The Dystrophin Gene
Duchenne Muscular Dystrophy is one of the most frequent hereditary diseases. About one in 3,500 boys is born with this disease, which is caused by a mutation or damage of the dystrophin gene with the consequence that the protein dystrophin is no longer present or exists only in traces in their muscle cells.
The dystrophin gene was identified in 1986 on the X chromosome and its structure elucidated shortly afterwards. With 2.6 million base pairs, it is the longest gene of man. Only 0,5 % of the base pairs, 13,973, belong to the 79 exons of the gene, which contain the active coding sequence, the information for the synthesis of the different forms of the protein dystrophin. The transcription of the genetic information of the dystrophin gene into mRNA is under the control of five promoters, DNA regions governing the splicing process so that a number of dystrophins of different length are produced. The main product is the full-length dystrophin, a very long protein consisting of 3,685 amino acids.
Dystrophin is part of the costamers, which connect the Z discs of the sarcomers, the contractile structures, with the sarcolemm, the cell membrane. It is thus important for the mechanical stability of the muscle cells during muscle contraction.
Dystrophin belongs to a network of many different proteins of which more than 50 are known. Among them are the dystro- and sarcoglycans, the synthrophins and integrins, dystrobrevin, nitric oxide synthase, and other components such as dysferlin, sarcospan, laminin, caveolin, telethonin, myotolin, agrin, neurexin, desmuslin, syncoilin, fukutin, aquaporin, spectrin, collagen, calpain and others. In the future, more components are expected to be identified.
Role of Dystrophin
Dystrophin is needed for the mechanical stability of the muscle cells. It is located on the inside of the muscle cell membranes. One of its ends, the C-terminal, is bound to a group of other proteins in the membrane, the dystrophin-glycoprotein complex, and the other end, the N-terminal, connects to the contractile structures inside the muscle cells. The central portion of dystrophin, the rod domain, consists of twisted amino acid chains that fold back on themselves several times. If the contraction movement of the muscle cell forces the dystrophin protein to change its length, its folded structure allows it to act like a spring or like a shock absorber. Thus dystrophin transmits the mechanical energy produced by the actin-myosin "contraction apparatus" to the muscle cell membranes and the structures outside them, the connective tissue and the tendons, in an well-balanced way that does not overstresses them.
Dystrophin has more roles: It organizes the complicated structure of the dystrophin-glycoprotein complex and the location of many other proteins. It also regulates complex processes like the maintenance of the corect amount of calcium in the cells and those controling the growth of the muscles. Many details of these intricate interactions between numerous components in a living cell are still unknown.
Duchenne boys have no or very little dystrophin in their muscle fibers. When its protective and organizing effects are missing, the muscle contraction causes the rupture of the muscle membranes, and this allows large amounts of calcium to flow into the fibers. The excessive calcium activates enzymes like calpain and other protetases that break down muscle proteins and initiate cell death programs. The consequences are a chain of events like inflammation and activation of fibroblasts which lead to fibrosis, scar tissue, which slows down muscle regeneration and causes the typical symptoms of older Duchenne patients.
Boys with the slower progressing Becker dystrophy mostly have lower than normal amounts of dystrophin that is also often shorter than normal. It still can fulfill its role, but canot work as effectively as the normal version. But not only the skeletal muscles suffer when dystrophin is missing but also the smooth and heart muscles. Damage to the heart muscles produces cardiomyopathy, and the weakness of the smooth muscles has many consequences, among them the reduced ability of blood vessels to relax when blood flow increases leading to respiratory and other problems, and also the gastro-intestinal tract is affected when the motility of the intestines is reduced. So the change in just one gene can affect the whole body.
(Günter Scheuerbrandt 2006)