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INTRODUCTION

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Muscular dystrophies are hereditary, progressive muscle diseases in which there is necrosis of muscle tissue and replacement by connective and fatty tissues, which helps to distinguish them from other hereditary myopathies. Before discussing specific types of muscular dystrophies, it is important to have an understanding of the relevant muscle proteins that are affected in the various dystrophies. The different forms of muscular dystrophies result from mutations affecting proteins localizable to the sarcolemma, myonuclei, basement membrane and extracellular matrix surrounding muscle fibers, sarcomere and nonstructural enzymatic proteins.1,2

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DYSTROPHIN–GLYCOPROTEIN COMPLEX AND RELATED PROTEINS

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DYSTROPHIN

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The identification and characterization of dystrophin as the abnormal gene product in Duchenne and Becker muscular dystrophies (DMD and BMD) were the major discoveries underlying our current understanding of muscular dystrophies (Fig. 27-1).13 Dystrophin is located on the cytoplasmic face of skeletal and cardiac muscle membrane and constitutes approximately 5% of the sarcolemmal cytoskeletal proteins. Dystrophin is a rod-shaped molecule composed of four domains.3 The amino-terminal domain binds to the cytoskeletal filamentous actin. The second domain bears similarity to spectrin and provides structural integrity to red blood cells. The third domain is a cysteine-rich region, and the fourth domain is the carboxy terminal. The cysteine-rich domain and the first half of the carboxy-terminal domain of dystrophin are important in linking dystrophin to β-dystroglycan and the glycoproteins that span the sarcolemma.

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Figure 27-1.

Proteins involved in muscular dystrophies. This schematic shows the location of various sarcolemmal, sarcomeric, nuclear, and enzymatic proteins associated with muscular dystrophies. The diseases associated with mutations in the genes responsible for encoding these proteins are shown in boxes. Dystrophin, via its interaction with the dystroglycan complex, connects the actin cytoskeleton to the extracellular matrix. Extracellularly, the sarcoglycan complex interacts with biglycan, which connects this complex to the dystroglycan complex and the extracellular matrix collagen. Various enzymes are important in the glycosylation of the α-dystroglycan and mediate its binding to the extracellular matrix and usually cause a congenital muscular dystrophy with severe brain and eye abnormalities, but may cause milder LGMD phenotype. Mutations in genes that encode for sarcomeric and Z-disc proteins cause forms of LGMD and distal myopathies (including myofibrillar myopathy, forms of hereditary inclusion body myopathy) as well as nemaline rod myopathy and other "congenital" myopathies. Mutations affecting nuclear membrane proteins are responsible for most forms of EDMD. Mutations in other nuclear genes cause other forms of dystrophy.

Graphic Jump Location
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Dystrophin is also present in the brain where it localizes subcellularly to the postsynaptic density, a disc-shaped structure beneath the postsynaptic membrane in chemical synapses. The postsynaptic density may play an important role in synaptic function by stabilizing the synaptic structure, anchoring postsynaptic receptors, and transducing extracellular matrix–cell signals.

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DYSTROPHIN-ASSOCIATED PROTEINS/GLYCOPROTEINS

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Dystrophin ...

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