its multiple biological functions. In this context, the Tyr-120 residue of MeCP2 appears worth of interest since it is both subjected to phosphorylation and associated with the development of Rett syndrome, with its substitution to aspartic acid resulting pathogenic in humans. Previous in vitro studies aimed at characterizing the Tyr-120 phospho-isoform permitted to reveal a novel localization of the protein at the centrosome and a functional association with this cellular organelle. To better investigate the relevance of this amino acid site and of its defective phosphorylation we generated a knock-in mouse model carrying the disease-causing Y120D mutation. Here we present the phenotypic, morphological and molecular characterization of this novel mouse line. We show that C57BL6J and CD1 Mecp2Y120D mice suffer from a host of RTT-like phenotypes, while the mutated neuronal cells and tissues do not present some of the abnormalities typically found in Mecp2-null models. Importantly, the Y120D alteration causes the subnuclear delocalization of the protein from pericentromeric heterochromatic foci. Moreover, adult, but not immature, brains from knock-in animals are characterized by altered levels of Mecp2 and of one of its phospho-isoforms. They also show increased solubility of the mutated protein and reduced chromatin compaction. Overall, these molecular defects – together with other aspects that need to be better analysed – likely contribute to the pathogenic mechanisms leading to RTT-like phenotypes. We believe that the study of this new genetically engineered mouse model will help to shed light on the importance of MeCP2 post-translational modifications and on their relevance in RTT pathogenesis.
Keywords: Rett syndrome, MeCP2, phosphorylation, characterization, mouse model, pathogenic mutation
Issue Date: 2015
Language: eng
Doctoral course: Neurobiologia
Academic cycle: 28
Publisher: Università degli Studi dell'Insubria
Citation: Gandaglia, A.Phenotypic and molecular consequences of a pathogenic mutation in MeCP2: characterization of a novel mouse model. (Doctoral Thesis, Università degli Studi dell'Insubria, 2015).

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