From dystrophinopathy to sarcoglycanopathy: Evolution of a concept of muscular dystrophy

Abstract

Duchenne and Becker muscular dystrophies are collectively termed dystrophinopathy. Dystrophinopathy and severe childhood autosomal recessive muscular dystrophy (SCARMD) are clinically very similar and had not been distinguished in the early 20th century. SCARMD was first classified separately from dystrophinopathy due to differences in the mode of inheritance. Studies performed several years ago clarified some immunohistochemical and genetic characteristics of SCARMD, but many remained to be clarified. In 1994, the sarcoglycan complex was discovered among dystrophin-associated proteins. Subsequently, on the basis of our immunohistochemical findings which indicated that all components of the sarcoglycan complex are absent in SCARMD muscles, and the previous genetic findings, we proposed that a mutation of any one of the sarcoglycan genes leads to SCARMD. This hypothesis explained and predicted various characteristics of SCARMD at the molecular level, most of which have been verified by subsequent discoveries in our own as well as various other laboratories. SCARMD is now called sarcoglycanopathy, which is caused by a defect of any one of four different sarcoglycan genes, and thus far mutations in sarcoglycan genes have been documented in the SCARMD patients. In this review, the evolution of the concept of sarcoglycanopathy separate from that of dystrophinopathy is explained by comparing studies on these diseases.

Specific Interaction of the Actin-binding Domain of Dystrophin with Intermediate Filaments Containing Keratin 19

“…The affinity of intact, fulllength dystrophin for actin is considerably higher, due to the presence of clusters of basic residues in its spectrin repeat region that greatly enhance actin binding Warner et al, 2002). We have not yet assayed the other regions of dystrophin for their possible contributions to binding to cytokeratin filaments, nor have we examined any of the proteins that are normally complexed with dystrophin (Ahn and Kunkel, 1993;Matsumura and Campbell, 1994;Ozawa et al, 1998) for similar activity. Nevertheless, the comparable affinities of the Dys-ABD for cytokeratin and actin filaments suggest that the severity of dystrophinopathies linked to mutations in the ABD may be due to changes in binding not only to actin but also to cytokeratins.…”

“…Dystrophin is the major cytoskeletal component of a large, transmembrane complex (Ahn and Kunkel, 1993;Matsumura and Campbell, 1994;Ozawa et al, 1998) that plays a role in signaling from the plasma membrane of skeletal myofibers (sarcolemma) to the cytoplasm (Rando, 2001;Lapidos et al, 2004) and in transmitting the force of contraction across the sarcolemma to extracellular structures (Campbell, 1995;Bloch and Gonzalez-Serratos, 2003). Here, we focus on the latter role, and particularly, on the nature of the connections made between the contractile apparatus and the sarcolemma, at sites termed "costameres" (Bloch and Gonzalez-Serratos, 2003;Ervasti, 2003).…”

rAAV vector-mediated sarcogylcan gene transfer in a hamster model for limb girdle muscular dystrophy

“…The disease is caused by mutations in a number of responsible genes, [13][14][15][16][17] including sarcoglycan genes ␣ (LGMD 2D), ␤ (LGMD 2E), ␥ (LGMD 2C) and ␦ (LGMD 2F), respectively. 14,[18][19][20][21][22][23][24] While the phenotype of the sarcoglycanopathies is variable, patients often show a severe progression, with fatality in the second or third decade.…”

Effects of prednisolone on the dystrophin-associated proteins in the blood–brain barrier and skeletal muscle of dystrophic mdx mice

“…Dystrophin is an actin-binding protein, which links cortical actin of the myofibers to the sarcolemma by dystrophin-associated proteins (DAPs). [4][5][6][7] Dystrophin has several truncated isoforms, including Dp260, Dp140, Dp116, and Dp71, as well as a full-length conformations (427 kDa), which have been demonstrated in the brain 8,9 and in the astrocyte perivascular endfeet, 10 forming the glio-vascular units in the blood-brain barrier (BBB).…”