Study sheds new light on molecular mechanisms contributing to Rett
Differential RNA processing may underlie changes, per patient, mice data
A new study highlights how MeCP2 protein dysfunction, particularly related to changes in alternative splicing — a process by which different proteins can be made from the same gene — implicated in brain function, may contribute to Rett syndrome.
Specifically, the researchers found that in both Rett patients and mouse models of Rett, there were changes in genes related to synaptic function, or the transmission of nerve signals between cells. Changes also were seen in the adhesion between cells and the extracellular matrix, known as the ECM, which is a network of molecules that provides structural and nutritional support to cells.
“Our extensive bioinformatics study indicates, for the first time, a significant dysregulation of [alternative splicing] in human [Rett] datasets, suggesting the crucial contribution of altered RNA processing to the [disease mechanisms]” of Rett, the researchers wrote.
The study, “Integrated gene expression and alternative splicing analysis in human and mouse models of Rett syndrome,” was published in the journal Scientific Reports.
Dysregulation found in molecular mechanisms in mice, patients
Rett syndrome is mainly caused by mutations in the MECP2 gene, which provides instructions for producing a protein with the same name that regulates the activity of other genes. The MECP2 protein is particularly important for the brain’s development and function.
Studies of Rett have also implicated abnormal alternative splicing — in which protein-coding sections from the same gene are joined in different combinations — as a contributor to the disease.
However, “despite the extensive preclinical and clinical research, it is still unclear how MECP2 dysfunction leads to the disease,” the researchers wrote.
To know more, a team of scientists in Italy analyzed data from publicly available RNA sequencing datasets in patients and mice. Selected samples were compared with controls without the disease.
In human data, from a total of 6,367 differentially expressed genes — meaning genes with high or low gene activity relative to normal — 96 were common to three or more datasets. Five genes were dysregulated in half of the human datasets. These were: CD44, SHISA6, PDLIM1, SLC16A3, and SOCS3.
Among the 96 genes, seven were autism-spectrum disorders risk genes, while 10 coded for transcription factors, meaning they’re involved in the regulation of gene activity. One coded for an RNA-binding protein, which is a type of protein that binds to RNA and regulates protein production.
Next, the investigators turned to bioinformatics, or software tools that help analyze biological data. These were used to find whether these dysregulated genes shared similar functions. The results showed that shared biological pathways involved cell communication, synaptic function, and the binding between cells and the extracellular matrix.
Although we are far from fully understanding the molecular mechanisms underlying [Rett], our … study provides new insights into [Rett] dysfunctional pathways, highlighting dysregulation in molecular processes … in both human and mouse models.
In mice, from 3,011 dysregulated genes, 113 were shared by at least three datasets. Three — Cacna1g, Irak1, and Sdk1 — were significantly altered in most of the datasets. Among the 113 genes, three were implicated in autism susceptibility, specifically Cacna1g, Oxtr, and Sema5a.
Overall, changes common to human and mouse datasets affected the interaction between cells and the extracellular matrix and calcium signaling. Calcium is essential for the normal functioning and communication between neurons, or nerve cells.
Regarding alternative splicing, 20 genes, from a total of 940, underwent alternative splicing in at least three datasets and two in half of the datasets — CD47 and ANKRD36C. Most of these genes were related to neurodevelopmental disorders.
In mice, from 394 genes with alternative splicing, 11 were shared by at least three datasets. Functional analysis also indicated that these genes were associated with proteins involved in synaptic function. However, none of the genes with differential alternative splicing in patients was also altered in its mouse counterpart.
“Although we are far from fully understanding the molecular mechanisms underlying [Rett], our … study provides new insights into [Rett] dysfunctional pathways, highlighting dysregulation in molecular processes … in both human and mouse models,” the researchers wrote.
According to the team, these “findings could enhance our understanding of disease mechanisms and lead to new opportunities for improving [Rett] therapeutic intervention.”
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