Meta-Analysis of Genetic Studies Essential to Discover New Therapeutic Targets for Rett Syndrome, Reviewers Contend

Joana Carvalho, PhD avatar

by Joana Carvalho, PhD |

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cohesins and the X chromosome

Implementation of meta-analysis — a statistical approach that combines information from different studies — using data from studies on the protein and genetic landscape of Rett syndrome is essential to discover new therapeutic targets for this disease, according to a recent review.

The study, “Genome-wide transcriptomic and proteomic studies of Rett syndrome mouse models identify common signalling pathways and cellular functions as potential therapeutic targets,” was published in Human Mutation.

Rett syndrome is a rare genetic disorder occurring mostly in girls and characterized by developmental and intellectual disabilities. The condition is caused by mutations in the MECP2 gene — located on the X chromosome — that provides instructions to make a protein called MeCP2. This protein is responsible for maintaining synapses, which are the junctions between nerve cells that allow them to communicate.

Despite the groundbreaking discovery in 1999 that Rett syndrome is caused by mutations in the MECP2 gene, no other biomarkers or genes related to the disorder have been identified.

That is why the diagnosis of Rett syndrome is still largely dependent on clinical observation, and the molecular mechanisms underlying the disorder are still not fully understood, which limits the development of new therapies.

“Over the years, a number of animal models have been developed contributing to our knowledge on the role of MECP2 (…). Transcriptomic and proteomic studies of animal models are useful in identifying perturbations in functional pathways and providing avenues for novel areas of research into disease,” the authors explained.

Transcriptomics and proteomics refer to the study of all the RNA molecules (transcripts) that work as templates for the production of proteins, or all the proteins found on a cell or tissue.

This review summarized the main findings of transcriptomic and proteomic animal studies that focused on the identification of dysregulated genes and signaling cascades that might be possible therapeutic targets for the disorder.

Signaling cascades are a series of chemical reactions that begin with the activation of one or more genes and directly affect the way cells respond to certain stimulus, be it production of certain proteins or activation/shut-down of other genes.

The review included a total of 36 studies that had been performed mainly on mice genetically engineered to lack a functional Mecp2 gene (the mouse equivalent to the human MECP2 gene), mimicking Rett syndrome. Most of the studies also focused on analyzing the transcripts and proteins found on brain samples that had been obtained from these animals.

“The most striking evidence emanating from this review is the lack of concordance in the dysregulated gene lists between the different studies. This may be attributed to (…) the fact that no two studies conducted gene expression profiling in the same mouse model, in the same tissue and at the same age,” the study authors explained.

“It would be expected that studies using the same, or similar sources of material would have a higher degree of concordance in their differential gene expression lists, however this is not the case, which highlights the complexity of the disorder and how delicately Mecp2 regulates gene expression both spatially and temporally,” they added. (Of note, gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.)

Despite the high degree of variability between studies, there were a few genes that were identified in three or more studies that appeared to be dysregulated in mice with Rett syndrome. Some of these included Irak1, Efna5, Fabp7, Fkbp5, Plagl1, Fgf11, Homer2, Nsdhl and Sgk1.

Even though not all studies attempted to group dysregulated genes into specific groups of signaling cascades, those that did reported a high degree of variability in the molecular pathways affected, which, according to authors, showcases the complexity of Rett syndrome.

Signaling cascades involved in immune response and inflammation, including the tumor-necrosis factor (TNF), nuclear factor-κB (NF-κB) and the Toll-like receptor (TLR) signaling pathways were some of the most affected in animals with Rett syndrome.

In addition, studies revealed a wide array of cellular functions that were perturbed in diseased animals, including mitochondrial and synaptic function, brain development and maturation. (Mitochondria are the the cell compartments responsible for the production of energy.)

“Despite all these studies, no meta-analysis has been conducted using the raw data in an attempt to tease out any converging genes or signalling pathways with the idea of identifying novel curative treatments for Rett syndrome,” the authors said.

“Moving forward, raw data from every study should be deposited in publicly accessible online repositories where meta-analysis, using standardized analysis approaches, may be conducted. Furthermore, combining transcriptomics with proteomics will enrich the investigations which may provide more reliable ‘druggable’ targets,” they conculded.