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Muscle Disorders Brain Pathology 7: 1289-1291 (1997) KEYNOTE LECTURE KL5.1 - Muscle Disorders KL5.1 Molecular diagnosis of muscular dystrophies various tissues and identified as the 156kDaa-dystro- glycan and 43kDap-dystroglycan in skeletal muscle. Dr. Hideo Sugita a-dystroglycan , an extracellular protein, binds to one National Center of Neurology and Psychiatry, Kodaira Tokyo of the main components of the extracellular matrix, 187, Japan laminin probably through its sugar chains. a-dystroglycan binds to P-dystroglycan, a trans- The muscular dystrophies comprise clinically and membraneous pro1 ein. genetically heterogeneous group of disorders. Inside the mussle cell, a-dystroglycan binds to the Since the discovery of the gene and gene product of cysteine-rich domain and fxst half of the C-terminal Duchenne (DMD)/Becker muscular dystrophy (BMD), domain of dystrorhin. At the N--terminal regions, dys- dystrophin by Louis Kunkel's group in late 1980, enor- trophin molecule binds to actin-filament. mous progress has been achieved in understanding the There is a connecting axis anchored by laminin pathomechanism, as well as the diagnosis of between the subsarcolemmal cytoskeletons and extra- DMDBMD and related muscular dystrophies at the cellular matrix, which is called the "dystrophin-axis" ( molecular level. actin-dystrophin-dystroglycan complex). In addition to interest in dystrophin, defects of which This axis may play an important role to construct a give rise to DMDBMD, much interest of researchers in cell-matrix adhesion junction to fix the sarcolemma to muscular dystrophies has been concentrated to plasma the mechanically tough basal lamina, forming a protec- membrane and its associated architectures of muscle tion system to the sarcolemma during contraction and fibers. Thls membrane contains the extensive cytoskele- relaxation of muscle fibers. tons that stabilize the myofibrillar membrane during So far, no abncrmality of the dystroglycan gene has contraction and relaxation. been identified as ihe cause of the muscular dystrophies. In skeletal muscle, dystrophin exists tightly associat- But, a-dystroglycatn has been reported to be remarkably ed with several sarcolemmal proteins, which are collec- reduced as a secondary phenomenon of the defect of tively called the dystrophin associated proteins (DAPs). dystrophin in DMD, but not P-dystroglycan. Recent studies have clarified that the DAPs are clas- 2) Structure of sarcoglycan complex and its abnor- sified into 3 groups; 1)dystroglycan complex, 2)sarco- malities, sarcoglyc anopathy. glycan complex and 3)syntrophin complex as shown in The sarcoglycan complex, which is a complex of the Figure. membrane integrated proteins is exclusively expressed In contrast to the sarcoglycan and syntrophin com- in skeletal and cardiac muscles. This complex is consid- plexes, the dystroglycan complex has been character- ered to be fixed at the dystrophin-axis, a connecting axis ized that this complex is a receptor of the extracellular between subsarcolemmal cytoskeleton, dystrophin and matrix protein, laminin and plays an important role in extracellular matrix, laminin by lateral association with the stabilization of the sarcolemma. In this presentation, the dystrophin complex. The sarcoglycan complex is the molecular architecture of these cytoskeletal proteins composed of at lesst 4 components; 5OkDa a-, 43kDa and their abnormalities as the cause of the phenotypi- p-and 35kDa y/6-:;ubunits. cally similar yet genetically distinct muscular dystro- Though the exact binding site of the sarcoglycan phies will be reviewed. complex to dystrophin complex and function of the 1) Structure of dystroglycan complex and its abnor- sarcoglycan comp ex itself have not been identified, the malities. Dystroglycan is distributed ubiquitously in basement mernbrane(6M) - dys t roglycan complex lR- sarcoglycan complex ---dyst rophin (427kD) Figure 1. Molecular architecture of dystrophin and other molecules at the muscle surface membrane. defect of this complex plays the crucial role in the muscular dystrophy. pathogenesis of muscular dystrophies. The severe child- 3)Structure of syntrophin complex and its abnorrnal- hood autosomal recessive muscular dystrophy (SCAF- ities . MD) is a disease clinically and pathologically similar to Syntrophin complex is consisted of 3 proteins. Each DMD, first reported by M.B. Hamida et al., in 1983. of these is slightly less than 60kDa.encoded by three Then, this disease phenotype has been reported to be separate genes. a-syntrophin is expressed solely in present in U.S.A.,Europe, Asia. and other countries. skeletal muscle while the other two are distributed wide- It is highly plausible that when any one of the corn- ly in various tissues. a-syntrophin is present along the ponents of the sarcoglycan complex which are coded by length of muscle cell, located at the inner membrane separate genes is absent. the complex may not be surface.The syntrophin proteins bind to the distal C-ter- formed and thus loss of the entire components may minal regions ofthe dystrophin as shown in Figure. ensue. There is no report of the defect of the syntrophin rnolc- Therefore, SCARMD phenotype may develop, irre- cule as the cause of the muscular dystrophies at present. spective of any mechanism involving the defect of gene, 4) Structure of basal lamina and its abnormalities. coding each component of sarcoglycan complex. The basal lamina of muscle fiber is specialized extra- This is the reason that SCARMD is collectively cellular matirx that has been shown to hate a static called sarcoglycanopathy. structure which is thought to contribute to the proper The sarcoglycanopathy is supposed to comprise migration, proliferation and regeneration of myogenic approximately 10% of autosomal recessive limb-girdle cells during development or after injury or grafting. The components of the basal lamina include variants of References laminin molecule which is paid attention recently as the 1. Ozawa E, Yoshida M, Suzuki A, Mizuno Y, Hagiwara Y, cause of the congenital muscular dystrophies. The large NoguchiS( 1995:f Dystrophin-associated proteins in mus- cular dystrophy Hum Mol Genet 4: 1711-1 71 6 laminin protein is a heterotrimer, and arranged in the 2. Brown RH JR (- 996) Dystrophin-associated proteins and cross with two smaller chains (B1 or pl and B2 or yl) the muscular dystrophies:A glossary Brain Pathol 6: 19- and one large chain (a2 or merosin). A deficiency of 24 laminin a2 or merosin has been found in patients with 3. Matsumura K, Yarnada H, Saito F, Sunada Y, Shimizu T 40% and 5% of classical autosomal recessive congenital (1997) Peripheral nerve involvement in merosin-deficient muscular dystrophy in Europe and Japan, respectively. congenital musc:ular dystrophy and dy mouse Neuromusc The patients show rather homogenous clinical feature, Disorders 7: 7-12 floppy infant, with severe muscular dystrophy, dys- 4. Arahata K, Hayashi Y, Koga R. Goto K, Lee JH, Miyagoe Y, lshii H, Tsukahara T, Takeda S, Woo M, Nonaka 1, myelinating neuropathy and white matter change in the Matsuzaki T,SLgita H (11993) Laminin in animal models brain without mental retardation. The affected muscle for muscular dystrophy. Defects of laminin M in skeletal showed the defect of a2 subunit with an increased and cardiac muscles and peripheral nerve of the homozy- expression of the a1 subunit, which is not expressed in gous dystrophic dy/dy mice Proc Japan Acad 69: 259-264 normal skeletal muscle. 5. Hayashi YK, Eigvall E. Arikawa-Hirasawa E. Goto K, Koga R, Nonaka 1, Sugita H. Arahata K (1993) Abnormal Dystrophin, the dystrophin complex and sarcoglycan localization of laminin subunits in muscular dystsrophies J complex are all well preserved. The architecture of the Neurol Sci 119 53-64 basal lamina itself and connection with the dystrophin - axis through laminin may not function correctly due to the lack of laminin, causing the clinical phenotype. In peripheral nerve, a2 subunit of laminin (laminin a2) is expressed in the endoneurium and its receptor, dystroglycan is also located in the outer membrane of Schwann cell myelin sheath. This finding indicates that the interaction of a2 subunit of laminin with dystrogly- can plays the essential role in peripheral nerve myelina- tion and that the disturbance of the interaction leads to dysmyelination of peripheral nerve. In an autosomal recessive muscular dystrophy in mice, dy mice, a2 chain of laminin is missing from skeletal and cardiac muscles and peripheral nerve in the affected consangenous dyldy mice, which is minic to laminin a2 negative congenital muscular dystrophy. Fukuyama type congenital muscular dystrophy (FCMD) is an autosomal recessive muscular dystrophy, endemic in Japan where its incidence is approximately half that of DMD, but it is rarely observed in other coun- tries, in strong contrast with laminin a2 missing con- genital muscular dystrophy. FCMD patients show profound mental retardation associated with structural brain abnormalities such as cobblestone lissencephaly and hydrocephalus. In FCMD, the gene locus of which is 9q31-33, differ- ent from that of a2 subunit of laminin (6q22-23),a sig- nificant reduction of laminin a2 was observed immuno- histochemically. Though the reduction of the laminin a2 may be a secondary phenomenon, this finding strongly suggests an important role for basal lamina in pathogenesis of FCMD muscle. ~_____ _- Keynote Lecture KL5.1 1291 .
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