Muscular Dystrophies and Dystrophin-Glycoprotein Complex
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Muscular Dystrophies and Dystrophin-Glycoprotein Complex
Muscular dystrophy is a genetically heterogeneous group of disorders characterized by progressive weakness and degeneration of the skeletal or voluntary muscles which control movement. This group of diseases has three features in common: they are hereditary, they are progressive and each causes a characteristic, selective pattern of weakness. Some forms of MD first appear in infancy or childhood, but others may not appear until middle age or later (Ref.1). Although the actual cause of this disorder is unknown, it is known that a gene defect is responsible for the onset. Even though females are known to carry the defective gene they remain unaffected. The recessive gene that is responsible is carried on the X-chromosome and while females who are carriers have a normal X-Chromosome that compensates for the defective gene, males do not. Although the disease is present from conception, symptoms usually do not develop until the child is five or six years old, or even a year or two later. There are various different types of muscular dystrophy including BMD (Beckers Muscular Dystrophy), DMD (Duchenne Muscular Dystrophy), Myotonic Dystrophy, LGMD (Limb Girdle Muscular Dystrophy), Landouzy-Dejerine Muscular Dystrophy and Facioscapulohumeral Muscular Dystrophy, which is also known as Steinerts Disease. Two other muscle diseases that are sometimes related to muscular dystrophy are Myotonia Congenital or Thomsens Disease and Pompes Disease. Although all forms of muscular dystrophy are considered rare, the most common form is DMD. With DMD the young men are almost totally missing an essential muscle protein known as Dystrophin, which is important to maintain the structure of the muscle cells. On the other hand young men with BMD do produce this essential muscle protein but it does not function properly because it is over sized (Ref.2).

Most human muscular dystrophies are caused by abnormalities in Dystrophin, the protein product of the DMD gene. Dystrophin is a large subsarcolemmal, actin-binding protein associated with a complex of sarcolemmal and cytoskeletal proteins in mature striatal muscle cell (myofibers), both skeletal and cardiac known as the DGC (Dystrophin-Glycoprotein Complex). It performs its functions through four major structural domains. The N-terminal domain binds to the F-actin of cytoskeletal structures, while the C-terminal cysteine-rich domain along with the distal C-terminus, anchors to the plasma membrane through Dystrophin Associated Protein complexes. Thus, Dystrophin crosslinks and stabilizes the muscle cell membrane and cytoskeleton. The lack of a functional Dystrophin results in the loss of Dystrophin associated protein complexes and causes instability of myofibril plasma membrane. These deficiencies in turn lead to chronic muscle damage and degenerative pathology. The DGC can be separated into three subcomplexes: DG (Dystroglycan), Dystrobrevin- Syntrophin, and SGC (Sarcoglycan Complexes), which together confer structural support by providing a link between the ECM (Extracellular Matrix) and the Actin. In muscle, there are at least four SG subunits, Alpha, Beta, Gamma, and Delta, and mutations in any of these four can result in autosomal recessive muscular dystrophy (Ref.3). The DG transcript encodes two polypeptides, Alpha-DG and Beta-DG, which are separated by post-translational cleavage and associate with each other to form an integral membrane protein complex. The extracellular Alpha-DG subunit can bind a variety of Laminin isoforms and the proteoglycan molecules agrin, neurexin and perlecan. Laminin is a component of the basal lamina (ECM), comprised of three subunits: Alpha, Beta and Gamma. The Laminin-Alpha2 (Merosin) subunit binds to Alpha-DG. Beta-DG is a transmembrane protein which, outside the cell, binds to Alpha-DG and, inside the cell, to the cysteine-rich domain, nNOS and the first half of the C-terminal domain of Dystrophin. In its N-terminus, Dystrophin binds cytoskeletal nNOS and connects Dystrophin with the MLP (Muscle LIM Protein) and sarcomere intracellularly (Ref.4). In skeletal muscle myotubes, this link is critical for mechanical integrity and resistance to hypoosmotic shock. The absence of Dystrophin may lead to disruptions of the muscle plasma membrane during repeated cycles of contraction and relaxation, resulting in muscle degeneration and muscular dystrophy.

The prognosis of muscular dystrophy varies according to the type and the progression of the disorder. Life expectancy depends on the degree of progression and late respiratory deficit. DMD is one of the most common, disabling and lethal genetic diseases, afflicting one of every 3500 male births. The onset of DMD begins at the age of three to five with progressive muscle degeneration and weakness. The patients become wheelchair-bound in their early teens and die prematurely by their early twenties due to respiratory and cardiac muscle failure. Myotonic Dystrophy affects the muscles in the hands and feet. LGMD begins late in childhood affecting mainly the muscles of the shoulders and hips. Facioscapulohumeral Muscular Dystrophy affects only the muscles of the upper arms, face and shoulder girdle. Landouzy-Dejerine Muscular Dystrophy, which is transmitted by an autosomal dominant gene, affects the face, shoulder and lower leg muscles. Steinerts Disease affects both males and females causing the muscles to be unable to relax after contracting while Thomsens Disease causes a stiffness of the legs, hands and eyelids. Pompes Disease, which is a glycogen storage disease, affects the liver, heart, nerves and muscles. Diagnosis is based on a comprehensive physical examination and sophisticated diagnostic tests such as genetic analysis and biopsy of muscle or nerve tissue to pinpoint the type of neuromuscular disease or myopathy (Ref.5). Although there is no known cure for muscular dystrophy, exercise and physical therapy are recommended. Corticosteriod drugs and gene therapies are being studied to help relieve the symptoms.