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Dystrophin-Associated Proteins and Muscular Dystrophies
Kay E. Davies

The cloning of the dystrophin gene in 1986 initiated a period of major advances in understanding the molecular genetic basis of the muscular dystrophies. In muscle, dystrophin associates with a complex of sarcolemma proteins, providing structural support to muscle fibers. While mutations in dystrophin are etiologic forDuchenne and Becker muscular dystrophies, mutations in genes encoding other members of the dystrophin-associated glycoprotein complex have been associated with other types of muscular dystrophies. Clarification of the functions of the different proteins and identification of their binding partners are paving the way for novel therapeutic stategies to treat these fatal muscle diseases.

M

usculardystrophies represent a heterogeneous group of inherited singlegene disorders that are characterized clinically by progressive muscle weakness and degeneration. Until recently, this large group of conditions was classified according to Mendelian inheritance patterns and clinical features. With evaluation by molecular genetic mapping techniques, however, it has become clear that these clinicallysimilar conditions are associated with an array of disparate genomic loci. In Duchenne and Becker muscular dystrophies, early investigations identified mutations involving the DMD gene located on the short arm of chromosome X. This gene encodes a large, 427-kilodalton cytoskeletal protein called dystrophin, which provides a structural link between the myofibril and muscle membrane. Whereas the mutation inDuchenne muscular dystrophy results in the complete absence of dystrophin, in Becker muscular dystrophy, a milder form of the disease, low levels of a truncated form of the dystrophin protein are seen. Correspondingly, in Duchenne muscular dystrophy, the disease is severe. Patients typically are confined to a wheelchair by age 12 and die by their late teens or early 20s of respiratorycomplications due to intercostal muscle weakness or respiratory infection. In contrast, in Becker muscular dystrophy, patients have a later onset of disease and longer survival.

In addition to the abnormalities in the DMD gene associated with these diseases, mutations have been identified in other genes encoding other components of the dystrophin-associated protein complex. This membrane-spanning complex,which is contiguous with dystrophin, forms a bridge from the muscle cytoskeleton to the extracellular matrix (ECM). These mutations result in other forms of muscular dystrophy, such as the limb-girdle muscular dystrophies and congenital muscular dystrophy. Recent advances have begun to elucidate the often-related functions of the many different products encoded by these genes. This research hasshed light on the cellular mechanisms responsible for the various types of muscular dystrophy. In this article, we review what has been learned about the molecular pathogenesis of the muscular dystrophies and examine potential therapeutic strategies aimed at correcting the abnormal cellular physiology that results from these primary genetic defects.

Cytoskeletal Connections Support Muscle FibersNormal skeletal muscle consists of a highly organized system of specialized cells and tissues, making them particularly susceptible to the effects of mutations. Small changes resulting from mutations are propogated throughout the
SCIENCE & MEDICINE

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BASAL LAMINA BASAL LAMINA

SARCOLEMMA

CYTOSKELETAL CONNECTIONS

MYOFIBRIL

Z LINE

ADAPTED FROM SPENCE HJ, ET AL: BIOESSAYS24:542-552, 2002; JOEL DUBIN.

musculoskeletal system, leading to system-wide effects. Mutations affecting the structural and contractile proteins of the sarcomere are particularly crucial. The sarcomere consists of a collection of muscle fibers as well as sarcoplasmic reticulum, T-tubules, mitochondria, and connections between myofibrils and the sarcolemma and between the sarcolemma and ECM....