MECP2

The MECP2 gene provides instructions for making a protein, known as MeCP2, whose exact function is unclear. It appears to help regulate gene activity (expression) by modifying chromatin, the complex of DNA and protein that packages DNA into chromosomes. The MeCP2 protein usually regulates genes involved in brain function, even though this protein is found throughout the body.

Within the brain, the MeCP2 protein is important for the function of nerve cells (neurons) and is present in high levels in mature neurons. This protein likely plays a role in maintaining connections (synapses) between neurons, where cell-to-cell communication occurs. Many of the genes that are known to be regulated by the MeCP2 protein play a role in normal brain function, particularly the maintenance of synapses.

Researchers believe that the MeCP2 protein is also involved in processing molecules called messenger RNA (mRNA), which serve as genetic blueprints for making proteins. By cutting and rearranging mRNA molecules in different ways, the MeCP2 protein controls the production of different versions of certain proteins. This process is known as alternative splicing. In the brain, the alternative splicing of proteins is critical for normal communication between neurons.

MECP2 duplication syndrome - caused by mutations in the MECP2 gene

An extra copy of the MECP2 gene in each cell causes MECP2 duplication syndrome, a condition characterized by intellectual disability, delayed development, and seizures. This additional copy of the MECP2 gene is caused by a duplication of genetic material on the long (q) arm of the X chromosome. The size of the duplication varies from 100,000 to 900,000 DNA building blocks (base pairs), also written as 100 to 900 kilobases (kb).

Duplication of the MECP2 gene leads to the production of extra MeCP2 protein. This overproduction results in an inability of the protein to regulate the expression of other genes properly. The misregulation of gene expression in the brain results in abnormal neuronal function. These neuronal abnormalities cause irregular brain activity, leading to the signs and symptoms of MECP2 duplication.

MECP2-related severe neonatal encephalopathy - caused by mutations in the MECP2 gene

Mutations in the MECP2 gene cause MECP2-related severe neonatal encephalopathy. These mutations cause small head size (microcephaly), movement disorders, breathing problems, and seizures in affected males. Many of the MECP2 gene mutations that cause this condition in males cause a similar disorder called Rett syndrome in females. Most of these mutations change single base pairs, insert or delete base pairs in the gene, or change how the gene is processed into a protein. These changes in DNA alter the structure of the MeCP2 protein or reduce the amount of protein that is produced. As a result, cells do not have enough MeCP2 protein to bind to DNA and silence other genes. Genes that are normally regulated by this protein remain active and continue to make proteins when they are not needed. Mutations in the MECP2 gene may also disrupt alternative splicing of proteins critical for communication between neurons. Although these defects disrupt normal brain development, it remains unclear how MECP2 gene mutations lead to the signs and symptoms of MECP2-related severe neonatal encephalopathy.

PPM-X syndrome - caused by mutations in the MECP2 gene

Mutations in the MECP2 gene have been found to cause PPM-X syndrome. Eight particular mutations are responsible for approximately half of all cases of PPM-X syndrome. These mutations either change single protein building blocks (amino acids) in the MeCP2 protein or create a premature stop signal in the instructions for making the protein. Mutations that cause PPM-X syndrome lead to the production of a MeCP2 protein that cannot properly interact with DNA or other proteins and so cannot control the expression of genes. It is unclear how MECP2 gene mutations lead to the signs and symptoms of PPM-X syndrome, but misregulation of genes in the brain likely play a role in the development of intellectual disability and movement and mood disorders in affected individuals.

Rett syndrome - caused by mutations in the MECP2 gene

More than 300 mutations in the MECP2 gene have been identified in females with Rett syndrome, a brain disorder that causes problems with communication, learning, and coordination. These mutations include changes in single base pairs, insertions or deletions of DNA in the gene, and changes that affect how the gene is processed into a protein. MECP2 gene mutations alter the structure of the MeCP2 protein or reduce the amount of protein that is produced. As a result, cells do not have enough MeCP2 protein to bind to DNA and regulate gene expression. Mutations in the MECP2 gene may also disrupt alternative splicing of proteins critical for communication between neurons. Although these defects disrupt normal brain development, it remains unclear how MECP2 gene mutations lead to the signs and symptoms of Rett syndrome.

other disorders - associated with the MECP2 gene

Mutations in the MECP2 gene have also been identified in people with several other disorders that affect the brain. For example, MECP2 gene mutations are associated with some cases of moderate to severe X-linked intellectual disability. In addition, several people with the features of Rett syndrome and signs and symptoms similar to Angelman syndrome (a condition characterized by intellectual disability, problems with movement, and inappropriate laughter and excitability) have mutations in the MECP2 gene. MECP2 gene mutations or changes in the gene's activity have been reported in some cases of autism, which is a developmental disorder that affects communication and social interaction.