Congenital myasthenic syndrome ... (Congenital myasthenic syndrome) - Genes CHRNE, RAPSN, CHAT, ColQ and DOK7.
Congenital myasthenic syndrome is a group of diseases characterized by myasthenia that worsens with physical exertion diseases. Muscle weakness usually begins in early childhood, but can also occur in adolescence or adulthood. Facial muscles are most affected, including the muscles that control the eyelids, muscles that move the eyes, and masticadors muscles and swallowing. However, none of the skeletal muscles due to muscle weakness affects, affected children may have feeding difficulties in motor skills and breathing, causing apnea can lead to cyanosis.
Congenital myasthenic syndrome is due to mutations in the CHAT, CHRNE, RAPSN, ColQ and DOK7 genes.
The CHAT gene, located on the long arm of chromosome 10 (10q11.2), encoding the protein choline acetyltransferase. This protein is found in presynaptic terminals of nerve cells, facilitating the synthesis of acetylcholine molecule. Acetylcholine is essential for normal muscle movement. When acetylcholine is released from the presynaptic terminal, it binds to a receptor protein located in the membrane of muscle cells, producing a flow of ions allowing muscu contraction and relaxation, resulting in muscle movement. They have identified more than 30 mutations in the CHAT gene cause of congenital myasthenic syndrome. Most of these mutations substitute nucleotides in the gene. The mutations result in decreased choline acetyltransferase or the synthesis of a protein with decreased activity. The resulting lack of acetylcholine reduces the availability of receivers, impairing the flow of ions through the muscle cells. A reduction in the flow of ions decreases muscle cells causing muscle movement muscle weakness. Persons with congenital myasthenic syndrome who have mutations in the CHAT gene are more likely than people affected by mutations in other genes to have apnea.
The CHRNE gene, located on the short arm of chromosome 17 (17p13.2), encoding component epsilon (?) (subunit) protein acetylcholine receptor (AChR). AChR protein found in the membrane of skeletal muscle cells and plays a critical role in the neuromuscular junction. AChR protein consisting of five subunits, each of which are encoded from a different gene. These subunits are assembled at the AChR protein in the endoplasmic reticulum before being transported to the cell membrane. There are two main forms of the protein AChR, a fetal type is present before birth and an adult type. The ? subunit is found only in adult AChR protein. Approximately 33 weeks of pregnancy, the ? subunit replaces the gamma subunit (?) (found only in fetal AChR) to form protein AChRs adults. They have identified more than 90 mutations in the gene CHRNE in people with congenital myasthenic syndrome. Most of these mutations replace nucleotides in the gene, but other mutations add or remove small sections of DNA. These mutations may alter the coding ? subunit, resulting in an increase in signaling AChR protein or a decrease AChR protein signaling, impairing cell-cell communication at the neuromuscular junction. A decrease signaling can lead to a decrease in muscle movement and cause weakness, while an increase in signaling can damage cells and cause muscle weakness. Some people with mutations in the CHRNE gene appears to have a milder disease course compared to others affected, probably due to fetal ? subunit (active at low concentrations after birth) that can partially compensate for the lack of ? subunit in adult AChR protein.
The ColQ gene, located on the short arm of chromosome 3 (3p25), encodes a protein that plays an important role in neuromuscular junction. This protein, acetylcholinesterase anchor protein to the membrane of the muscle cell at the neuromuscular junction. Acetylcholinesterase plays a role in regulating the length of the signaling between nerve cells and muscle cells to decompose acetylcholine signaling protein. They have identified more than 35 mutations in the gene ColQ cause of congenital myasthenic syndrome. Most of these mutations change the amino acids in protein or result in a nonfunctional coding shortened protein, leading to a reduction in the amount of acetylcholinesterase which is available at the neuromuscular junction. As a result, acetylcholine is not decomposed so that signaling between nerve and muscle cells is prolonged. This signaling overhead can damage muscle cells.
The DOK7 gene, located on the short arm of chromosome 4 (4p16.3), encodes a protein that is necessary for the formation of connections occurring at the neuromuscular junction. This protein is involved in the activation of MuSK protein that plays a key role in organizing various important to the development and maintenance of the neuromuscular junction proteins. In particular, the MuSK protein is involved in the concentration of the acetylcholine receptor (AChR) in the muscle membrane at the neuromuscular junction. The AChR protein is critical for signaling between nerve and muscle cells, which is necessary for movement. They have identified at least 45 mutations in the gene DOK7 in people with the disease. A mutation that occurs frequently is the addition of four nucleotides in the gene (1124_1127dupTGCC). Mutations in this gene result in a defective protein coding can not activate the MuSK protein. As a result, signaling between nerve and muscle cells is reduced. These abnormalities cause decreased muscle movement and weakness. For reasons that are unclear, individuals with mutations in the gene DOK7 tend to have muscle weakness girdle.
The RAPSN gene, located on the short arm of chromosome 11 (11p11.2), encoding the protein which binds RapSyn to different protein subunits acetylcholine (AChR). This bond helps keep the receptor subunits together and anchor AChR protein in the membrane of the muscle cell. AChR protein plays a critical role in the normal function of the neuromuscular junction. They have identified at least 45 mutations in the gene that cause RAPSN congenital myasthenic syndrome. Most of these mutations change the amino acids in protein RapSyn. A common mutation replaces the amino acid asparagine to the amino acid lysine at position 88 in the RapSyn (Asn88Lys or N88K) protein. Most mutations in the gene, causing a reduction in functional RapSyn protein, which leads to disorganization of the receptor protein in the membrane of the muscle cell and a reduction in the number of receptors. As a result, signaling at the neuromuscular junction is reduced, leading to decreased muscle movement and muscle weakness characteristic of congenital myasthenic syndrome.
This disease is inherited most often an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease. Rarely, this disorder is inherited as an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to cause disease. In some cases, an affected person inherits the mutation from an affected parent. Other cases result from new mutations in the gene and occur in people with no history of disease in your family.
Tests in IVAMI: in IVAMI perform detection of mutations associated with congenital myasthenic syndrome by complete PCR amplification of the exons of CHRNE, RAPSN, CHAT, ColQ and DOK7 genes, respectively, and subsequent sequencing.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).