A plasma proteomic approach in Rett syndrome: classical versus preserved speech variant

Abstract

Rett syndrome (RTT) is a progressive neurodevelopmental disorder mainly caused by mutations in the gene encoding the methyl-CpG-binding protein 2 (MeCP2). Although over 200 mutations types have been identified so far, nine of which the most frequent ones. A wide phenotypical heterogeneity is a well-known feature of the disease, with different clinical presentations, including the classical form and the preserved speech variant (PSV). Aim of the study was to unveil possible relationships between plasma proteome and phenotypic expression in two cases of familial RTT represented by two pairs of sisters, harbor the same MECP2 gene mutation while being dramatically discrepant in phenotype, that is, classical RTT versus PSV. Plasma proteome was analysed by 2-DE/MALDI-TOF MS. A significant overexpression of six proteins in the classical sisters was detected as compared to the PSV siblings. A total of five out of six (i.e., 83.3%) of the overexpressed proteins were well-known acute phase response (APR) proteins, including alpha-1-microglobulin, haptoglobin, fibrinogen beta chain, alpha-1-antitrypsin, and complement C3. Therefore, the examined RTT siblings pairs proved to be an important benchmark model to test the molecular basis of phenotypical expression variability and to identify potential therapeutic targets of the disease.

Figure 1

In the pedigrees the two RTT sisters families are represented by grey circles (milder variant = preserved speech variant, PSV-RTT) or black circles (more severe phenotype = classical RTT) with their respective clinical scores as derived by the approbation of phenotypical severity scale [9]. In the 2-DE maps typical control plasma proteome (healthy control), RTT sisters Family 1 (no. 1, no. 2) and RTT sisters Family 2 (no. 3, no. 4) are shown. Arrows indicate the protein spots with significant variations in their major or minor relative volume; circles are used to indicate the absence of the spots (i.e., qualitative variations).

Figure 2

Plasma proteins expression in sisters with classical Rett syndrome as protein expression ratios of classical RTT versus PSV-RTT plasma proteome. Data are expressed as box-and-whiskers plots. Results of the Kruskal-Wallis ANOVA are shown.