Abstract
Rett syndrome is a rare neuropsychiatric disorder with a wide symptomatology including impaired communication and movement, cardio-respiratory abnormalities, and seizures. The clinical presentation is typically associated to mutations in the gene coding for the methyl-CpG-binding protein 2 (MECP2), which is a transcription factor. The gene is ubiquitously present in all the cells of the organism with a peak of expression in neurons. For this reason, most of the studies in Rett models have been performed in brain. However, some of the symptoms of Rett are linked to the peripheral expression of MECP2, suggesting that the effects of the mutations affect gene expression levels in tissues other than the brain. We used RNA sequencing in Mecp2 mutant mice and matched controls, to identify common genes and pathways differentially regulated across different tissues. We performed our study in brain and peripheral blood, and we identified differentially expressed genes (DEGs) and pathways in each tissue. Then, we compared the genes and mechanisms identified in each preparation. We found that some genes and molecular pathways that are differentially expressed in brain are also differentially expressed in blood of Mecp2 mutant mice at a symptomatic—but not presymptomatic—stage. This is the case for the gene Ube2v1, linked to ubiquitination system, and Serpin1, involved in complement and coagulation cascades. Analysis of biological functions in the brain shows the enrichment of mechanisms correlated to circadian rhythms, while in the blood are enriched the mechanisms of response to stimulus—including immune response. Some mechanisms are enriched in both preparations, such as lipid metabolism and response to stress. These results suggest that analysis of peripheral blood can reveal ubiquitous altered molecular mechanisms of Rett and have applications in diagnosis and treatments’ assessments.
Highlights
Rett syndrome (RTT) is a rare neurological disease, affecting approximately 1 in every 10,000 live female births
To identify the ideal brain region for the developmental stage of our study (i.e., 7 weeks, when symptoms are advanced in the Mecp2-null male), we measured the temporal expression of methyl-CpG-binding protein 2 (MeCP2) protein in wild-type (WT) C57Bl/6 male mice in different brain areas and compared them to the full brain expression (Figure 1)
We screened for the expression of MeCP2 protein at 4 and 12 weeks of age, at which stage there were no significant differences between the full brain and the specific areas
Summary
Rett syndrome (RTT) is a rare neurological disease, affecting approximately 1 in every 10,000 live female births. The symptoms manifest after a period of apparent normality, corresponding to the first 6–18 months of life After this stage, patients present neurological features (microcephaly, seizure), motor disability (ataxia, loss of purposeful hand use, stereotyped hand movements, loss of the ability to walk, hypotonia), social impairment (loss of speech, unresponsiveness to social cues, lack of emotional expression), and autonomic complications (respiratory anomalies, cardiac dysfunction, constipation) [2]. Patients present neurological features (microcephaly, seizure), motor disability (ataxia, loss of purposeful hand use, stereotyped hand movements, loss of the ability to walk, hypotonia), social impairment (loss of speech, unresponsiveness to social cues, lack of emotional expression), and autonomic complications (respiratory anomalies, cardiac dysfunction, constipation) [2] The symptoms and their severity can be variable from one patient to another. One of the reasons for this variability is thought to be skewed X-inactivation, as patients with an X-inactivation biased to the nonmutated copy of MECP2 have shown little to no symptoms [3]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
