What is the Rett Syndrome Gene and How Does it Work?

Rett Syndrome is a rare neurodevelopmental condition that primarily affects girls. It is characterized by a period of seemingly normal development in early infancy, followed by a regression of skills. This loss of abilities often impacts speech, purposeful hand movements, and motor skills. The condition presents a trajectory where a child’s development slows, and they may lose interest in their surroundings or social interaction.

The MECP2 Gene Identified

The gene primarily responsible for Rett Syndrome is the Methyl-CpG-binding protein 2 gene, or MECP2. This gene is located on the X chromosome. Its discovery as the cause of Rett Syndrome in 1999 was the result of research led by Huda Zoghbi and her team, who studied the genetic material of affected families.

The MECP2 gene contains instructions for creating the MeCP2 protein, which is abundant in the brain. The identification of mutations in this gene provided a biological marker for a condition previously diagnosed only by clinical observation. This discovery provided answers to families and opened new avenues for understanding the disorder’s mechanisms.

MECP2’s Role in Healthy Development

The MeCP2 protein plays an important part in the normal development and function of the brain. It acts as a transcriptional regulator, meaning it can influence the activity of many other genes, turning them “on” or “off.” This function is important for the maturation of neurons and the maintenance of synapses, the connections between nerve cells where communication happens.

The MeCP2 protein is involved in modifying chromatin, the structure of DNA and proteins within the cell’s nucleus. By interacting with chromatin, MeCP2 helps regulate the architecture of the genetic material, which affects which genes are active. The protein is also believed to be involved in the processing of messenger RNA (mRNA), a process that allows a single gene to produce multiple protein variants.

Through its functions, the MeCP2 protein ensures the proper development of neuronal circuits. It is not so much involved in the initial creation of neurons, but in their refinement and the maturation of their connections. The protein’s presence in mature brain cells underscores its role in maintaining long-term neurological health.

Impact of MECP2 Gene Mutations

Mutations in the MECP2 gene disrupt the MeCP2 protein’s function, leading to Rett Syndrome. The result is a protein that is non-functional, partially functional, or absent. These mutations can take several forms:

• Missense mutations that change a single amino acid in the protein.
• Nonsense mutations that prematurely stop the protein from being made.
• Frameshift or deletion mutations that alter the genetic code downstream.

These mutations are de novo, meaning they occur spontaneously and are not inherited from the parents. Over 99% of cases are sporadic, with the mutation arising in the paternal germline (sperm cells). This explains why families with one affected child rarely have another with the same condition.

Rett Syndrome predominantly affects females because the MECP2 gene is located on the X chromosome. Females have two X chromosomes, while males have one X and one Y.

In females, a process called X-chromosome inactivation randomly “switches off” one of the two X chromosomes in every cell. If the X chromosome with the mutated MECP2 gene is active in a large proportion of brain cells, symptoms can be more severe. If the healthy X chromosome is more frequently active, symptoms may be milder.

In males, who have only one X chromosome, a mutation in MECP2 is often much more severe and frequently lethal before or shortly after birth.

Genetic Testing for MECP2 Variants

Genetic testing is an important component in diagnosing Rett Syndrome. It is recommended when a child displays clinical signs consistent with the disorder. While the diagnosis is primarily clinical, based on observing these symptoms, a genetic test can confirm the presence of a mutation in the MECP2 gene.

The testing process involves a blood sample from which DNA is extracted and analyzed. Laboratories perform a sequence analysis of the MECP2 gene to find mutations known to cause the condition. In some cases, other tests are used to detect larger deletions or duplications in the gene that sequencing might miss.

A positive test for a pathogenic MECP2 variant provides diagnostic certainty for families and healthcare providers. This confirmation can end a lengthy “diagnostic odyssey” and allow for access to resources, support networks, and clinical trials. When a child has clinical features of Rett Syndrome but the MECP2 test is negative, it may suggest the involvement of other genes like CDKL5 or FOXG1. Genetic counseling is recommended to help families understand the results and their implications.

Gene-Focused Research and Therapies

The discovery of the MECP2 gene’s role has directed research toward developing therapies that target the genetic cause of the disorder. These strategies are in various stages of research and are not yet standard treatments, but they aim to restore the function of the MeCP2 protein in the brain.

One area of investigation is gene therapy. The goal is to deliver a healthy copy of the MECP2 gene to the brain’s cells using a modified virus as a delivery vehicle. Clinical trials are evaluating the safety and efficacy of this approach. A challenge is ensuring the correct dosage, as both too little and too much MeCP2 protein can be harmful.

Another strategy focuses on reactivating the healthy, silent copy of the MECP2 gene on the inactive X chromosome in females. Researchers are exploring methods to “awaken” this dormant gene, using small molecules or modified CRISPR technology to remove the epigenetic marks that keep it silenced. These gene-focused approaches hold the potential to address the root cause of Rett Syndrome.