Mutations Causing Rett Syndrome Lead to Changes in Several Genes, Study Finds

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Mutations in the MECP2 gene, the underlying cause of Rett syndrome, affect  genes that regulate several cellular functions, including inflammation, cellular stress responses, and organization of cellular structures.

The study with that finding, “Integrated analysis of human transcriptome data for Rett syndrome finds a network of involved genes,” was published in The World Journal of Biological Psychiatry.

Rett syndrome is a neurological disorder that severely affects neuronal development and function. Fairly uncommon — Rett syndrome affects between one in 10,000 to 20,000 children — the disease affects girls almost exclusively.

Rett’s symptoms start early in life and its progression leads to stagnation, regression, and loss of motor and communication skills at 6 to 18 months of age, after a normal development during pregnancy and after birth.

The disorder is caused by a mutation on a gene located in the X chromosome that provides instructions to make a protein called methyl-CpG binding protein 2, or MECP2. This protein helps regulate nerve cell function and development.

During embryonic development, MECP2 protein expression is low; however, it increases during postnatal development “which may explain the late and gradual onset of the syndrome,” researchers wrote.

“Switching off MECP2 in juvenile or adult stage in mice induced the [Rett]-like phenotype indicating that MECP2 is not only essential during neuronal development but also required for neurological function and maintenance,” they added.

In this study, researchers explored which genetic alterations are caused by mutations in the MECP2 gene, with the goal of understanding how MECP2 genetic events result in the symptoms associated with Rett syndrome.

The team used data from five previously published studies that contained RNA profiles of Rett syndrome patients and matched healthy controls. All genetic information contained within genes (DNA) is first transformed into RNA and ultimately into a protein.

Researchers divided the data into three groups according to the tissue of origin: human brain tissue; fibroblasts (cells whose main job is to produce a “glue” called extracellular matrix that hold tissues together); and neuronal cells.

They then looked for genes that had different expression levels compared to control cells, which are cells with normal MECP2 expression. (Of note, gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.)

The team observed that only 11 genes whose expression changed were common between the studies included in the analysis. This increased to 51 in neuronal cells.

“After grouping the available experimental data in three sub-groups (brain tissue, fibroblasts, and neuronal cells) we identified several genes, which were not yet mentioned in relation to [Rett syndrome],” researchers wrote.

Researchers then performed a computational analysis to identify the molecular signaling pathways affected in each group of cells.

Genes in human brain cells with impaired MECP2 were involved mostly in regulating synaptic transmission (the junctions between two nerve cells that allow them to communicate), but also with inflammatory and stress-related processes.

Neuronal cells derived from Rett patients were specially affected in cellular pathways responsible for neuronal function. These same samples also were positive for alterations in cell stress, cell adhesion, and cytoskeleton and blood vessel formation. (The cytoskeleton is composed of a series of protein filaments that function to provide structural support and acts as the “frame” that gives shape to a cell.)

In fibroblasts of Rett patients, genes that regulate extracellular matrix organization and vascular endothelial growth factor were altered in all samples analyzed.

“[O]ne gene — one disease is definitively true as a basis for [Rett], but the link between mutation and phenotypic [disease characteristic] outcome is defined by a broader range of pathways and processes than just neurological or neurodevelopmental ones. This connection involves a complex network in which individual genetic variation and environmental influence determine the disorder outcome,” researchers concluded.