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Markus A Ruegg - One of the best experts on this subject based on the ideXlab platform.
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t o 2 omigapil snt 317 prevents apoptosis and ameliorates the pathology of Laminin Alpha2 deficient muscle dystrophy
Neuromuscular Disorders, 2008Co-Authors: T Meier, Sarina Meinen, Patrizia Barzaghi, Markus A RueggAbstract:Mutations in LAMA2, the gene encoding the Laminin-Alpha2 chain of the extracellular matrix of muscle cells, cause a rare and severe form of congenital muscular dystrophy, called MDC1A. The disease is characterized by early onset, progressive muscle degeneration and impaired regeneration. As consequence, affected children are often never able to walk and, as there is no effective treatment available, frequently die in early childhood. Genetic evidence has shown that overexpression of the apoptosis inhibitor protein BCL-2 can protect from disease-relevant pathologies in the Laminin-Alpha2 deficient dyW/dyW mouse, a model for MDC1A. In addition, expression of a miniaturized form of the extracellular matrix molecule agrin (mini-agrin) has been shown to be an alternative way to ameliorate disease symptoms. The efficacy of omigapil (N-(dibenz(b,f)oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine maleate; SNT-317, TCH346), a chemical derivative of selegiline, was tested in dyW/dyW mice by oral administration at a daily dose of 0.1 or 1 mg/kg starting at 3-weeks of age. Control animals were treated with vehicle. We show that omigapil, a well characterized inhibitor of apoptosis that targets GAPDH, ameliorated key pathology hallmarks of the dyW/dyW mouse. Specifically, oral administration of omigapil reduced apoptosis in muscle and preserved muscle histology, reduced body weight loss, mitigated skeletal deformation and improved locomotion. Moreover, omigapil increased the 50% survival time from 35 days in vehicle treated dyW/dyWmice to 85 days and 105 days in dyW/dyW mice treated with 0.1 and 1 mg/kg omigapil, respectively. In addition, we show that co-administration of mini-agrin had additive beneficial effects. The preclinical and clinical development of omigapil is well advanced and omigapil was proven to be safe in large clinical trials. Based on its efficacy in the dyW/dyW mouse, this orally bioavailable drug is well suited to be tested clinically as a potential therapy for MDC1A.
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T.O.2 Omigapil/SNT-317 prevents apoptosis and ameliorates the pathology of Laminin-Alpha2 deficient muscle dystrophy
Neuromuscular Disorders, 2008Co-Authors: T Meier, Sarina Meinen, Patrizia Barzaghi, Markus A RueggAbstract:Mutations in LAMA2, the gene encoding the Laminin-Alpha2 chain of the extracellular matrix of muscle cells, cause a rare and severe form of congenital muscular dystrophy, called MDC1A. The disease is characterized by early onset, progressive muscle degeneration and impaired regeneration. As consequence, affected children are often never able to walk and, as there is no effective treatment available, frequently die in early childhood. Genetic evidence has shown that overexpression of the apoptosis inhibitor protein BCL-2 can protect from disease-relevant pathologies in the Laminin-Alpha2 deficient dyW/dyW mouse, a model for MDC1A. In addition, expression of a miniaturized form of the extracellular matrix molecule agrin (mini-agrin) has been shown to be an alternative way to ameliorate disease symptoms. The efficacy of omigapil (N-(dibenz(b,f)oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine maleate; SNT-317, TCH346), a chemical derivative of selegiline, was tested in dyW/dyW mice by oral administration at a daily dose of 0.1 or 1 mg/kg starting at 3-weeks of age. Control animals were treated with vehicle. We show that omigapil, a well characterized inhibitor of apoptosis that targets GAPDH, ameliorated key pathology hallmarks of the dyW/dyW mouse. Specifically, oral administration of omigapil reduced apoptosis in muscle and preserved muscle histology, reduced body weight loss, mitigated skeletal deformation and improved locomotion. Moreover, omigapil increased the 50% survival time from 35 days in vehicle treated dyW/dyWmice to 85 days and 105 days in dyW/dyW mice treated with 0.1 and 1 mg/kg omigapil, respectively. In addition, we show that co-administration of mini-agrin had additive beneficial effects. The preclinical and clinical development of omigapil is well advanced and omigapil was proven to be safe in large clinical trials. Based on its efficacy in the dyW/dyW mouse, this orally bioavailable drug is well suited to be tested clinically as a potential therapy for MDC1A.
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Linker molecules between Laminins and dystroglycan ameliorate Laminin-α2–deficient muscular dystrophy at all disease stages
The Journal of cell biology, 2007Co-Authors: Sarina Meinen, Patrizia Barzaghi, Shuo Lin, Hanns Lochmüller, Markus A RueggAbstract:Mutations in Laminin-Alpha2 cause a severe congenital muscular dystrophy, called MDC1A. The two main receptors that interact with Laminin-Alpha2 are dystroglycan and alpha7beta1 integrin. We have previously shown in mouse models for MDC1A that muscle-specific overexpression of a miniaturized form of agrin (mini-agrin), which binds to dystroglycan but not to alpha7beta1 integrin, substantially ameliorates the disease (Moll, J., P. Barzaghi, S. Lin, G. Bezakova, H. Lochmuller, E. Engvall, U. Muller, and M.A. Ruegg. 2001. Nature. 413:302-307; Bentzinger, C.F., P. Barzaghi, S. Lin, and M.A. Ruegg. 2005. Matrix Biol. 24:326-332.). Now we show that late-onset expression of mini-agrin still prolongs life span and improves overall health, although not to the same extent as early expression. Furthermore, a chimeric protein containing the dystroglycan-binding domain of perlecan has the same activities as mini-agrin in ameliorating the disease. Finally, expression of full-length agrin also slows down the disease. These experiments are conceptual proof that linking the basement membrane to dystroglycan by specifically designed molecules or by endogenous ligands, could be a means to counteract MDC1A at a progressed stage of the disease, and thus opens new possibilities for the development of treatment options for this muscular dystrophy.
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Overexpression of mini-agrin in skeletal muscle increases muscle integrity and regenerative capacity in Laminin-α2-deficient mice
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2005Co-Authors: C. Florian Bentzinger, Patrizia Barzaghi, Shuo Lin, Markus A RueggAbstract:Mutations in the gene encoding the Alpha2 subunit of Laminins cause the severe "merosin-deficient congenital muscular dystrophy" (MDC1A). We have recently shown that overexpression of a miniaturized form of the molecule agrin (mini-agrin) counteracts the disease in dy(W)/dy(W) mice, a model for MDC1A. However, these mice express some residual truncated Laminin-Alpha2, suggesting that the observed amelioration might be due to mini-agrin's presenting the residual Laminin-Alpha2 to its receptors. Here we show that the mini-agrin counteracts the disease in dy(3K)/dy(3K) mice, which are null for Laminin-Alpha2. As in dy(W)/dy(W) mice, mini-agrin improves both the function and structure of muscle. We show that muscle regeneration after injury is severely impaired in dy(3K)/dy(3K) mice but is restored in the mini-agrin-expressing littermates. In summary, our results 1) show that the direct linkage of muscle basal lamina with the sarcolemma is the basis of mini-agrin-mediated amelioration and 2) provide unprecedented evidence that this linkage is important for proper regeneration of muscle fibers after injury. Our findings thus suggest that treatment with mini-agrin might be beneficial over the entire spectrum of the MDC1A disease, whose severity inversely correlates with expression levels and the size of the truncation in Laminin-Alpha2.
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Laminin α2 deficiency and muscular dystrophy; genotype-phenotype correlation in mutant mice
Neuromuscular disorders : NMD, 2003Co-Authors: Ling T. Guo, Markus A Ruegg, X. Zhang, Wen Kuang, Shin'ichi Takeda, L.a. Liu, J.-t. Vilquin, Y. Miyagoe-suzuki, Ulla M. WewerAbstract:Deficiency of Laminin Alpha2 is the cause of one of the most severe muscular dystrophies in humans and other species. It is not yet clear how particular mutations in the Laminin Alpha2 chain gene affect protein expression, and how abnormal levels or structure of the protein affect disease. Animal models may be valuable for such genotype-phenotype analysis and for determining mechanism of disease as well as function of Laminin. Here, we have analyzed protein expression in three lines of mice with mutations in the Laminin Alpha2 chain gene and in two lines of transgenic mice overexpressing the human Laminin Alpha2 chain gene in skeletal muscle. The dy(3K)/dy(3K) experimental mutant mice are completely deficient in Laminin Alpha2; the dy/dy spontaneous mutant mice have small amounts of apparently normal Laminin; and the dy(W)/dy(W) mice express even smaller amounts of a truncated Laminin Alpha2, lacking domain VI. Interestingly, all mutants lack Laminin Alpha2 in peripheral nerve. We have demonstrated previously, that overexpression of the human Laminin Alpha2 in skeletal muscle in dy(2J)/dy(2J) and dy(W)/dy(W) mice under the control of a striated muscle-specific creatine kinase promoter substantially prevented the muscular dystrophy in these mice. However, dy(W)/dy(W) mice, expressing the human Laminin Alpha2 under the control of the striated muscle-specific portion of the desmin promoter, still developed muscular dystrophy. This failure to rescue is apparently because of insufficient production of Laminin Alpha2. This study provides additional evidence that the amount of Laminin Alpha2 is most critical for the prevention of muscular dystrophy. These data may thus be of significance for attempts to treat congenital muscular dystrophy in human patients.
Madeleine Durbeej - One of the best experts on this subject based on the ideXlab platform.
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Distinct roles for Laminin globular domains in Laminin alpha1 chain mediated rescue of murine Laminin Alpha2 chain deficiency.
PLOS ONE, 2010Co-Authors: Kinga I Gawlik, Mikael Åkerlund, Virginie Carmignac, Harri Elamaa, Madeleine DurbeejAbstract:BACKGROUND: Laminin Alpha2 chain mutations cause congenital muscular dystrophy with dysmyelination neuropathy (MDC1A). Previously, we demonstrated that Laminin alpha1 chain ameliorates the disease in mice. Dystroglycan and integrins are major Laminin receptors. Unlike Laminin Alpha2 chain, alpha1 chain binds the receptors by separate domains; Laminin globular (LG) domains 4 and LG1-3, respectively. Thus, the Laminin alpha1 chain is an excellent tool to distinguish between the roles of dystroglycan and integrins in the neuromuscular system. METHODOLOGY/PRINCIPAL FINDINGS: Here, we provide insights into the functions of Laminin alpha1LG domains and the division of their roles in MDC1A pathogenesis and rescue. Overexpression of Laminin alpha1 chain that lacks the dystroglycan binding LG4-5 domains in Alpha2 chain deficient mice resulted in prolonged lifespan and improved health. Importantly, diaphragm and heart muscles were corrected, whereas limb muscles were dystrophic, indicating that different muscles have different requirements for LG4-5 domains. Furthermore, the regenerative capacity of the skeletal muscle did not depend on Laminin alpha1LG4-5. However, this domain was crucial for preventing apoptosis in limb muscles, essential for myelination in peripheral nerve and important for basement membrane assembly. CONCLUSIONS/SIGNIFICANCE: These results show that Laminin alpha1LG domains and consequently their receptors have disparate functions in the neuromuscular system. Understanding these interactions could contribute to design and optimization of future medical treatment for MDC1A patients.
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Intrinsic laryngeal muscles are spared from degeneration in the dy3k/dy3k mouse model of congenital muscular dystrophy type 1A
Muscle & nerve, 2009Co-Authors: Mattias Häger, Madeleine DurbeejAbstract:Deficiency of Laminin Alpha2 chain leads to a severe form of congenital muscular dystrophy (MDC1A). Here, we analyzed whether the intrinsic laryngeal muscles (ILM) are spared in the dy(3K)/dy(3K) mouse model of complete Laminin Alpha2 chain absence. No muscle degeneration was evident; expression of various Laminin chains was similar to that of limb muscles, and sustained integrin alpha7B expression was noted in Laminin Alpha2 chain-deficient ILM. We conclude that ILM are spared in MDC1A.
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Laminin alpha1 chain improves Laminin Alpha2 chain deficient peripheral neuropathy
Human Molecular Genetics, 2006Co-Authors: Kinga I Gawlik, Asa Petersen, Madeleine DurbeejAbstract:Absence of Laminin Alpha2 chain leads to a severe form of congenital muscular dystrophy (MDC1A) associated with peripheral neuropathy. Hence, future therapies should be aimed at alleviating both muscle and neurological dysfunctions. Pre-clinical studies in animal models have mainly focused on ameliorating the muscle phenotype. Here we show that transgenic expression of Laminin alpha1 chain in muscles and the peripheral nervous system of Laminin Alpha2 chain deficient mice reduced muscular dystrophy and largely corrected the peripheral nerve defects. The presence of Laminin alpha1 chain in the peripheral nervous system resulted in near-normal myelination, restored Schwann cell basement membranes and improved rotarod performance. In summary, we postulate that Laminin alpha1 chain is an excellent substitute for Laminin Alpha2 chain in multiple tissues and suggest that treatment with Laminin alpha1 chain may be beneficial for MDC1A in humans.
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Extraocular muscle is spared upon complete Laminin Alpha2 chain deficiency: comparative expression of Laminin and integrin isoforms.
Matrix biology : journal of the International Society for Matrix Biology, 2006Co-Authors: Alexander Nyström, Takako Sasaki, Fatima Pedrosa-domellöf, Johanna Holmblad, Madeleine DurbeejAbstract:Mutations in the gene encoding Laminin (LM) Alpha2 chain cause congenital muscular dystrophy. Here, we show that extraocular muscle (EOM) is spared upon complete LMAlpha2 chain absence. The major LM chains in limb muscle basement membranes are Alpha2, beta1, beta2 and gamma1 whereas Alpha2, alpha4, beta1, beta2 and gamma1 chains are expressed in EOM. Expression of LMalpha4 chain mRNA is further increased in LMAlpha2 chain deficient EOM. Mainly integrin alpha7X1 subunit, which binds to Laminin-411, is expressed in EOM and in contrast to dystrophic limb muscle, sustained integrin alpha7B expression is seen in LMAlpha2 chain deficient EOM. We propose that LMalpha4 chain, possibly by binding to integrin alpha7BX1beta1D, protects EOM in LMAlpha2 chain deficient muscular dystrophy.
Peter D. Currie - One of the best experts on this subject based on the ideXlab platform.
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Cellular rescue in a zebrafish model of congenital muscular dystrophy type 1A
NPJ Regenerative medicine, 2019Co-Authors: Thomas E. Hall, A.j. Wood, Ophelia V Ehrlich, Carmen Sonntag, Nicholas J. Cole, Inken G. Huttner, Tamar E. Sztal, Peter D. CurrieAbstract:Laminins comprise structural components of basement membranes, critical in the regulation of differentiation, survival and migration of a diverse range of cell types, including skeletal muscle. Mutations in one muscle enriched Laminin isoform, Laminin Alpha2 (Lama2), results in the most common form of congenital muscular dystrophy, congenital muscular dystrophy type 1A (MDC1A). However, the exact cellular mechanism by which Laminin loss results in the pathological spectrum associated with MDC1A remains elusive. Here we show, via live tracking of individual muscle fibres, that dystrophic myofibres in the zebrafish model of MDC1A maintain sarcolemmal integrity and undergo dynamic remodelling behaviours post detachment, including focal sarcolemmal reattachment, cell extension and hyper-fusion with surrounding myoblasts. These observations imply the existence of a window of therapeutic opportunity, where detached cells may be "re-functionalised" prior to their delayed entry into the cell death program, a process we show can be achieved by muscle specific or systemic Laminin delivery. We further reveal that Laminin also acts as a pro-regenerative factor that stimulates muscle stem cell-mediated repair in lama2-deficient animals in vivo. The potential multi-mode of action of Laminin replacement therapy suggests it may provide a potent therapeutic axis for the treatment for MDC1A.
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epistatic dissection of Laminin receptor interactions in dystrophic zebrafish muscle
Human Molecular Genetics, 2012Co-Authors: Tamar E. Sztal, Thomas E. Hall, Carmen Sonntag, Peter D. CurrieAbstract:Laminins form essential components of the basement membrane and are integral to forming and maintaining muscle integrity. Mutations in the human Laminin-Alpha2 (LAMA2) gene result in the most common form of congenital muscular dystrophy, MDC1A. We have previously identified a zebrafish model of MDC1A called candyfloss (caf), carrying a loss-of-function mutation in the zebrafish lama2 gene. In the skeletal muscle, Laminins connect the muscle cell to the extracellular matrix (ECM) by binding either dystroglycan or integrins at the cell membrane. Through epistasis experiments, we have established that both adhesion systems individually contribute to the maintenance of fibre adhesions and exhibit muscle detachment phenotypes. However, larval zebrafish in which both adhesion systems are simultaneously genetically inactivated possess a catastrophic failure of muscle attachment that is far greater than a simple addition of individual phenotypes would predict. We provide evidence that this is due to other crucial Laminins present in addition to Lama2, which aid muscle cell attachments and integrity. We have found that lama1 is important for maintaining attachments, whereas lama4 is localized and up-regulated in damaged fibres, which appears to contribute to fibre survival. Importantly, our results show that endogenous secretion of Laminins from the surrounding tissues has the potential to reinforce fibre attachments and strengthen Laminin-ECM attachments. Collectively these findings provide a better understanding of the cellular pathology of MDC1A and help in designing effective therapies.
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Epistatic dissection of Laminin–receptor interactions in dystrophic zebrafish muscle
Human molecular genetics, 2012Co-Authors: Tamar E. Sztal, Thomas E. Hall, Carmen Sonntag, Peter D. CurrieAbstract:Laminins form essential components of the basement membrane and are integral to forming and maintaining muscle integrity. Mutations in the human Laminin-Alpha2 (LAMA2) gene result in the most common form of congenital muscular dystrophy, MDC1A. We have previously identified a zebrafish model of MDC1A called candyfloss (caf), carrying a loss-of-function mutation in the zebrafish lama2 gene. In the skeletal muscle, Laminins connect the muscle cell to the extracellular matrix (ECM) by binding either dystroglycan or integrins at the cell membrane. Through epistasis experiments, we have established that both adhesion systems individually contribute to the maintenance of fibre adhesions and exhibit muscle detachment phenotypes. However, larval zebrafish in which both adhesion systems are simultaneously genetically inactivated possess a catastrophic failure of muscle attachment that is far greater than a simple addition of individual phenotypes would predict. We provide evidence that this is due to other crucial Laminins present in addition to Lama2, which aid muscle cell attachments and integrity. We have found that lama1 is important for maintaining attachments, whereas lama4 is localized and up-regulated in damaged fibres, which appears to contribute to fibre survival. Importantly, our results show that endogenous secretion of Laminins from the surrounding tissues has the potential to reinforce fibre attachments and strengthen Laminin-ECM attachments. Collectively these findings provide a better understanding of the cellular pathology of MDC1A and help in designing effective therapies.
Pascale Guicheney - One of the best experts on this subject based on the ideXlab platform.
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Severe MDC1A congenital muscular dystrophy due to a splicing mutation in the LAMA2 gene resulting in exon skipping and significant decrease of mRNA level.
Genetic Testing, 2007Co-Authors: Olfa Siala, Pascale Guicheney, Pascale Richard, Nacim Louhichi, Chahnez Triki, Madeleine Morinière, Faouzi Baklouti, Ahmed Rebai, Faiza FakhfakhAbstract:Congenital muscular dystrophies (CMDs) are a clinically and genetically heterogeneous group of neuromuscular disorders, with autosomal recessive inheritance. We report a patient with severe congenital muscular dystrophy and total deficiency in the Laminin Alpha2 chain. Genetic analyses showed a linkage to the MDC1A locus for the patient's family, and DNA sequencing revealed in the propositus of a new homozygous mutation in the donor splice site of intron 58 of the LAMA2 gene. RT-PCR experiments performed on total RNA from a patient's muscle biopsy showed a complete skipping of exon 58 in LAMA2 cDNA and a significant decrease in the LAMA2 mRNA level. This exon skipping altered the open reading frame of the mutant transcript and generated a premature termination codon (PTC) within exon 59, which potentially elicits the nonsense mRNA to degradation by NMD (nonsense-mediated mRNA decay). However, the residual exon 58-lacking mRNA could potentially be translated, and the resulting truncated Alpha2 chain would lack its LG4 and LG5 domains that are involved in binding with alpha-dystroglycan. These results demonstrate the utility of mRNA analysis to understand the mutation primary impact and the disease phenotype in the patients.
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Expression profiling of muscles from Fukuyama-type congenital muscular dystrophy and Laminin-α2 deficient congenital muscular dystrophy; is congenital muscular dystrophy a primary fibrotic disease?
Biochemical and biophysical research communications, 2006Co-Authors: Mariko Taniguchi, Satoru Noguchi, Pascale Guicheney, Hiroki Kurahashi, Jun Sese, Takeshi Okinaga, Toshifumi Tsukahara, Keiichi Ozono, Ichizo Nishino, Shinichi MorishitaAbstract:Fukuyama-type congenital muscular dystrophy (FCMD) and Laminin-Alpha2 deficient congenital muscular dystrophy (MDC1A) are congenital muscular dystrophies (CMDs) and they both are categorized into the same clinical entity of muscular dystrophy as Duchenne muscular dystrophy (DMD). All three disorders share a common etiologic defect in the dystrophin-glycoprotein complex, which connects muscle structural proteins with the extracellular basement membrane. To investigate the pathophysiology of these CMDs, we generated microarray gene expression profiles of skeletal muscle from patients in various clinical stages. Despite diverse pathological changes, the correlation coefficient of overall gene expression among these samples was considerably high. We performed a multi-dimensional statistical analysis, the Distillation, to extract determinant genes that distinguish CMD muscle from normal controls. Up-regulated genes were primarily extracellular matrix (ECM) components, whereas down-regulated genes included structural components of mature muscle. These observations reflect active interstitial fibrosis with less active regeneration of muscle cell components in the CMDs, characteristics that are clearly distinct from those of DMD. Although the severity of fibrosis varied among the specimens tested, ECM gene expression was consistently high without substantial changes through the clinical course. Further, in situ hybridization showed more prominent ECM gene expression on muscle cells than on interstitial tissue cells, suggesting that ECM components are induced by regeneration process rather than by 'dystrophy.' These data imply that the etiology of FCMD and MDC1A differs from that of the chronic phase of classical muscular dystrophy, and the major pathophysiologic change in CMDs might instead result from primary active fibrosis.
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Novel mutations in LAMA2 gene responsible for a severe phenotype of congenital muscular dystrophy in two Tunisian families.
Archives de l'Institut Pasteur de Tunis, 2006Co-Authors: Nacim Louhichi, Pascale Guicheney, Pascale Richard, Meziou M, Hammadi Ayadi, Faiza FakhfakhAbstract:Congenital muscular dystrophies are a group of common genetically determined disorders often transmitted with a recessive mode of inheritance. In recent years, several deficiencies of proteins from the muscle membrane, extra cellular matrix, sarcomere, muscle cytosol and the nucleus have been described to cause CMD. The occidental type of CMD (MDC1A) in which the primary defect is a deficiency in Laminin Alpha2 chain (merosin) encoded by LAMA2 gene, accounts for 30-40% of cases. The clinical course of CMD with complete Laminin Alpha2 chain deficiency may be variable but most often; severe forms characterized by hypotonia at birth, profound muscle weakness, marked delay in motor milestones are observed. Since the identification of the first LAMA2 gene mutations leading to merosin deficiency in 1995, several mutations have subsequently been reported in many exons of this gene without any "hotspot" region. In this work, we report two novel homozygous mutations c.8005delT and c.8244+1G>A in the LAMA2 gene in four Tunisian patients with a severe MDC1A phenotype belonging to two unrelated consanguineous families.
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Partial Laminin α2 chain deficiency in a patient with myopathy resembling inclusion body myositis
Annals of neurology, 2000Co-Authors: Claudia Di Blasi, Pascale Guicheney, Marina Mora, Ferdinando Cornelio, Davide Pareyson, Laura Farina, Angelo Sghirlanzoni, Nicolas Vignier, Flavia Blasevich, Lucia MorandiAbstract:It is becoming evident that clinical phenotypes associated with partial Laminin Alpha2 chain deficiency are variable. We recently observed a 29-year-old man with leukoencephalopathy and vacuolar myopathy resembling inclusion body myositis. Laminin Alpha2 immunohistochemical analysis showed reduction of the protein on muscle fiber surfaces. Molecular analysis revealed two novel compound heterozygous mutations in the LAMA2 gene. This is the first report linking a mutation in the LaMA2 gene with leukoencephalopathy and inclusion body-like myositis.
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PCR based mutation screening of the Laminin Alpha2 chain gene (LAMA2): application to prenatal diagnosis and search for founder effects in congenital muscular dystrophy.
Journal of medical genetics, 1998Co-Authors: Pascale Guicheney, A. Helbling-leclerc, C. Cruaud, Pascale Richard, N. Vignier, Xu Zhang, V. Frey, Brigitte Estournet, Luciano MerliniAbstract:Classical congenital muscular dystrophy with merosin deficiency is caused by mutations in the Laminin Alpha2 chain gene (LAMA2). Extended sequencing of the introns flanking the 64 LAMA2 exons was carried out and, based on these sequences, oligonucleotide primers were designed to amplify the coding region of each exon separately. By PCR-SSCP analysis, we identified eight new mutations in nine families originating from various countries. All induced a premature truncation of the protein, either in the short arm or in the globular C-terminal domain. A 2 bp deletion in exon 13, 2098delAG, was found in three French non-consanguineous families and a nonsense mutation of exon 20, Cys967stop, in two other non-consanguineous families originating from Italy. Determination of rare intragenic polymorphisms permitted us to show evidence of founder effects for these two mutations suggesting a remote degree of consanguinity between the families. Other, more frequent polymorphisms, G to A 1905 (exon 12), A to G 2848 (exon 19), A to G 5551 (exon 37), and G to A 6286 (exon 42), were used as intragenic markers for prenatal diagnosis. This study provides valuable methods for determining the molecular defects in LAMA2 causing merosin deficient congenital muscular dystrophy.
Yukiko K. Hayashi - One of the best experts on this subject based on the ideXlab platform.
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Fukutin-related protein gene mutated in the original kindred limb-girdle MD 2I
Neurology, 2003Co-Authors: Adel Driss, Satoru Noguchi, Kazuma Sugie, Yukiko K. Hayashi, Rim Amouri, M. Kefi, T. Sasaki, S. Souilem, N. Shimizu, Shinsei MinoshimaAbstract:The authors mapped an autosomal recessive form of limb-girdle MD on chromosome 19q13.3 (LGMD2I), further narrowed down the candidate region to 1.1 Mb, and identified one new homozygous mutation in the fukutin-related protein (FKRP) gene on patients of the original Tunisian family. Immunohistochemical and immunoblot analysis showed abnormal expression of alpha-dystroglycan and Laminin-Alpha2 supporting the hypothesis that FKRP has a role in the interaction between the extracellular matrix components.
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Mutations in the integrin alpha7 gene cause congenital myopathy.
Nature genetics, 1998Co-Authors: Yukiko K. Hayashi, Eva Engvall, Fan-li Chou, Megumu Ogawa, Chie Matsuda, Shinichi Hirabayashi, Kenji Yokochi, Barry L. Ziober, Randall H. Kramer, Stephen J. KaufmanAbstract:The basal lamina of muscle fibers plays a crucial role in the development and function of skeletal muscle. An important Laminin receptor in muscle is integrin alpha7beta1D. Integrin beta1 is expressed throughout the body, while integrin alpha7 is more muscle-specific. To address the role of integrin alpha7 in human muscle disease, we determined alpha7 protein expression in muscle biopsies from 117 patients with unclassified congenital myopathy and congenital muscular dystrophy by immunocytochemistry. We found three unrelated patients with integrin alpha7 deficiency and normal Laminin Alpha2 chain expression. To determine if any of these three patients had mutations of the integrin alpha7 gene, ITGA7, we cloned and sequenced the full-length human ITGA7 cDNA, and screened the patients for mutations. One patient had splice mutations on both alleles; one causing a 21-bp insertion in the conserved cysteine-rich region, and the other causing a 98-bp deletion. A second patient was a compound heterozygote for the same 98-bp deletion, and had a 1-bp frame-shift deletion on the other allele. A third showed marked deficiency of ITGA7 mRNA. Clinically, these patients showed congenital myopathy with delayed motor milestones. Our results demonstrate that mutations in ITGA7 are involved in a form of congenital myopathy.
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Altered expression of the alpha7beta1 integrin in human and murine muscular dystrophies
Journal of Cell Science, 1997Co-Authors: Bradley L. Hodges, Yukiko K. Hayashi, Ikuya Nonaka, Weigwang Wang, K. Arahata, Stephen J. KaufmanAbstract:The alpha7beta1 integrin is the primary Laminin receptor on skeletal myoblasts and adult myofibers. It has distinct functions during muscle development and contributes to muscle structural integrity. We have studied this integrin in cases where expression of dystrophin or Laminin are compromised. Immunofluorescence demonstrates an increase in alpha7beta1 in patients with Duchenne muscular dystrophy and in mdx mice that lack dystrophin. Analysis of RNA from mdx mice and from patients with Duchenne and Becker muscular dystrophies indicates that the increase in the alpha7beta1 integrin is regulated at the level of alpha7 gene transcription. In contrast, the levels of alpha7beta1 integrin are severely diminished in patients with Laminin Alpha2 chain congenital dystrophy muscular dystrophy and in dy/dy mice that also do not make the Alpha2 Laminin chain. Analysis of RNA from the hindlimbs of dy/dy mice demonstrated that in the absence of Laminin alpha7 gene transcription is inhibited and limited to specific alternatively spliced isoforms. We suggest that the increased expression of alpha7beta1 integrin in the absence of dystrophin compensates for the reduced dystrophin-mediated linkage of fibers with the basal lamina and modulates the development of pathology associated with these diseases. The decrease in alpha7beta1 integrin and its transcripts in the absence of Laminin likely contributes to the severe myopathy that results from Laminin Alpha2 chain deficiency and suggests that Laminin-2 regulates expression of the alpha7 integrin gene. The role of the alpha7beta1 integrin in muscle integrity also suggests that compromised expression of this receptor may underlie as yet undefined myopathies.
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Congenital muscular dystrophies
Current Opinion in Neurology, 1995Co-Authors: Kiichi Arahata, Hiroko Ishii, Yukiko K. HayashiAbstract:: Considerable advances in the understanding of congenital muscular dystrophy made during the past year may allow a new clinical classification of this disease. In particular, (1) evidence has accumulated to suggest that a Laminin Alpha2-chain (Alpha2 subunit of Laminin-2 or merosin) deficiency causes a type of congenital muscular dystrophy, and (2) it has been postulated that Fukuyama-type congenital muscular dystrophy and Walker-Warburg syndrome (but not Finnish muscle-eye-brain disease) are genetically identical diseases.
