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Masashi Aoki - One of the best experts on this subject based on the ideXlab platform.
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G.P.288
Neuromuscular Disorders, 2014Co-Authors: N. Fahmy, I Nonaka, Naoki Suzuki, Toshiyuki Takahashi, A. Abd Elhady, A. Abd El-naser, S. Ashour, A. Etribi, N. Minami, Masashi AokiAbstract:Dysferlinopathy is caused by mutations of the dysferlin gene (DYSF) on chromosome 2p13. This gave rise to a spectrum of neuromuscular disorders including: limb-girdle (LGMD2B) and distal muscular dystrophies (Miyoshi Myopathy: MM). Aim: to study the clinical, pathological and genetic characteristics of dysferlinopathy patients in Egypt. Subjects & Methods: Patients were selected from those with progressive muscular dystrophy referred to Muscle and Nerve Research Laboratory, Cairo, Egypt. We studied 77 patients with dystrophic muscle biopsy. Patients had neurological assessment, family pedigree study, Serum Creatine Kinase, ECHO cardiography, electromyography and Dystrophin gene testing. A battery of histochemical tests, immunohistochemistry using both fluorescent and automated methods against a panel of antibodies were done. Mini-multiplex Western Blotting was also done. Genetic study of Dysferlin gene was done for some patients. We found 40 patients with limb-girdle muscular dystrophy, 12 with dysferlinopathy, 6 with calpainopathy, 6 with sarcoglycanopathy and 16 with non-specified limb-girdle muscular dystrophy. Dysferlinopathy patients showed 3 patients with proximal type, 3 patients with Miyoshi Myopathy and 6 patients with anterior compartment Myopathy. Weakness was asymmetrical in 5 patients and symmetrical in 7 patients. Some muscles were uniformly affected in most patients: gluteus maximus, hamstrings, gastrocnemius, tibialis anterior and deltoids. Pathological study showed dystrophic changes of all biopsies, mitochondrial changes in 2 biopsies and inflammatory changes in 3 biopsies. Dysferlin gene analysis was done for only 6 patients of 4 families, showed homozygous mutations in two families, one heterozygous mutation in one family, and no mutation (only polymorphisms) in one family. Dysferlinopathy is a common condition in Egypt. Many clinical, pathological and genetic characteristics are found and help in its diagnosis.
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A novel compound heterozygous dysferlin mutation in Miyoshi Myopathy siblings responding to dantrolene.
European journal of neurology, 2007Co-Authors: Hidenori Hattori, Masashi Aoki, Eiichiro Nagata, Y. Oya, T. Takahashi, Daisuke Ito, Norihiro SuzukiAbstract:Miyoshi Myopathy (MM) is an autosomal recessive distal muscular dystrophy characterized by mutations of the dysferlin gene. Although several pairs of homozygous/ heterozygous mutations have been reported, few effective treatments of MM are available. We had observed the decreased serum creatine kinase (CK) before and after administration of dantrolene in the elder brother and the increased serum CK before and after discontinuance of the drug on suspicion of drug-induced hepatopathy in the younger sister. We report a novel pair of heterozygous mutations in the 3'-splicing site of exon 26 and the translation site of exon 28 of the dysferlin gene in two siblings, and effective treatment of their MM with dantrolene.
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Mutational and clinical features of Japanese patients with dysferlinopathy (Miyoshi Myopathy and limb girdle muscular dystrophy type 2B)
Rinsho shinkeigaku = Clinical neurology, 2005Co-Authors: Masashi Aoki, Toshiaki TakahashiAbstract:Abstract Mutations in the dysferlin gene cause both Miyoshi Myopathy (MM) and limb girdle muscular dystrophy 2B (LGMD2B). We examined patients with dysferlinopathy in Japan, and identified 28 and 12 different mutations respectively in MM and LGMD2B patients. The mean age at onset of the patients with MM was 22 +/- 9 years (range 12-48 years) and that of the patients with LGMD2B was 26 +/- 10 years (range 11-43 years). On the average, the first use of a cane was at 33 years (14 years after the onset) for MM and 39 years (15 years after onset) for LGMD 2B. Patients became wheelchair-bound at 41 years (21 years after onset) in MM and 45 years (21 years after onset) for LGMD2B. The mean maximum serum CK level at any age of the patients was 5,829 +/- 4,273 IU/l (range 1,289-12,566 IU/l ) for MM and 3,787 +/- 2,493 IU/l (627-10,000 IU/l) for LGMD2B: in both disorders, the serum CK level fell in proportion to the duration of the illness. We have identified four common four mutations (C1939G, G3370T, 3746delG, and 4870delT) in Japanese patients with MM, accounting for 48 percent of all MM mutations in this population. Two of the four mutations (G3370T, and 4870delT) accounted for 52 percent of the mutations in LGMD2B patients, while the 3746delG mutation was not found in patients with LGMD2B. The G3370T mutation may be associated with a milder form of MM and LGMD2B. By contrast, the G3510A mutation appears to be associated with a severe form of MM.
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novel dysferlin mutations and characteristic muscle atrophy in late onset Miyoshi Myopathy
Muscle & Nerve, 2004Co-Authors: Naoki Suzuki, Masashi Aoki, Toshiaki Takahashi, Daiki Takano, Masahiro Asano, Yusei Shiga, Yoshiaki Onodera, Maki Tateyama, Yasuto ItoyamaAbstract:Miyoshi Myopathy is characterized by weakness of the calf muscles during early adulthood. We report a case of late-onset Miyoshi Myopathy presenting at 48 years of age, with novel mutations in the dysferlin gene. Muscle computed tomography clearly revealed severe atrophy in the soleus and medial gastrocnemius muscles. Even older patients with atrophy in the posterior compartment of the distal lower extremities and a relatively high serum creatine kinase level should be examined for the dysferlin gene.
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Novel dysferlin mutations and characteristic muscle atrophy in late‐onset Miyoshi Myopathy
Muscle & nerve, 2004Co-Authors: Naoki Suzuki, Masashi Aoki, Toshiaki Takahashi, Daiki Takano, Masahiro Asano, Yusei Shiga, Yoshiaki Onodera, Maki Tateyama, Yasuto ItoyamaAbstract:Miyoshi Myopathy is characterized by weakness of the calf muscles during early adulthood. We report a case of late-onset Miyoshi Myopathy presenting at 48 years of age, with novel mutations in the dysferlin gene. Muscle computed tomography clearly revealed severe atrophy in the soleus and medial gastrocnemius muscles. Even older patients with atrophy in the posterior compartment of the distal lower extremities and a relatively high serum creatine kinase level should be examined for the dysferlin gene.
Robert H. Brown - One of the best experts on this subject based on the ideXlab platform.
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Chapter 7 – Dysferlinopathies
Handbook of clinical neurology, 2011Co-Authors: Anthony A. Amato, Robert H. BrownAbstract:Dysferlin is a sarcolemmal protein that plays an important role in patching defects in skeletal membrane by regulating vesicle fusion with the sarcolemma. Mutations in the dysferlin gene can lead to a variety of clinical phenotypes. Affected individuals usually present with early involvement of the posterior calf muscles (Miyoshi Myopathy) in their teens or early twenties, but can present with proximal greater than distal weakness similar to other limb-girdle muscular dystrophies (LGMD2B), with anterior tibial weakness, an axial Myopathy (e.g., rigid spine syndrome or hyperkyphosis resembling bent spine syndrome), or any combination of the above. Muscle biopsies may be quite inflammatory, often resulting in a misdiagnosis as polymyositis. Unfortunately, there are no medical therapies available at this time.
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A novel, blood-based diagnostic assay for limb girdle muscular dystrophy 2B and Miyoshi Myopathy.
Annals of neurology, 2002Co-Authors: Eduard Gallardo, Diane Mckenna-yasek, Noemi De Luna, Isabel Illa, Robert H. BrownAbstract:Limb girdle muscular dystrophy 2B and Miyoshi Myopathy were recently found to be allelic disorders arising from defects in the dysferlin gene. We have developed a new diagnostic assay for limb girdle muscular dystrophy 2B and Miyoshi Myopathy, which screens for dysferlin expression in blood using a commercially available monoclonal antibody. Unlike current methods that require muscle biopsy for immunodiagnosis, the new method is simple and entails a significantly less invasive procedure for tissue sampling. Moreover, it overcomes some of the problems associated with the handling and storage of muscle specimens. In our analysis of 12 patients with limb girdle muscular dystrophy 2B or Miyoshi Myopathy, the findings obtained using the new assay are fully consistent with the results from muscle immunodiagnosis.
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Dysferlin is a surface membrane–associated protein that is absent in Miyoshi Myopathy
Neurology, 1999Co-Authors: C. Matsuda, Kiichi Arahata, Masashi Aoki, Yukiko K. Hayashi, Robert H. BrownAbstract:Article abstract Recently we reported that mutations in a muscle protein “dysferlin” are present in limb girdle muscular dystrophy–2B and a related, adult-onset, distal dystrophy known as Miyoshi Myopathy (MM). We report that antibodies to dysferlin identify a protein of approximately 230 kDa and show that dysferlin is located in the muscle membrane. This protein is absent in MM and LGMD-2B muscle. By contrast, dystrophin and other dystrophin-associated proteins are normal in these patients. Thus, dysferlin is a membrane-associated protein that is not likely to be an integral component of the dystrophin complex. Although it is not essential for initial myogenesis, it appears to be critical for sustained normal function in mature muscle.
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dysferlin is a surface membrane associated protein that is absent in Miyoshi Myopathy
Neurology, 1999Co-Authors: C. Matsuda, Kiichi Arahata, Masashi Aoki, Yukiko K. Hayashi, Robert H. BrownAbstract:Article abstract Recently we reported that mutations in a muscle protein “dysferlin” are present in limb girdle muscular dystrophy–2B and a related, adult-onset, distal dystrophy known as Miyoshi Myopathy (MM). We report that antibodies to dysferlin identify a protein of approximately 230 kDa and show that dysferlin is located in the muscle membrane. This protein is absent in MM and LGMD-2B muscle. By contrast, dystrophin and other dystrophin-associated proteins are normal in these patients. Thus, dysferlin is a membrane-associated protein that is not likely to be an integral component of the dystrophin complex. Although it is not essential for initial myogenesis, it appears to be critical for sustained normal function in mature muscle.
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Positional cloning of the gene for Miyoshi Myopathy and limb-girdle muscular dystrophy
Rinsho shinkeigaku = Clinical neurology, 1999Co-Authors: Masashi Aoki, Kiichi Arahata, Robert H. BrownAbstract:Miyoshi Myopathy (MM) is autosomal recessive distal muscular dystrophy that we have mapped to chromosome 2 p13. We constructed a 3 Mb P 1-derived artificial chromosome contig spanning the MM candidate region. Using this and new polymorphic markers within it, we recently identified a novel, full-length 6.9 kb muscle cDNA, whose corresponding protein we designated "dysferlin" (Nature Genet, 1998: 20: 31-36). We described eighteen mutations in the dysferlin gene with MM or limb-girdle muscular dystrophy type 2 B (LGMD 2 B). Most are predicted to block translation of dysferlin protein. In some cases, corresponding Western immunoblotting reveals absence of dysferlin in muscle biopsies. Identical mutations in the dysferlin gene can produce more than one Myopathy phenotype (MM, limb-girdle dystrophy, distal Myopathy with anterior tibial onset).
Kevin P. Campbell - One of the best experts on this subject based on the ideXlab platform.
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Dysferlin and the plasma membrane repair in muscular dystrophy. Trends Cell Biol
2015Co-Authors: Dimple Bansal, Kevin P. CampbellAbstract:Muscular dystrophy covers a group of genetically deter-mined disorders that cause progressive weakness and wasting of the skeletal muscles. Dysferlin was identified as a gene mutated in limb–girdle muscular dystrophy (type 2B) and Miyoshi Myopathy. The discovery of dys-ferlin revealed a new family of proteins, known as the ferlin family, which includes four different genes. Recent work suggests the function of dysferlin in mem-brane repair and demonstrates that defective membrane repair is a novel mechanism of muscle degeneration. These findings reveal the importance of a basic cellular function in skeletal muscle and a new class of muscu-lar dystrophy where the defect lies in the maintenance, not the structure, of the plasma membrane. Here, we discuss the current knowledge of dysferlin function i
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Dysferlin and the plasma membrane repair in muscular dystrophy
Trends in cell biology, 2004Co-Authors: Dimple Bansal, Kevin P. CampbellAbstract:Muscular dystrophy covers a group of genetically determined disorders that cause progressive weakness and wasting of the skeletal muscles. Dysferlin was identified as a gene mutated in limb-girdle muscular dystrophy (type 2B) and Miyoshi Myopathy. The discovery of dysferlin revealed a new family of proteins, known as the ferlin family, which includes four different genes. Recent work suggests the function of dysferlin in membrane repair and demonstrates that defective membrane repair is a novel mechanism of muscle degeneration. These findings reveal the importance of a basic cellular function in skeletal muscle and a new class of muscular dystrophy where the defect lies in the maintenance, not the structure, of the plasma membrane. Here, we discuss the current knowledge of dysferlin function in the repair of the plasma membrane of the skeletal muscle cells.
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Intracellular accumulation and reduced sarcolemmal expression of dysferlin in limb--girdle muscular dystrophies.
Annals of neurology, 2000Co-Authors: F. Piccolo, Steven A. Moore, Gwendolyn C. Ford, Kevin P. CampbellAbstract:Dysferlin has recently been identified as a novel gene involved in limb-girdle muscular dystrophy type 2B (LGMD2B) and its allelic disease, Miyoshi Myopathy. The predicted structure of dysferlin suggests that it is a transmembrane protein possibly involved in membrane fusion. Thus, unlike previously identified structural proteins in muscular dystrophy, dysferlin is likely involved in a novel pathogenic mechanism for this disease. In this study, we have analyzed the expression of dysferlin in skeletal muscle of patients with disruptions in the dystrophin-glycoprotein complex and patients with a clinical diagnosis of LGMD2B or Miyoshi Myopathy. We show expression of dysferlin at the sarcolemma in normal muscle and reduced sarcolemmal expression along with accumulation of intracellular staining in dystrophic muscle. Electron microscopy in Miyoshi Myopathy biopsies suggests that the cytoplasmic staining could be a result of the abundance of intracellular vesicles. Our results indicate that dysferlin expression is perturbed in LGMD and that both mutations in the dysferlin gene and disruption of the dystrophin-glycoprotein complex can lead to the accumulation of dysferlin within the cytoplasm.
Robert J. Bloch - One of the best experts on this subject based on the ideXlab platform.
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Dysferlin at transverse tubules regulates Ca2+ homeostasis in skeletal muscle
Frontiers in physiology, 2014Co-Authors: Jaclyn P. Kerr, Christopher W. Ward, Robert J. BlochAbstract:The class of muscular dystrophies linked to the genetic ablation or mutation of dysferlin, including Limb Girdle Muscular Dystrophy 2B (LGMD2B) and Miyoshi Myopathy (MM), are late-onset degenerative diseases. In lieu of a genetic cure, treatments to prevent or slow the progression of dysferlinopathy are of the utmost importance. Recent advances in the study of dysferlinopathy have highlighted the necessity for the maintenance of calcium handling in altering or slowing the progression of muscular degeneration resulting from the loss of dysferlin. This review highlights new evidence for a role for dysferlin at the transverse (t-) tubule of striated muscle, where it is involved in maintaining t-tubule structure and function.
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Dysferlin stabilizes stress-induced Ca2+ signaling in the transverse tubule membrane.
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Jaclyn P. Kerr, Andrew P. Ziman, Amber L. Mueller, Joaquin Muriel, Emily Kleinhans-welte, Jessica D. Gumerson, Steven S. Vogel, Christopher W. Ward, Joseph A. Roche, Robert J. BlochAbstract:Dysferlinopathies, most commonly limb girdle muscular dystrophy 2B and Miyoshi Myopathy, are degenerative myopathies caused by mutations in the DYSF gene encoding the protein dysferlin. Studies of dysferlin have focused on its role in the repair of the sarcolemma of skeletal muscle, but dysferlin’s association with calcium (Ca2+) signaling proteins in the transverse (t-) tubules suggests additional roles. Here, we reveal that dysferlin is enriched in the t-tubule membrane of mature skeletal muscle fibers. Following experimental membrane stress in vitro, dysferlin-deficient muscle fibers undergo extensive functional and structural disruption of the t-tubules that is ameliorated by reducing external [Ca2+] or blocking L-type Ca2+ channels with diltiazem. Furthermore, we demonstrate that diltiazem treatment of dysferlin-deficient mice significantly reduces eccentric contraction-induced t-tubule damage, inflammation, and necrosis, which resulted in a concomitant increase in postinjury functional recovery. Our discovery of dysferlin as a t-tubule protein that stabilizes stress-induced Ca2+ signaling offers a therapeutic avenue for limb girdle muscular dystrophy 2B and Miyoshi Myopathy patients.
Yukiko K. Hayashi - One of the best experts on this subject based on the ideXlab platform.
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Dysferlin mutation analysis in a group of Italian patients with limb-girdle muscular dystrophy and Miyoshi Myopathy.
European journal of neurology, 2004Co-Authors: Kiyokazu Kawabe, Kanako Goto, Corrado Angelini, Ichizo Nishino, Yukiko K. HayashiAbstract:Mutations in the dysferlin gene (DYSF) on chromosome 2p13 cause distinct phenotypes of muscular dystrophy: limb-girdle muscular dystrophy type 2B (LGMD2B), Miyoshi Myopathy (MM), and distal anterior compartment Myopathy, which are known by the term 'dysferlinopathy'. We performed mutation analyses of DYSF in 14 Italian patients from 10 unrelated families with a deficiency of dysferlin protein below 20% of the value in normal controls by immunoblotting analysis. We identified 11 different mutations, including eight missense and three deletion mutations. Nine of them were novel mutations. We also identified a unique 6-bp insertion polymorphism within the coding region of DYSF in 15% of Italian population, which was not observed in East Asian populations. The correlation between clinical phenotype and the gene mutations was unclear, which suggested the role of additional genetic and epigenetic factors in modifying clinical symptoms.
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A patient with distal muscular dystrophy without mutations in dysferlin gene but with abnormal dysferlin localization in muscle fibers
Rinsho shinkeigaku = Clinical neurology, 2004Co-Authors: Isao Hozumi, Masashi Aoki, Toshiaki Takahashi, Yukiko K. Hayashi, Naoteru Suzuki, Zenjiro Matsuyama, Takashi Inuzuka, Ikuya NonakaAbstract:We report a 40-year-old man who noticed difficulty in standing on his tiptoe from approximately 36 years-old. He presented with selective calf muscle weakness on flexion. The serum creatine kinase (CK) level slightly increased to 569IU/l. Muscle computed tomography (CT) revealed selective gastrocnemius and soleus muscle atrophy with fat tissue replacement. A biopsy of the left gastrocnemius muscle revealed a marked variation in muscle fiber size and some necrotic and regenerating fibers. Immunohistochemical analysis using an anti-dysferlin antibody showed a faint and irregular immunostaining of the muscle surface membrane and abnormal immunoreactive depositions in the cytoplasm, although normal dysferlin content was detected by Western blotting. The sequence analysis of all exons of the dysferlin gene revealed no responsible mutations. The case had clinical and pathological findings similar to those of Miyoshi Myopathy. The present study indicates that there may be a secondary abonormality of dysferlin derived from some other factors in patients with clinical and pathological findings similar to those of Miyoshi Myopathy. The mechanism of dysferlin expression should be elucidated to obtain a conclusive pathogenetic mechanism underlying this disorder.
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Dysferlin is a surface membrane–associated protein that is absent in Miyoshi Myopathy
Neurology, 1999Co-Authors: C. Matsuda, Kiichi Arahata, Masashi Aoki, Yukiko K. Hayashi, Robert H. BrownAbstract:Article abstract Recently we reported that mutations in a muscle protein “dysferlin” are present in limb girdle muscular dystrophy–2B and a related, adult-onset, distal dystrophy known as Miyoshi Myopathy (MM). We report that antibodies to dysferlin identify a protein of approximately 230 kDa and show that dysferlin is located in the muscle membrane. This protein is absent in MM and LGMD-2B muscle. By contrast, dystrophin and other dystrophin-associated proteins are normal in these patients. Thus, dysferlin is a membrane-associated protein that is not likely to be an integral component of the dystrophin complex. Although it is not essential for initial myogenesis, it appears to be critical for sustained normal function in mature muscle.
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dysferlin is a surface membrane associated protein that is absent in Miyoshi Myopathy
Neurology, 1999Co-Authors: C. Matsuda, Kiichi Arahata, Masashi Aoki, Yukiko K. Hayashi, Robert H. BrownAbstract:Article abstract Recently we reported that mutations in a muscle protein “dysferlin” are present in limb girdle muscular dystrophy–2B and a related, adult-onset, distal dystrophy known as Miyoshi Myopathy (MM). We report that antibodies to dysferlin identify a protein of approximately 230 kDa and show that dysferlin is located in the muscle membrane. This protein is absent in MM and LGMD-2B muscle. By contrast, dystrophin and other dystrophin-associated proteins are normal in these patients. Thus, dysferlin is a membrane-associated protein that is not likely to be an integral component of the dystrophin complex. Although it is not essential for initial myogenesis, it appears to be critical for sustained normal function in mature muscle.
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molecular genetic analysis of dysferlin in japanese patients with Miyoshi Myopathy
Proceedings of the Japan Academy. Ser. B: Physical and Biological Sciences, 1999Co-Authors: Tsuyoshi Matsumura, Kanako Goto, Masanori Nakagawa, Masashi Aoki, Yukiko K. Hayashi, Atsushi Nagano, Chie Asada, Megumu Ogawa, Gaku Yamanaka, Hisayoshi OkaAbstract:Miyoshi Myopathy (MM) is an autosomal recessive distal muscular dystrophy first described by Miyoshi in 1967. MM is caused by mutations of a dysferlin gene (DYSF) at chromosome 2p13. We identified 8 novel mutations and 3 polymorphisms in the DYSF among seven unrelated Japanese families. The mutations in our MM occurred throughout the DYSF and showed no mutational hot spot. Expression of dysferlin at the plasma membrane of skeletal muscle was deficient in all the patients studied. In two families, we found two distinct clinical phenotypes (distal and proximal dominancies) within a family. This is the first report of DYSF mutations and dysferlin deficiency in Japanese patients with MM. Our findings suggest, (1) the specific deficiency of dysferlin at the plasma membrane of skeletal muscle in MM, (2) the ethnic difference in DYSF mutations and (3) the presence of possible genetic or environmental modification factors which influence the clinical variability of MM.