The Experts below are selected from a list of 189138 Experts worldwide ranked by ideXlab platform
David Beeson - One of the best experts on this subject based on the ideXlab platform.
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the clinical phenotypic spectrum of gfpt1 associated congenital myasthenic syndrome
Journal of Neurology Neurosurgery and Psychiatry, 2012Co-Authors: Amina Chaouch, J S Mueller, Velina Guergueltcheva, Jacqueline Palace, Kate Bushby, Angela Abicht, Volker Straub, Francesco Muntoni, David Beeson, Hanns LochmüllerAbstract:We report on the clinical features of a distinct group of DOK 7 negative limb girdle congenital myasthenic syndrome (LG-CMS), the cause of which has only recently been unravelled. Congenital myasthenic syndromes are a rare group of inherited neuromuscular disorders associated with distinct clinical and genetic abnormalities, in which neuromuscular transmission is impaired. An interesting and often difficult group to recognise is the LG-CMS. This typically manifests with shoulder and pelvic girdle muscle weakness with or without additional features including ocular and bulbar involvement. Until recently, DOK 7 gene mutations have been the only recognised genetic cause of this phenotype and were found in half of all LG-CMS patients. Mutations in a novel CMS gene (GFPT1) were recently implicated in an undiagnosed, DOK 7 negative, LG-CMS cohort of 24 patients. All patients had proximal limb weakness with no ocular or bulbar features and showed a positive response to pyridostigmine. Although age of onset of disease was usually in early childhood, a great number of patients presented to medical attention well into adulthood. Furthermore, tubular aggregates arising from the sarcoplasmic reticulum were seen in the majority of patients.
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ephedrine treatment in congenital myasthenic syndrome due to mutations in dok7
Neurology, 2010Co-Authors: D Lashley, Jacqueline Palace, Sandeep Jayawant, S Robb, David BeesonAbstract:Background: Mutations in the postsynaptic adaptor protein Dok-7 underlie congenital myasthenic syndrome (CMS) with a characteristic limb girdle pattern of muscle weakness. Patients usually do not respond to or worsen with the standard CMS treatments: cholinesterase inhibitors and 3,4-diaminopyridine. However, anecdotal reports suggest they may improve with ephedrine. Methods: This was an open prospective follow-up study to determine muscle strength in response to ephedrine in Dok-7 CMS. Patients were first evaluated as inpatients for suitability for a trial of treatment with ephedrine. The response was assessed at 2 and 6 to 8 months follow-up clinic visits using a quantitative myasthenia gravis (severity) score (QMG) and mobility measures. Results: Ten out of 12 of the cohort with DOK7 mutations tolerated ephedrine. We noted a progressive response to treatment over the 6 to 8 months assessment period with a significant improvement at the final QMG score ( p = 0.009). Mobility scores also improved ( p = 0.0006). Improvements in the subcomponents of the QMG score that measured proximal muscle function (those muscle groups most severely affected) were most marked, and in some cases were dramatic. All patients reported enhanced activities of daily living at 6–8 months. Conclusion: Ephedrine appears to be an effective treatment for Dok-7 CMS. It is well-tolerated by most patients and improvement in strength can be profound. Determining the long-term response and the most effective dosing regimen will require further research. Classification of evidence: This study provides Class IV evidence that ephedrine given at doses between 15 and 90 mg/day improves muscle strength in patients with documented mutations in DOK7.
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dok 7 mutations underlie a neuromuscular junction synaptopathy
Science, 2006Co-Authors: David Beeson, Jacqueline Palace, Osamu Higuchi, J Cossins, Hayley Spearman, Susan Maxwell, John Newsomdavis, G Burke, Peter R W Fawcett, Masakatsu MotomuraAbstract:Congenital myasthenic syndromes (CMSs) are a group of inherited disorders of neuromuscular transmission characterized by fatigable muscle weakness. One major subgroup of patients shows a characteristic “limb girdle” pattern of muscle weakness, in which the muscles have small, simplified neuromuscular junctions but normal acetylcholine receptor and acetylcholinesterase function. We showed that recessive inheritance of mutations in Dok-7, which result in a defective structure of the neuromuscular junction, is a cause of CMS with proximal muscle weakness.
Kinji Ohno - One of the best experts on this subject based on the ideXlab platform.
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SRSF1 suppresses selection of intron-distal 5′ splice site of DOK7 intron 4 to generate functional full-length Dok-7 protein
Nature Publishing Group, 2017Co-Authors: Khalid Bin Ahsan, Akio Masuda, Mohammad Alinoor Rahman, Jun-ichi Takeda, Mohammad Nazim, Bisei Ohkawara, Mikako Ito, Kinji OhnoAbstract:Abstract Dok-7 is a non-catalytic adaptor protein that facilitates agrin-induced clustering of acetylcholine receptors (AChR) at the neuromuscular junction. Alternative selection of 5′ splice sites (SSs) of DOK7 intron 4 generates canonical and frame-shifted transcripts. We found that the canonical full-length Dok-7 enhanced AChR clustering, whereas the truncated Dok-7 did not. We identified a splicing cis-element close to the 3′ end of exon 4 by block-scanning mutagenesis. RNA affinity purification and mass spectrometry revealed that SRSF1 binds to the cis-element. Knocking down of SRSF1 enhanced selection of the intron-distal 5′ SS of DOK7 intron 4, whereas MS2-mediated artificial tethering of SRSF1 to the identified cis-element suppressed it. Isolation of an early spliceosomal complex revealed that SRSF1 inhibited association of U1 snRNP to the intron-distal 5′ SS, and rather enhanced association of U1 snRNP to the intron-proximal 5′ SS, which led to upregulation of the canonical DOK7 transcript. Integrated global analysis of CLIP-seq and RNA-seq also indicated that binding of SRSF1 immediately upstream to two competing 5′ SSs suppresses selection of the intron-distal 5′ SS in hundreds of human genes. We demonstrate that SRSF1 critically regulates alternative selection of adjacently placed 5′ SSs by modulating binding of U1 snRNP
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Congenital Myasthenic Syndromes - Molecular Bases of Congenital Defects of Proteins at the Neuromuscular Junction
Neuromuscular Disorders, 2012Co-Authors: Kinji Ohno, Andrew G EngelAbstract:Congenital myasthenic syndromes (CMS) are heterogeneous disorders caused by mutations in molecules expressed at the neuromuscular junction (NMJ) (Fig. 1). Each mutation affects the expression level or the functional properties or both of the mutant molecule. No fewer than 11 defective molecules at the NMJ have been identified to date. The mutant molecules include (i) acetylcholine receptor (AChR) subunits that forms nicotinic AChR and generate endplate potentials (Ohno et al., 1995; Sine et al., 1995), (ii) rapsyn that anchors and clusters AChRs at the endplate (Ohno et al., 2002; Milone et al., 2009), (iii) agrin that is released from nerve terminal and induces AChR clustering by stimulating the downstream LRP4/MuSK/Dok-7/rapsyn/AChR pathway (Huze et al., 2009), (iv) muscle-specific receptor tyrosine kinase (MuSK) that transmits the AChR-clustering signal from agrin/LRP4 to Dok-7/rapsyn/AChR (Chevessier et al., 2004; Chevessier et al., 2008), (v) Dok-7 that interacts with MuSK and exerts the AChR-clustering activity (Beeson et al., 2006; Hamuro et al., 2008), (vi) plectin that is an intermediate filament-associate protein concentrated at sites of mechanical stress (Banwell et al., 1999; Selcen et al., 2011), (vii) glutamine-fructose-6phosphate aminotransferase 1 encoded by GFPT1, the function of which at the NMJ has not been elucidated (Senderek et al., 2011), (viii) skeletal muscle sodium channel type 1.4 (NaV1.4) that spreads depolarization potential from endplate throughout muscle fibers (Tsujino et al., 2003), (ix) collagen Q that anchors acetylcholinesterase (AChE) to the synaptic basal lamina (Ohno et al., 1998; Ohno et al., 1999; Kimbell et al., 2004), (x) 2-laminin that forms a cruciform heterotrimeric lamins-221, -421, and -521 and links extracellular matrix molecules to the -dystroglycan at the NMJ (Maselli et al., 2009), (xi) choline acetyltransferase (ChAT) that resynthesizes acetylcholine from recycled choline at the nerve terminal (Ohno et al., 2001). AChR (Lang & Vincent, 2009), MuSK (Hoch et al., 2001; Cole et al., 2008), and LRP4 (Higuchi et al., 2011) are also targets of myasthenia gravis, in which autoantibody against each molecule impairs the neuromuscular transmission.
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Congenital Myasthenic Syndromes - Molecular Bases of Congenital Defects of Proteins at the Neuromuscular Junction
Neuromuscular Disorders, 2012Co-Authors: Kinji Ohno, Andrew G EngelAbstract:Congenital myasthenic syndromes (CMS) are heterogeneous disorders caused by mutations in molecules expressed at the neuromuscular junction (NMJ) (Fig. 1). Each mutation affects the expression level or the functional properties or both of the mutant molecule. No fewer than 11 defective molecules at the NMJ have been identified to date. The mutant molecules include (i) acetylcholine receptor (AChR) subunits that forms nicotinic AChR and generate endplate potentials (Ohno et al., 1995; Sine et al., 1995), (ii) rapsyn that anchors and clusters AChRs at the endplate (Ohno et al., 2002; Milone et al., 2009), (iii) agrin that is released from nerve terminal and induces AChR clustering by stimulating the downstream LRP4/MuSK/Dok-7/rapsyn/AChR pathway (Huze et al., 2009), (iv) muscle-specific receptor tyrosine kinase (MuSK) that transmits the AChR-clustering signal from agrin/LRP4 to Dok-7/rapsyn/AChR (Chevessier et al., 2004; Chevessier et al., 2008), (v) Dok-7 that interacts with MuSK and exerts the AChR-clustering activity (Beeson et al., 2006; Hamuro et al., 2008), (vi) plectin that is an intermediate filament-associate protein concentrated at sites of mechanical stress (Banwell et al., 1999; Selcen et al., 2011), (vii) glutamine-fructose-6phosphate aminotransferase 1 encoded by GFPT1, the function of which at the NMJ has not been elucidated (Senderek et al., 2011), (viii) skeletal muscle sodium channel type 1.4 (NaV1.4) that spreads depolarization potential from endplate throughout muscle fibers (Tsujino et al., 2003), (ix) collagen Q that anchors acetylcholinesterase (AChE) to the synaptic basal lamina (Ohno et al., 1998; Ohno et al., 1999; Kimbell et al., 2004), (x) 2-laminin that forms a cruciform heterotrimeric lamins-221, -421, and -521 and links extracellular matrix molecules to the -dystroglycan at the NMJ (Maselli et al., 2009), (xi) choline acetyltransferase (ChAT) that resynthesizes acetylcholine from recycled choline at the nerve terminal (Ohno et al., 2001). AChR (Lang & Vincent, 2009), MuSK (Hoch et al., 2001; Cole et al., 2008), and LRP4 (Higuchi et al., 2011) are also targets of myasthenia gravis, in which autoantibody against each molecule impairs the neuromuscular transmission.
Robert L Wollmann - One of the best experts on this subject based on the ideXlab platform.
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Mutations in MUSK causing congenital myasthenic syndrome impair MuSK–Dok-7 interaction
Human Molecular Genetics, 2010Co-Authors: Ricardo A Maselli, Juan Arredondo, Órla Cagney, Jarae J. Ng, Jennifer A. Anderson, Colette Williams, Bae J. Gerke, Betty Soliven, Robert L WollmannAbstract:We describe a severe congenital myasthenic syndrome (CMS) caused by two missense mutations in the gene encoding the muscle specific receptor tyrosine kinase (MUSK). The identified MUSK mutations M605I and A727V are both located in the kinase domain of MuSK. Intracellular microelectrode recordings and microscopy studies of the neuromuscular junction conducted in an anconeus muscle biopsy revealed decreased miniature endplate potential amplitudes, reduced endplate size and simplification of secondary synaptic folds, which were consistent with postsynaptic deficit. The study also showed a striking reduction of the endplate potential quantal content, consistent with additional presynaptic failure. Expression studies in MuSK deficient myotubes revealed that A727V, which is located within the catalytic loop of the enzyme, caused severe impairment of agrin-dependent MuSK phosphorylation, aggregation of acetylcholine receptors (AChRs) and interaction of MuSK with Dok-7, an essential intracellular binding protein of MuSK. In contrast, M605I, resulted in only moderate impairment of agrin-dependent MuSK phosphorylation, aggregation of AChRs and interaction of MuSK with Dok-7. There was no impairment of interaction of mutants with either the low-density lipoprotein receptor-related protein, Lrp4 (a co-receptor of agrin) or with the mammalian homolog of the Drosophila tumorous imaginal discs (Tid1). Our findings demonstrate that missense mutations in MUSK can result in a severe form of CMS and indicate that the inability of MuSK mutants to interact with Dok-7, but not with Lrp4 or Tid1, is a major determinant of the pathogenesis of the CMS caused by MUSK mutations.
Andrew G Engel - One of the best experts on this subject based on the ideXlab platform.
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Congenital Myasthenic Syndromes - Molecular Bases of Congenital Defects of Proteins at the Neuromuscular Junction
Neuromuscular Disorders, 2012Co-Authors: Kinji Ohno, Andrew G EngelAbstract:Congenital myasthenic syndromes (CMS) are heterogeneous disorders caused by mutations in molecules expressed at the neuromuscular junction (NMJ) (Fig. 1). Each mutation affects the expression level or the functional properties or both of the mutant molecule. No fewer than 11 defective molecules at the NMJ have been identified to date. The mutant molecules include (i) acetylcholine receptor (AChR) subunits that forms nicotinic AChR and generate endplate potentials (Ohno et al., 1995; Sine et al., 1995), (ii) rapsyn that anchors and clusters AChRs at the endplate (Ohno et al., 2002; Milone et al., 2009), (iii) agrin that is released from nerve terminal and induces AChR clustering by stimulating the downstream LRP4/MuSK/Dok-7/rapsyn/AChR pathway (Huze et al., 2009), (iv) muscle-specific receptor tyrosine kinase (MuSK) that transmits the AChR-clustering signal from agrin/LRP4 to Dok-7/rapsyn/AChR (Chevessier et al., 2004; Chevessier et al., 2008), (v) Dok-7 that interacts with MuSK and exerts the AChR-clustering activity (Beeson et al., 2006; Hamuro et al., 2008), (vi) plectin that is an intermediate filament-associate protein concentrated at sites of mechanical stress (Banwell et al., 1999; Selcen et al., 2011), (vii) glutamine-fructose-6phosphate aminotransferase 1 encoded by GFPT1, the function of which at the NMJ has not been elucidated (Senderek et al., 2011), (viii) skeletal muscle sodium channel type 1.4 (NaV1.4) that spreads depolarization potential from endplate throughout muscle fibers (Tsujino et al., 2003), (ix) collagen Q that anchors acetylcholinesterase (AChE) to the synaptic basal lamina (Ohno et al., 1998; Ohno et al., 1999; Kimbell et al., 2004), (x) 2-laminin that forms a cruciform heterotrimeric lamins-221, -421, and -521 and links extracellular matrix molecules to the -dystroglycan at the NMJ (Maselli et al., 2009), (xi) choline acetyltransferase (ChAT) that resynthesizes acetylcholine from recycled choline at the nerve terminal (Ohno et al., 2001). AChR (Lang & Vincent, 2009), MuSK (Hoch et al., 2001; Cole et al., 2008), and LRP4 (Higuchi et al., 2011) are also targets of myasthenia gravis, in which autoantibody against each molecule impairs the neuromuscular transmission.
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Congenital Myasthenic Syndromes - Molecular Bases of Congenital Defects of Proteins at the Neuromuscular Junction
Neuromuscular Disorders, 2012Co-Authors: Kinji Ohno, Andrew G EngelAbstract:Congenital myasthenic syndromes (CMS) are heterogeneous disorders caused by mutations in molecules expressed at the neuromuscular junction (NMJ) (Fig. 1). Each mutation affects the expression level or the functional properties or both of the mutant molecule. No fewer than 11 defective molecules at the NMJ have been identified to date. The mutant molecules include (i) acetylcholine receptor (AChR) subunits that forms nicotinic AChR and generate endplate potentials (Ohno et al., 1995; Sine et al., 1995), (ii) rapsyn that anchors and clusters AChRs at the endplate (Ohno et al., 2002; Milone et al., 2009), (iii) agrin that is released from nerve terminal and induces AChR clustering by stimulating the downstream LRP4/MuSK/Dok-7/rapsyn/AChR pathway (Huze et al., 2009), (iv) muscle-specific receptor tyrosine kinase (MuSK) that transmits the AChR-clustering signal from agrin/LRP4 to Dok-7/rapsyn/AChR (Chevessier et al., 2004; Chevessier et al., 2008), (v) Dok-7 that interacts with MuSK and exerts the AChR-clustering activity (Beeson et al., 2006; Hamuro et al., 2008), (vi) plectin that is an intermediate filament-associate protein concentrated at sites of mechanical stress (Banwell et al., 1999; Selcen et al., 2011), (vii) glutamine-fructose-6phosphate aminotransferase 1 encoded by GFPT1, the function of which at the NMJ has not been elucidated (Senderek et al., 2011), (viii) skeletal muscle sodium channel type 1.4 (NaV1.4) that spreads depolarization potential from endplate throughout muscle fibers (Tsujino et al., 2003), (ix) collagen Q that anchors acetylcholinesterase (AChE) to the synaptic basal lamina (Ohno et al., 1998; Ohno et al., 1999; Kimbell et al., 2004), (x) 2-laminin that forms a cruciform heterotrimeric lamins-221, -421, and -521 and links extracellular matrix molecules to the -dystroglycan at the NMJ (Maselli et al., 2009), (xi) choline acetyltransferase (ChAT) that resynthesizes acetylcholine from recycled choline at the nerve terminal (Ohno et al., 2001). AChR (Lang & Vincent, 2009), MuSK (Hoch et al., 2001; Cole et al., 2008), and LRP4 (Higuchi et al., 2011) are also targets of myasthenia gravis, in which autoantibody against each molecule impairs the neuromuscular transmission.
Jacqueline Palace - One of the best experts on this subject based on the ideXlab platform.
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the clinical phenotypic spectrum of gfpt1 associated congenital myasthenic syndrome
Journal of Neurology Neurosurgery and Psychiatry, 2012Co-Authors: Amina Chaouch, J S Mueller, Velina Guergueltcheva, Jacqueline Palace, Kate Bushby, Angela Abicht, Volker Straub, Francesco Muntoni, David Beeson, Hanns LochmüllerAbstract:We report on the clinical features of a distinct group of DOK 7 negative limb girdle congenital myasthenic syndrome (LG-CMS), the cause of which has only recently been unravelled. Congenital myasthenic syndromes are a rare group of inherited neuromuscular disorders associated with distinct clinical and genetic abnormalities, in which neuromuscular transmission is impaired. An interesting and often difficult group to recognise is the LG-CMS. This typically manifests with shoulder and pelvic girdle muscle weakness with or without additional features including ocular and bulbar involvement. Until recently, DOK 7 gene mutations have been the only recognised genetic cause of this phenotype and were found in half of all LG-CMS patients. Mutations in a novel CMS gene (GFPT1) were recently implicated in an undiagnosed, DOK 7 negative, LG-CMS cohort of 24 patients. All patients had proximal limb weakness with no ocular or bulbar features and showed a positive response to pyridostigmine. Although age of onset of disease was usually in early childhood, a great number of patients presented to medical attention well into adulthood. Furthermore, tubular aggregates arising from the sarcoplasmic reticulum were seen in the majority of patients.
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ephedrine treatment in congenital myasthenic syndrome due to mutations in dok7
Neurology, 2010Co-Authors: D Lashley, Jacqueline Palace, Sandeep Jayawant, S Robb, David BeesonAbstract:Background: Mutations in the postsynaptic adaptor protein Dok-7 underlie congenital myasthenic syndrome (CMS) with a characteristic limb girdle pattern of muscle weakness. Patients usually do not respond to or worsen with the standard CMS treatments: cholinesterase inhibitors and 3,4-diaminopyridine. However, anecdotal reports suggest they may improve with ephedrine. Methods: This was an open prospective follow-up study to determine muscle strength in response to ephedrine in Dok-7 CMS. Patients were first evaluated as inpatients for suitability for a trial of treatment with ephedrine. The response was assessed at 2 and 6 to 8 months follow-up clinic visits using a quantitative myasthenia gravis (severity) score (QMG) and mobility measures. Results: Ten out of 12 of the cohort with DOK7 mutations tolerated ephedrine. We noted a progressive response to treatment over the 6 to 8 months assessment period with a significant improvement at the final QMG score ( p = 0.009). Mobility scores also improved ( p = 0.0006). Improvements in the subcomponents of the QMG score that measured proximal muscle function (those muscle groups most severely affected) were most marked, and in some cases were dramatic. All patients reported enhanced activities of daily living at 6–8 months. Conclusion: Ephedrine appears to be an effective treatment for Dok-7 CMS. It is well-tolerated by most patients and improvement in strength can be profound. Determining the long-term response and the most effective dosing regimen will require further research. Classification of evidence: This study provides Class IV evidence that ephedrine given at doses between 15 and 90 mg/day improves muscle strength in patients with documented mutations in DOK7.
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dok 7 mutations underlie a neuromuscular junction synaptopathy
Science, 2006Co-Authors: David Beeson, Jacqueline Palace, Osamu Higuchi, J Cossins, Hayley Spearman, Susan Maxwell, John Newsomdavis, G Burke, Peter R W Fawcett, Masakatsu MotomuraAbstract:Congenital myasthenic syndromes (CMSs) are a group of inherited disorders of neuromuscular transmission characterized by fatigable muscle weakness. One major subgroup of patients shows a characteristic “limb girdle” pattern of muscle weakness, in which the muscles have small, simplified neuromuscular junctions but normal acetylcholine receptor and acetylcholinesterase function. We showed that recessive inheritance of mutations in Dok-7, which result in a defective structure of the neuromuscular junction, is a cause of CMS with proximal muscle weakness.