Centronuclear myopathy (Centronuclear myopathy) - Genes DNM2, BIN1 and TTN
Centronuclear myopathy is the disease characterized by muscle weakness and atrophy, mainly affecting the skeletal muscles. Centronuclear severity of myopathy varies among affected individuals, even among members of the same family.
Centronuclear myopathy people with muscle weakness begin to manifest at any time from birth to early adulthood. Muscle weakness worsens slowly over time and can lead to delayed development of motor, such as crawling or walking skills; muscle pain during exercise; and difficulty walking. Some affected individuals may need a wheelchair because the muscles atrophy and weakness becomes more severe. In rare cases, muscle weakness improves with time. Some people with Centronuclear myopathy with respiratory problems related to the weakness of the respiratory muscles. Other signs and symptoms related to the disease may include ptosis and weakness in other facial muscles, including the muscles that control eye movement; Abnormalities in the feet; high - arched palate; and scoliosis. Rarely, people with myopathy Centronuclear have cardiomyopathy, neuropathy, or intellectual disability.
A key feature of the centronuclear myopathy is the displacement of the core in muscle cells. Normally the core is located at the edges of the muscle cells in stick form, but in people with centronuclear myopathy the core is in the center of these cells. However, it is unknown how the change of location of the nucleus affects the function of muscle cells.
This may be due to mutations in genes DNM2 (dynamin 2), BIN1 (bridging integrator 1) or TTN (Titin). The proteins encoded from the DNM2 and BIN1 genes are involved in endocytosis, a process that enters the cell. The protein encoded from BIN1 gene plays an additional role in the formation of the transverse tubules or T - tubules, which are inside the membrane of muscle fibers. These tubules help transmit electrical impulses necessary for muscle contraction and relaxation. The protein encoded from DNM2 gene also regulates the actin cytoskeleton, which constitutes the structural framework of the muscle fiber.
The DNM2 gene (dynamin 2), located on the short arm of chromosome 19 (19p13.2), encoding dynamin 2 protein, involved in endocytosis. This protein also is associated with the microtubule cytoskeleton. The cytoskeleton defined cell shape, organizes the content location of the cell, and helps in cell movement. Microtubules are also essential for cell division. In a related paper, the dynamin 2 protein seems to be important for centrosome microtubules. We found at least 24 DNM2 mutations in the gene in people with centronuclear myopathy. Most of these nucleotide mutations change in some exons of the gene as exons 8, 11 and 16. These mutations change the protein structure, which deteriorates their interaction with microtubules and other components of the centrosome. Following DNM2 mutations gene, the structure of muscle cells is abnormal and can not normally contract and relax, leading to muscle weakness characteristic of centronuclear myopathy.
The BIN1 (bridging integrator 1) gene, located on the long arm of chromosome 2 (2q14), encoding a protein that interacts with other proteins (including dynamin 2) and is likely to be involved in the structure of the cell membrane. It is believed to be involved in the process of endocytosis and apoptosis. The protein may act as a tumor suppressor protein. Several isoforms of the protein are encoded from BIN1 gene. These isoforms vary according to size and are expressed in different tissues. It is believed that the isoform that is expressed in muscle cells is involved in the formation of the transverse tubule or tubules T. These structures are exclusively in the membranes of the muscle cells, playing a role in the contraction and relaxation of the muscle. They have identified at least 10 mutations in the gene BIN1 in people with Centronuclear myopathy. Most of these mutations change the amino acids in protein, interfering with their ability to interact with other proteins. Mutations in the gene BIN1, probably disrupt tubule formation T, which can alter the function of muscle cells.
The gene TTN (Titin), located on the long arm of chromosome 2 (2q31) encodes titin protein, which plays a major role in skeletal and cardiac muscles. Within muscle cells, titin is an essential component of the sarcomeres. Sarcomeres consist of proteins that generate the necessary mechanical strength for the muscles to contract. Titin protein has several functions within the sarcomeres. One of its most important tasks is to provide structure, flexibility and stability to these cellular structures. In addition, it also plays a role in chemical signaling and assembly of new sarcómeros.Se have identified at least 12 TTN mutations in the gene responsible for the development of the disease. Most of these mutations alter the way in which titin is encoded, which results in the synthesis of an abnormal protein with reduced or abnormal activity in muscle cells. Although it is unclear how these mutations cause myopathy centronuclear, it is likely that altered protein can not interact with other proteins in the sarcomere, leading to dysfunction of the sarcomere. Abnormal muscle sarcomeres prevent cells contract and relax normally.
The Centronuclear myopathy may have different inheritance patterns depending on the gene involved. When the disease is due to mutations in the DNM2 gene is inherited in an autosomal dominant pattern, which means that a copy of the altered gene in each cell is sufficient to cause disease. When the disease is due to mutations in the TTN gene and in most cases due to mutations in the BIN1 gene is inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for that the 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, BIN1 mutations that are inherited gene an autosomal dominant pattern, may lead to the development of centronuclear myopathy.
Tests in IVAMI: in IVAMI perform detection of mutations associated with centronuclear myopathy, by complete PCR amplification of the exons of DNM2, BIN1 and TTN, respectively, and subsequent sequencing genes.
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).