Zebrafish Assays for Identifying Potential Muscular Dystrophy Drug Candidates - Zebrafish: Methods for Assessing Drug Safety and Toxicity - page 226

18.1.1 Muscular Dystrophy and
Dystrophin-Glycoprotein Complex
Muscular dystrophy refers to a number of clinically and genetically heterogeneous
disorders characterized by degeneration of skeletal or voluntary muscles and pro-
gressive weakness. In some forms of MD, heart and involuntary muscles are also
affected. Major forms of MD, which can occur at any age, include Becker, Duchenne,
myotonic, limb-girdle, facioscapulohumeral, congenital, oculopharyngeal, distal,
and Emery-Dreifuss (Mathews, 2003). Duchenne is the most common childhood
form and myotonic is the most common adult form. Identification of defective
dystrophin in Duchenne muscular dystrophy (DMD) and isolation of a number of
dystrophin-associated proteins in skeletal muscle have provided valuable clues for
MD pathogenesis.
The large oligomeric dystrophin-glycoprotein complex (DGC), which connects
the extracellular matrix with the actin cytoskeleton, contains both structural and
signal transduction properties (Lapidos et al., 2004) and causes specialization of
cardiac and skeletal muscle membranes. Dystrophin binds to filamentous g-actin
through the actin amino-terminal binding domain (Rybakova et al., 2000) and binds to
b-dystroglycan through the C-terminal cysteine-rich domain. DGC elements lacking
dystrophin are smaller at the sarcolemma and unstable. Dystroglycan, originally
isolated from skeletal muscle, was later found to be expressed during development
and it is present in nearly all cell types. In vertebrates, dystroglycan is comprised of
alpha- and beta-subunits encoded by a single gene (Holt et al., 2000). At the
sarcolemma, b-dystroglycan binds intracellularly to dystrophin and extracellularly
to a-dystroglycan. a-Dystroglycan binds to extracellular matrix proteins including
laminin, neurexin, agrin, and perlecan, completing the link from the cytoskeleton to
the basal lamina. In addition to dystrophin and dystroglycan, the DGC contains the
sarcoglycan complex and sarcospan. The sarcolemmal DGC interacts with a pair of
syntrophins and a-dystrobrevin within the cytosol via dystrophin. DGC contributes to
the structural stability of muscle cell membranes and protects muscles from stress-
induced damage.
In humans, dystrophin gene mutations have been shown to cause Duchenne and
Becker muscular dystrophy. Additional gene mutations in the DGC have been
identified in different forms of MD including sarcoglycans (limb-girdle muscular
dystrophies, LGMD2C-F; a, b, d, g), laminine a2 chain (congenital muscular
dystrophy), laminine a7 (congenital muscular dystrophy), and dysferlin (LGMD
2B and Miyoshi myopathy) (Xu et al., 1994; Lim et al., 1995; Araishi et al., 1999;
Weiler et al., 1999). Other defective non-DGCmolecules have also been found inMD
patients, including calpain, an intracellular calcium-activated protease (autosomal
recessive limb-girdle muscular dystrophy, LGMD2A), telethonin (TCAP), a muscle-
specific protein that localizes to the Z-disc of skeletal muscle (LBMD2G), Trim 32, a
potential E3-ubiquitin ligase (LGMD2H), emerin, an integral nuclear membrane
protein (Emery Dreifuss syndrome), dystrophia myotonica protein kinase (DMPK)
(myotonic dystrophy, DM1), and ZFF9, a zinc finger protein (DM2) (Allamand and
Campbell, 2000; Mathews, 2003).