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Our trails and trials in the subsarcolemmal cytoskeleton network and muscular dystrophy researches in the dystrophin era.

Ozawa E - Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. (2010)

Bottom Line: After we discovered that dystrophin is located on the cell membrane in 1988, we studied the architecture of dystrophin and dystrophin-associated proteins (DAPs) complex in order to investigate the function of dystrophin and pathomechanism of DMD.Our prediction was confirmed to be true by many researchers including ourselves.In this review, I will try to explain what we observed and how we considered concerning the architecture and function of the dystrophin-DAP complex, and the pathomechanisms of DMD and related muscular dystrophies.

View Article: PubMed Central - PubMed

Affiliation: National Center of Neuroscience, NCNP, Kodairashi, Tokyo 187-8502, Japan. ozawa@ncnp.go.jp

ABSTRACT
In 1987, about 150 years after the discovery of Duchenne muscular dystrophy (DMD), its responsible gene, the dystrophin gene, was cloned by Kunkel. This was a new substance. During these 20 odd years after the cloning, our understanding on dystrophin as a component of the subsarcolemmal cytoskeleton networks and on the pathomechanisms of and experimental therapeutics for DMD has been greatly enhanced. During this paradigm change, I was fortunately able to work as an active researcher on its frontiers for 12 years. After we discovered that dystrophin is located on the cell membrane in 1988, we studied the architecture of dystrophin and dystrophin-associated proteins (DAPs) complex in order to investigate the function of dystrophin and pathomechanism of DMD. During the conduct of these studies, we came to consider that the dystrophin-DAP complex serves to transmembranously connect the subsarcolemmal cytoskeleton networks and basal lamina to protect the lipid bilayer. It then became our working hypothesis that injury of the lipid bilayer upon muscle contraction is the cause of DMD. During this process, we predicted that subunits of the sarcoglycan (SG) complex are responsible for respective types of DMD-like muscular dystrophy with autosomal recessive inheritance. Our prediction was confirmed to be true by many researchers including ourselves. In this review, I will try to explain what we observed and how we considered concerning the architecture and function of the dystrophin-DAP complex, and the pathomechanisms of DMD and related muscular dystrophies.

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Related in: MedlinePlus

Dystrophin: Molecular domains and functional domains. AB-D: actin-binding domain that binds to γ-actin filament composing the subsarcolemmal cytoskelton network. Rod: also termed ‘triple helical segments.’ The rod contains AB-S (another binding site to γ-actin) encoded by exons (EX) 38–40. CR: cysteine rich domain. C-ter: C-terminal domain. DGBD:binding site on dystrophin for β-DG. Hot Spot 1 & 2: the sites that are deleted with high frequency in the dystrophin gene. The frequency of mutation in Hot Spot 2 is much higher than that in Hot Spot 1. AA #: Range of AA residues, spanning each domain.
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fig01: Dystrophin: Molecular domains and functional domains. AB-D: actin-binding domain that binds to γ-actin filament composing the subsarcolemmal cytoskelton network. Rod: also termed ‘triple helical segments.’ The rod contains AB-S (another binding site to γ-actin) encoded by exons (EX) 38–40. CR: cysteine rich domain. C-ter: C-terminal domain. DGBD:binding site on dystrophin for β-DG. Hot Spot 1 & 2: the sites that are deleted with high frequency in the dystrophin gene. The frequency of mutation in Hot Spot 2 is much higher than that in Hot Spot 1. AA #: Range of AA residues, spanning each domain.

Mentions: In 1983, Davies, Kunkel and Worton started to search for the responsible gene for DMD under the auspices of the Muscular Dystrophy Association of America. In 1987, Kunkel first cloned the gene,8,9) which was then named the dystrophin gene. Dystrophin was a new substance. Some characteristics of the gene and its products and other related matters are described here for better understanding of this review (Fig. 1).8,9) The dystrophin gene is localized at chromosome Xp21, its size is 3 megabases, occupying about 1/1,000 of the total genome size, and is composed of 79 exons. The size of the mRNA is 14 kb. The number of amino acid (AA) residues in dystrophin is 3,685, as deduced from the nucleotide sequence, and it has a molecular weight of 427 kDa. Dystrophin is a roughly slender protein. The primary sequence of the N-terminal portion is highly homologous to those of the N-terminal portion of α-actinin, and this portion was named the actin-binding domain (AB domain: AA #14–240, exons 2–8). Tandem domains of this region are the rod or triple helical segment (AA #253–3040, exons 8–61), the cysteine-rich domain (CR domain: AA #3080–3360, exons 62–69) and finally the C-terminal domain (AA #3361–3685, exons 69–79). The length of the rod was assumed to be 125 nm. Four potential small hinges were found in the rod. This molecular structure was constructed on the basis of the analogy of dystrophin and α-actinin, and dystrophin was initially considered to be present as an anti-parallel homodimer until 1997, except ourselves (see Discussion (2)).


Our trails and trials in the subsarcolemmal cytoskeleton network and muscular dystrophy researches in the dystrophin era.

Ozawa E - Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. (2010)

Dystrophin: Molecular domains and functional domains. AB-D: actin-binding domain that binds to γ-actin filament composing the subsarcolemmal cytoskelton network. Rod: also termed ‘triple helical segments.’ The rod contains AB-S (another binding site to γ-actin) encoded by exons (EX) 38–40. CR: cysteine rich domain. C-ter: C-terminal domain. DGBD:binding site on dystrophin for β-DG. Hot Spot 1 & 2: the sites that are deleted with high frequency in the dystrophin gene. The frequency of mutation in Hot Spot 2 is much higher than that in Hot Spot 1. AA #: Range of AA residues, spanning each domain.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3037518&req=5

fig01: Dystrophin: Molecular domains and functional domains. AB-D: actin-binding domain that binds to γ-actin filament composing the subsarcolemmal cytoskelton network. Rod: also termed ‘triple helical segments.’ The rod contains AB-S (another binding site to γ-actin) encoded by exons (EX) 38–40. CR: cysteine rich domain. C-ter: C-terminal domain. DGBD:binding site on dystrophin for β-DG. Hot Spot 1 & 2: the sites that are deleted with high frequency in the dystrophin gene. The frequency of mutation in Hot Spot 2 is much higher than that in Hot Spot 1. AA #: Range of AA residues, spanning each domain.
Mentions: In 1983, Davies, Kunkel and Worton started to search for the responsible gene for DMD under the auspices of the Muscular Dystrophy Association of America. In 1987, Kunkel first cloned the gene,8,9) which was then named the dystrophin gene. Dystrophin was a new substance. Some characteristics of the gene and its products and other related matters are described here for better understanding of this review (Fig. 1).8,9) The dystrophin gene is localized at chromosome Xp21, its size is 3 megabases, occupying about 1/1,000 of the total genome size, and is composed of 79 exons. The size of the mRNA is 14 kb. The number of amino acid (AA) residues in dystrophin is 3,685, as deduced from the nucleotide sequence, and it has a molecular weight of 427 kDa. Dystrophin is a roughly slender protein. The primary sequence of the N-terminal portion is highly homologous to those of the N-terminal portion of α-actinin, and this portion was named the actin-binding domain (AB domain: AA #14–240, exons 2–8). Tandem domains of this region are the rod or triple helical segment (AA #253–3040, exons 8–61), the cysteine-rich domain (CR domain: AA #3080–3360, exons 62–69) and finally the C-terminal domain (AA #3361–3685, exons 69–79). The length of the rod was assumed to be 125 nm. Four potential small hinges were found in the rod. This molecular structure was constructed on the basis of the analogy of dystrophin and α-actinin, and dystrophin was initially considered to be present as an anti-parallel homodimer until 1997, except ourselves (see Discussion (2)).

Bottom Line: After we discovered that dystrophin is located on the cell membrane in 1988, we studied the architecture of dystrophin and dystrophin-associated proteins (DAPs) complex in order to investigate the function of dystrophin and pathomechanism of DMD.Our prediction was confirmed to be true by many researchers including ourselves.In this review, I will try to explain what we observed and how we considered concerning the architecture and function of the dystrophin-DAP complex, and the pathomechanisms of DMD and related muscular dystrophies.

View Article: PubMed Central - PubMed

Affiliation: National Center of Neuroscience, NCNP, Kodairashi, Tokyo 187-8502, Japan. ozawa@ncnp.go.jp

ABSTRACT
In 1987, about 150 years after the discovery of Duchenne muscular dystrophy (DMD), its responsible gene, the dystrophin gene, was cloned by Kunkel. This was a new substance. During these 20 odd years after the cloning, our understanding on dystrophin as a component of the subsarcolemmal cytoskeleton networks and on the pathomechanisms of and experimental therapeutics for DMD has been greatly enhanced. During this paradigm change, I was fortunately able to work as an active researcher on its frontiers for 12 years. After we discovered that dystrophin is located on the cell membrane in 1988, we studied the architecture of dystrophin and dystrophin-associated proteins (DAPs) complex in order to investigate the function of dystrophin and pathomechanism of DMD. During the conduct of these studies, we came to consider that the dystrophin-DAP complex serves to transmembranously connect the subsarcolemmal cytoskeleton networks and basal lamina to protect the lipid bilayer. It then became our working hypothesis that injury of the lipid bilayer upon muscle contraction is the cause of DMD. During this process, we predicted that subunits of the sarcoglycan (SG) complex are responsible for respective types of DMD-like muscular dystrophy with autosomal recessive inheritance. Our prediction was confirmed to be true by many researchers including ourselves. In this review, I will try to explain what we observed and how we considered concerning the architecture and function of the dystrophin-DAP complex, and the pathomechanisms of DMD and related muscular dystrophies.

Show MeSH
Related in: MedlinePlus