Molecular diagnosis of muscular dystrophies

Abstract

Dystrophin, the protein product of the DMD/BMD (Duchenne muscular dystrophy/Becker muscular dystrophy) gene, is associated with dystrophin‐associated proteins (DAPs), which are classified into three groups: the dystroglycan complex, the sarcoglycan complex and the syntrophin complex. There is a connecting axis between subsarcolemmal actin filaments and laminin, one of the main components of the extracellular matrix through dystrophin and dystroglycan. This system may play an important role in protecting the sarcolemma during contraction and relaxation of muscle fibers. In this paper, the abnormalities of DAPs and laminin as a cause of muscular dystrophies are reviewed. While there are no reports on the role of mutations of dystroglycan and the syntrophin gene as being a cause of muscular dystrophies, the immunostaining intensities of these complexes are reduced as a secondary phenomenon of defects of dystrophin in DMD. The sarcoglycan complex, which is comprised of membrane‐integrated proteins, contains at least four components, each of which is encoded by a separate gene. This complex plays a crucial role in the development of severe childhood autosomal recessive muscular dystrophy (SCARMD). In this disease, the absence of any single component may result in a loss of the complex function. Therefore, SCARMD develops irrespective of any mechanism involving a defect of individual genes. As such SCARMD is collectively referred to as sarcoglycanopathy. Laminin, a heterotrimer and genetic defect of the α2 subunit, has been shown to be the cause of the classical type of congenital muscular dystrophy. This disease is characterized by floppy infants with severe muscular dystrophy, dysmyelinating neuropathy and white matter changes in the brain. In the clinical setting and in the mouse model of this disease a defect of the laminin α2 subunit in skeletal muscle has been demonstrated. α2 subunit‐null mutant mice also exhibit the muscular dystrophy phenotype and a muscle pathology compatible with dystrophia muscularis (dy) mice. A final common mechanism of muscle‐cell necrosis in many of the muscular dystrophies is associated with the destabilization of the sarcolemma.