Rett syndrome is a rare genetic disorder that mostly affects females. The disease is characterized by normal early development, followed by slowed growth and a loss of motor control. As the disease progresses, patients may display symptoms such as repetitive motions, difficulty walking, and seizures.
What causes Rett syndrome?
Almost all cases of Rett syndrome are caused by mutations in the MECP2 (methyl CpG binding protein 2) gene, which provides instructions for making a protein of the same name. The MECP2 protein is involved in regulating the activity of other genes by modifying the structure of chromatin, the bundle of protein and DNA that makes up chromosomes. By making changes to chromatin, MECP2 controls which genes are “turned on” or “turned off,” which has substantial effects on cellular activity.
The MECP2 protein is present in most cells, but it plays a particularly important role in the brain. There, it is thought to help maintain connections between nerve cells by making sure the right genes are active at the right time.
The MECP2 protein also may be involved in processing molecules called messenger RNA (mRNA), which is a temporary copy of a gene that is used as a template by the protein-making machinery of the cell. Sometimes different proteins can be made from the same gene through a process called alternative splicing. The MECP2 protein may be involved in cutting and rearranging mRNA, so having a faulty MECP2 gene may mean that some proteins are not made. Alternative splicing is thought to play a crucial role in nerve cell communication and also may be important for the function of other brain cells.
Other genetic causes of Rett
Scientists have identified mutations in the CDKL5 and FOXG1 genes in individuals who have atypical or congenital Rett syndrome, but it is not yet clear how these mutations cause the disease. It is likely there are mutations in other genes that can cause Rett syndrome.
Inheritance of Rett syndrome
Although Rett syndrome is a genetic disease, less than 1% of cases are inherited. The remainder of cases are caused by de novo (new) mutations. The MECP2 gene is located on the X-chromosome, which is one of the chromosomes whose inheritance helps determine biological sex.
Females have two copies of the X-chromosome. As such, they can inherit one copy of the X-chromosome that has a mutated MECP2 gene, while the MECP2 gene on the other copy of the X-chromosome is normal. This is what usually occurs in Rett syndrome.
By contrast, males have only one X-chromosome, so if they inherit a mutant version of MECP2 they do not have a working copy of the gene. Without a functional version of MECP2, boys typically do not survive early infancy.
Yet, there are a few reported cases of males with Rett syndrome. These individuals have one of the rarer mutations that causes the disease, and may reach adulthood.
Last updated: April 27, 2021
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