DMD muscular dystrophy results from an X-linked genetic mutation leading to the absence of the dystrophin protein, which is essential for muscle integrity.
Duchenne Muscular Dystrophy (DMD) is a severe neuromuscular disease inherited in an X-linked pattern, causing progressive muscle weakness and loss. At the core of the disease lie mutations in the DMD gene, one of the largest genes in the human genome. This gene is responsible for the production of a protein called dystrophin, which plays a critical role in maintaining the structural integrity of muscle fibers. Dystrophin acts as a bridge connecting the muscle cell membrane to the cytoskeleton and absorbing the mechanical stress generated during muscle contraction. In DMD patients, due to this genetic error, functional dystrophin protein is either not produced at all or is produced in very small, non-functional amounts. This condition leads to continuous damage to muscle fibers, eventually causing necrosis and their replacement by fat and fibrous tissue, which determines the progressive course of the disease. Understanding the disease primarily depends on grasping this genetic mechanism and the biological importance of the dystrophin protein. The molecular pathogenesis of DMD is shaped around specific types of mutations in the dystrophin gene. These mutations have an effect that disrupts the reading frame of the gene, prematurely terminating or completely preventing protein synthesis.
Mutation Types and Effects in the DMD Gene
The vast majority of mutations in the dystrophin gene occur in the form of the deletion of one or more exons of the gene. Less commonly, errors such as the duplication of certain parts of the gene or the change of a single nucleotide (point mutation) can also cause DMD. The common result of these genetic changes is the shifting of the reading frame during the translation of mRNA. When the reading frame shifts, the amino acid sequence that normally forms the dystrophin protein changes completely, and a premature stop codon appears. This situation causes the synthesis of the protein to end early, resulting in a non-functional, very short protein fragment. The fundamental pathology caused by this genetic defect is the continuous damage to muscle fibers. The absence of dystrophin causes the tension generated during muscle contraction to be transmitted directly to the cell membrane, leading to the disruption of the membrane's integrity. This condition increases the flow of calcium into the cell, which disrupts cellular processes and eventually leads to the death of the muscle cell (necrosis). Although the body tries to repair this damage, the rate of continuous destruction exceeds the rate of regeneration, and the dead muscle fibers are replaced over time by connective tissue and fat tissue. This process is called fibrosis and fatty infiltration, and it causes the muscles to lose their function completely.
Inheritance Mechanism and Gender Differences
DMD exhibits an X-linked recessive inheritance pattern. Since the dystrophin gene is located on the X chromosome, males (XY) have only one copy of this gene. Therefore, the presence of a single mutated X chromosome in boys is sufficient for the disease to manifest. Girls (XX), on the other hand, have two X chromosomes and can usually compensate for a mutation on one X chromosome with the other healthy X chromosome, in which case they become carriers. Carrier women are generally asymptomatic, but rarely, they may show mild muscle symptoms (symptomatic carriers) due to the imbalance of X inactivation. In the emergence of the disease, approximately two-thirds of cases are passed through inheritance from the mother, while the remaining one-third occurs as a result of new (de novo) mutations. This means that the disease can also be seen in individuals without a family history. Understanding these mechanisms explains why DMD is a progressive and devastating disease and forms the fundamental scientific basis for modern treatment approaches, especially methods such as gene therapy and exon skipping, to focus on partially or completely restoring the function of the dystrophin protein. /
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