Genes Related to Mitochondrial Functions, Protein Degradation, and Chromatin Folding Are Differentially Expressed in Lymphomonocytes of Rett Syndrome Patients

Alessandra Pecorelli,Joussef Hayek,Alessio Cortelazzo,Raffaella Canali,Silvia Leoncini,Guido Leoni,Giuseppe Valacchi,Claudio De Felice,Franco Cervellati,Cinzia Signorini,Lucia Ciccoli

doi:10.1155/2013/137629

Abstract

Rett syndrome (RTT) is mainly caused by mutations in the X-linked methyl-CpG binding protein (MeCP2) gene. By binding to methylated promoters on CpG islands, MeCP2 protein is able to modulate several genes and important cellular pathways. Therefore, mutations in MeCP2 can seriously affect the cellular phenotype. Today, the pathways that MeCP2 mutations are able to affect in RTT are not clear yet. The aim of our study was to investigate the gene expression profiles in peripheral blood lymphomonocytes (PBMC) isolated from RTT patients to try to evidence new genes and new pathways that are involved in RTT pathophysiology. LIMMA (Linear Models for MicroArray) and SAM (Significance Analysis of Microarrays) analyses on microarray data from 12 RTT patients and 7 control subjects identified 482 genes modulated in RTT, of which 430 were upregulated and 52 were downregulated. Functional clustering of a total of 146 genes in RTT identified key biological pathways related to mitochondrial function and organization, cellular ubiquitination and proteosome degradation, RNA processing, and chromatin folding. Our microarray data reveal an overexpression of genes involved in ATP synthesis suggesting altered energy requirement that parallels with increased activities of protein degradation. In conclusion, these findings suggest that mitochondrial-ATP-proteasome functions are likely to be involved in RTT clinical features.

Highlights

Rett syndrome (RTT) is a rare form of autism spectrum disorder (ASD), which mostly affects girls with worldwide prevalence rate ranges from 1 : 10,000 to 1 : 20,000 live births [1,2,3,4,5]
Given that RTT results from dysfunction of the transcriptional modulator MeCP2, several strategies have been developed to identify its target genes in order to gain insights into the disease pathogenesis [12,13,14,15,16,17,18]
To identify gene expression changes associated with and potentially related to MeCP2 mutations and to delineate alterations of pathways associated with the disease, we evaluated and compared transcriptomic profiles in peripheral blood lymphomonocytes (PBMC) from RTT patients and control subjects

Summary

Introduction

Rett syndrome (RTT) is a rare form of autism spectrum disorder (ASD), which mostly affects girls with worldwide prevalence rate ranges from 1 : 10,000 to 1 : 20,000 live births [1,2,3,4,5]. The clinical picture of classical form progresses through 4 stages and is characterized by normal development for the first 6 to 18 months, followed by loss of purposeful hand movements, failure of speech development, autistic-like behavior, slowed brain and head growth, and mental retardation [9]. To date, it is not known how MeCP2 mutations lead to RTT phenotypes; the identification of the pathways. MeCP2 is considered a multifunctional protein, since it is implicated in genome transcriptional silencing, and in transcriptional activation, by regulating chromatin and nuclear architecture [11]; its malfunction or mutation can lead to severe cellular function alterations

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