DMD gene

dystrophin (muscular dystrophy, Duchenne and Becker types). The DMD gene is also known by other names, BMD, DMD_HUMAN ,Dystrophin

Normal function of the DMD gene

DMD, the largest known human gene, provides instructions for making a protein called dystrophin. There are many different versions of dystrophin, some of which are specific to certain cell types. Dystrophin is located chiefly in muscles used for movement (skeletal muscles) and the muscles of the heart (cardiac muscles). Small amounts of the protein are present in nerve cells in the brain. In skeletal and cardiac muscles, dystrophin is part of a group of proteins that work together (a protein complex) that strengthens muscle fibers and protects them from injury as muscles contract and relax. The dystrophin complex acts as an anchor, connecting each muscle cell's structural framework (cytoskeleton) with the lattice of proteins and other molecules outside the cell (extracellular matrix). The dystrophin complex may also play a role in cell signaling by interacting with proteins that send and receive chemical signals. Little is known about the function of dystrophin in nerve cells. Research suggests that the protein is important for the normal structure and function of synapses, which are specialized connections between nerve cells where cell-to-cell communication occurs.

DMD genes and health conditions

Duchenne and Becker muscular dystrophy - Hundreds of mutations in the DMD gene have been identified in people with the Duchenne and Becker forms of muscular dystrophy. Most of these mutations delete part of the DMD gene. Other mutations abnormally duplicate part of the gene or change a small number of DNA building blocks (nucleotides) in the gene. Mutations that cause Becker muscular dystrophy, which typically has milder features and a later age of onset than Duchenne muscular dystrophy, usually lead to an abnormal version of dystrophin that retains some function. Mutations that cause the more severe Duchenne muscular dystrophy typically prevent any functional dystrophin from being produced. Skeletal and cardiac muscle cells without enough functional dystrophin become damaged as the muscles repeatedly contract and relax with use. The damaged cells weaken and die over time, causing the characteristic muscle weakness and heart problems seen in Duchenne and Becker muscular dystrophy. other disorders - Mutations in the DMD gene also cause a form of heart disease called X-linked dilated cardiomyopathy. This condition enlarges and weakens the cardiac muscle, preventing it from pumping blood efficiently. Although dilated cardiomyopathy is a sign of Duchenne and Becker muscular dystrophy, the isolated X-linked form of this heart condition is not associated with weakness and wasting of skeletal muscles. Researchers are not certain why some mutations in the DMD gene cause X-linked

cardiomyopathy instead of muscular dystrophy. They believe that some DMD mutations affect a version of dystrophin that is specific to heart muscle.

DMD gene location

Cytogenetic Location: Xp21.2 Molecular Location on the X chromosome: base pairs 31,047,265 to 33,267,646 CLONING The study of Duchenne and Becker muscular dystrophy resulted in one of the first successful attempts at reverse genetics, better described as positional cloning, in humans. (The other disorder was chronic granulomatous disease, which is also X-linked and yielded to positional cloning in 1986.) Discovery and subsequent analysis of the gene mutation that results in the clinical disorder led to the discovery of the encoded protein, dystrophin. This coinage set a precedent for the naming of proteins discovered by positional cloning of human disease genes: for example, huntingtin, emerin, and ataxin. Wood et al. (1987) noted that the gene for Duchenne muscular dystrophy, symbolized DMD (the same abbreviation as that used for the disorder Duchenne muscular dystrophy) encodes an mRNA of about 16 kb; thus, if the message encodes a single protein, it would be about 500 kD in size. The largest proteins in muscle then known were nebulin (550 kD) and titin (over 1000 kD). Both proteins are located at the junction of the A band (the area of the sarcomere composed of myosin thick filaments) and I band (the area of the sarcomere containing actin thin filaments attached to the Z line). Wood et al. (1987) found that the band identified as nebulin was absent or extremely faint in all 30 patients with DMD whereas it was clear in all controls, and the bands of all other proteins seen in control muscle were equally prominent in muscle from patients with DMD. Specifically, titin was equally prominent in control and DMD muscle. The authors suggested that nebulin may be the defective gene product in DMD; this is now known not to be the case.

Duchenne and Becker muscular dystrophy

Muscular dystrophies are a group of genetic conditions characterized by progressive muscle weakness and wasting (atrophy). The Duchenne and Becker types of muscular dystrophy primarily affect the skeletal muscles, which are used for movement, and the muscles of the heart. These conditions occur much more frequently in males than in females. Duchenne and Becker muscular dystrophies have similar signs and symptoms and are caused by different mutations in the same gene. The two conditions differ in their severity, age of onset, and rate of progression. In people with Duchenne muscular dystrophy, muscle weakness tends to appear in early childhood and progress rapidly. Affected children may have delayed motor skills, such as sitting, standing, and walking. They are usually wheelchair-dependent by adolescence. The signs and symptoms of Becker muscular dystrophy are usually milder and exhibit a large range of variation. In

most cases, muscle weakness becomes apparent later in childhood or adolescence and progresses at a much slower rate. Both the Duchenne and Becker forms of muscular dystrophy are associated with a heart condition called dilated cardiomyopathy. This form of heart disease enlarges and weakens the heart (cardiac) muscle, preventing it from pumping blood efficiently. Dilated cardiomyopathy progresses rapidly and is life-threatening in many cases. In people with Duchenne muscular dystrophy, the signs and symptoms of cardiomyopathy typically appear in adolescence. The onset of cardiomyopathy in people with Becker muscular dystrophy is later, usually in early to mid-adulthood.

Incidence of Duchenne and Becker muscular dystrophy

Duchenne and Becker muscular dystrophies together affect 1 in 3,500 to 5,000 newborn males. Between 400 and 600 boys in the United States are born with these conditions each year. Females are rarely affected by these forms of muscular dystrophy.

Genes related to Duchenne and Becker muscular dystrophy

The DMD gene provides instructions for making a protein called dystrophin. This protein helps stabilize and protect muscle fibers and may play a role in chemical signaling within cells. Mutations in the DMD gene alter the structure or function of dystrophin, or prevent any functional dystrophin from being produced. Muscle cells without this protein become damaged as muscles repeatedly contract and relax with use. The damaged fibers weaken and die over time, leading to the muscle weakness and heart problems characteristic of Duchenne and Becker muscular dystrophies.

Inheritance of Duchenne and Becker muscular dystrophy

This condition is inherited in an X-linked recessive pattern. A condition is considered Xlinked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation must be present in both copies of the gene to cause the disorder. Males are affected by X-linked recessive disorders much more frequently than females. A striking characteristic of X-linked inheritance is that fathers cannot pass Xlinked traits to their sons. In about two thirds of cases, an affected male inherits the mutation from a mother who carries an altered copy of the DMD gene. The other one third of cases probably result from new mutations in the gene. In X-linked recessive inheritance, a female with one mutated copy of the gene in each cell is called a carrier. She can pass on the altered gene, but usually does not experience signs and symptoms of the disorder. Occasionally, however, females who carry a DMD mutation may have muscle weakness and cramping. These symptoms are typically milder than the severe muscle weakness and atrophy seen in affected males. Females who carry a DMD mutation also have an increased risk of developing heart abnormalities including dilated cardiomyopathy.