Rett syndrome (RTT) is a neurodevelopmental disorder mainly caused by mutations in the methyl-CpG-binding-protein-2 gene (MECP2). MeCP2 is a multifunctional protein involved in many cellular processes, but the mechanisms by which its dysfunction causes disease are not fully understood. The duplication of MECP2 is the cause of a different disorder, MECP2 duplication syndrome (MDS). There are patients with an overlap phenotype with RTT and mutations in genes other than MECP2 (RTT-like). The purpose of this study was to characterize the molecular alterations in patients with RTT in order to identify potential biomarkers or therapeutic targets for this disorder.

We used a combination of transcriptomics (RNAseq) and proteomics (TMT-mass spectrometry) to characterize the expression patterns in fibroblast cell lines from 22 patients with RTT-MECP2,15 patients with MDS,12 patients with RTT-like phenotypes and 13 healthy controls. 

We identified molecular alterations in cellular functions and pathways that may contribute to the disease phenotype in patients with RTT,such as deregulated cytoskeletal components, vesicular transport elements, ribosomal subunits and mRNA processsing machinery. We compared RTT expression profiles with MDS seeking changes in opposite directions that could lead to the identification of MeCP2 direct targets. Some of the deregulated transcripts and proteins were consistently affected in patients with RTT-like phenotypes, revealing potentially relevant molecular processes in patients with overlapping traits and different genetic aetiology.

The integration of data in a multi-omic analysis has helped to interpret the molecular consequences of MECP2 dysfunction, contributing to the characterisation of the molecular landscape in patients with RTT.