MeCP2 and Treatment

MeCP2

The development of genetic and genomic research has clarified much of the mystery surrounding Rett syndrome. Rett syndrome is a purely genetic disease. Because of genetic research, we know how Rett syndrome occurs, and why symptoms occur. In the coming years, new treatments and gene therapies will be developed to reduce symptoms and potentially provide a cure. 
Through genomic research, Rett Syndrome has been linked to the X chromosome, which is one of the sex chromosomes. A chromosome is a large strand of DNA. DNA is like an instruction booklet for an organism. DNA has an alphabet of A,T, C and G. Most cases a mutation occurs in the MeCp2 gene. A gene is a specific set of instructions, written in the A, T, C, and G alphabet, that serves a specific purpose. A mutation is a change in that specific set of instructions. There is no single type of mutation that causes Rett Syndrome. It has been revealed that MeCp2 is a highly important gene, so important that it has remained the same in other species like rats and mice. Because we know that MeCp2 is linked to Rett syndrome. Researchers can cause mutations in other species like mice, to make a model for the disease. Mouse models have been very useful revealing how an organism develops with a mutated copy of MeCp2.Mice that have a mutation in MeCp2 develop tremors, breathing abnormalities, jaw misalignment, and have smaller less dense neurons, which are brain cells, similar to humans with the disease. 

Examples of other organisms withe MeCp2.

Since research has shown that it is a mutation in MeCp2 that causes Rett Syndrome. Rett is not condition that is typically passed down through families. Most of the time the mutation occurs in father’s X-chromosome, in the sperm cell. This means that the mutated cell is only passed on to the child, but is not present in the parent. However, there are familial cases, but it is only in 1% of the cases. Fortunately, most cases are sporadic and not inherited. Typically, having one child with Rett does not signal that another child is at risk for having the disorder. 
The MeCp2 gene produces a very important protein that is a necessity in regulation of genes. MeCp2 protein binds to certain genes to block DNA from being transcribed, which means copied into RNA which is then translated, or made into proteins, which perform many different functions in the cell. With a properly functioning copy of MeCp2, protein is made in the proper ratios for a healthy organism.

MeCP2 binds to BDNF promotor III. This represses function of the BDNF gene, which is involved in brain development. It is required for the development and maturation of neurons. Mecp2 binds to genes in a methylation-dependent manner. This means that methylation, which is the addition of methyl group to a gene,  acts like a chemical tag that signals to MeCP2 to bind to that gene.

An illustration of MeCp2 binding to DNA

The mouse on the right has been altered to have Rett Syndrome. It has odd paw movements, and over grooms

The FXYD1 promotor  is a target for MeCP2 to bind to. In mice models it was found that there was increased expression of FXYD1 is found in those with Rett Syndrome, and it is associated with poorer quality brain cells . MECP2 also represses the ANT1 gene. It has also been found in mice that those with a mutated MeCP2 allele had more anxiety and an abnormal stress response, similar to Rett patients. In mice, mutant MeCP2 did not bind to the promoter of CrH. Too much CrH may be related to Rett Syndrome. MeCp2 is not working properly, there is widespread abnormal gene transcription, leading to Rett Syndrome .
RTT syndrome is mainly found in females. Females are able to survive with impairment as they have a functional copy of MeCP2, as females have two X-chromosomes. The mutant copy MeCP2 causes more damage to development, as they only have one x chromosome. This normally results in death in infancy or early childhood.

Structurally, there are two main parts that have a main function for MeCP2. One is 85 amino acid, which is the substances that make up proteins, long methyl-CpG binding domain (MBD). MBD is essential for binding to DNA. The second is a 104 amino acid long transcriptional repression domain (TRD). TRD causes transcriptional repression, which prevents RNA copies from being made. . When a mutation occurs, the MBD can change and the function will be interfered with. Many mutations lead to partial or complete loss of functioning of MeCP2.

Twin studies have revealed interesting information about Rett syndrome It has pointed to the fact that Rett syndrome may be lethal in males. It has also been used to investigate the different types of mutations of MeCp2. Interestingly, the severity of Rett syndrome is linked with the type of mutation in MeCp2. This has been discovered due to DNA sequencing technology. Mutations in which a single A, T, C or G is changed, added, or missing, are linked with a relatively less severe case. In contrast, mutations that cause a large change in sequence size to the MeCp2 sequence lead to a more severe case of Rett Syndrome. The studies have also shown that twins can have the same mutation of MeCP2, and have slightly different cases of Rett Syndrome.



Illustration of the MeCP2 gene

Treatment

Many people with Rett have scoliosis or curving of the spine.

There are no cures for Rett syndrome. It can be managed, and the symptoms can be reduced. Physical therapy is used to improve or maintain mobility, and balance, and to reduce misshapen limbs, and back. Occupational therapy is used to improve use of hands, to reduce the hand-wringing gesture, and to teach the girls how to do self-directed activities, like eating or brushing hair . Dietary changes include the use of calcium and minerals to slow scoliosis and strengthen bones, the implementation of high fat, high calorie diets in increase height and weight, and a feeding tube. Braces and surgery are used to correct scoliosis and splints to adjust hand movements. Medication is used to reduce breathing problems, eliminate abnormal heart rhythm, relieve indigestion and diarrhea, and to control seizures.

Animal models are being used to come up with therapy. In a mouse model, researchers were able to find that loss of function of MeCp2 causes abnormal brain cell growth. A potential gene therapy has been found using mouse models. It was found that injecting mice with AAV9, may stabilize the symptoms or reverse them. Another study found that fat metabolism is perturbed in brains and livers of mice with Rett Syndrome. Drugs were able to improve fat metabolism, improve motor functioning and help with longevity in the mice. Additionally improvement was found in mouse models when given the drugs Levodopa and Dopa-Decarboxylase Inhibitor. Mouse models are often used to investigate the role of oxidiate stress, or damage caused by reactive oxygen in the body, in  those with Rett Syndrome, and to develop interventions. There needs to be more research done to come up with a cure in humans.

This mouse has been genetically modified to have Rett Syndrome.