95 results match your criteria agrin mutant


The lncRNA H19 alleviates muscular dystrophy by stabilizing dystrophin.

Nat Cell Biol 2020 11 26;22(11):1332-1345. Epub 2020 Oct 26.

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Dystrophin proteomic regulation in muscular dystrophies (MDs) remains unclear. We report that a long noncoding RNA (lncRNA), H19, associates with dystrophin and inhibits E3-ligase-dependent polyubiquitination at Lys 3584 (referred to as Ub-DMD) and its subsequent protein degradation. In-frame deletions in BMD and a DMD non-silent mutation (C3340Y) resulted in defects in the ability of the protein to interact with H19, which caused elevated Ub-DMD levels and dystrophin degradation. Read More

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November 2020

Identification of the downstream molecules of agrin/Dok-7 signaling in muscle.

FASEB J 2020 04 11;34(4):5144-5161. Epub 2020 Feb 11.

Department of Physiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

The development of the neuromuscular junction depends on signaling processes that involve protein phosphorylation. Motor neuron releases agrin to activate muscle protein Dok-7, a key tyrosine kinase essential for the formation of a mature and functional neuromuscular junction. However, the signaling cascade downstream of Dok-7 remains poorly understood. Read More

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A mechanism in agrin signaling revealed by a prevalent Rapsyn mutation in congenital myasthenic syndrome.

Elife 2019 09 24;8. Epub 2019 Sep 24.

Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, United States.

Neuromuscular junction is a synapse between motoneurons and skeletal muscles, where acetylcholine receptors (AChRs) are concentrated to control muscle contraction. Studies of this synapse have contributed to our understanding of synapse assembly and pathological mechanisms of neuromuscular disorders. Nevertheless, underlying mechanisms of NMJ formation was not well understood. Read More

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September 2019

Vezatin is required for the maturation of the neuromuscular synapse.

Mol Biol Cell 2019 09 14;30(20):2571-2583. Epub 2019 Aug 14.

Helen L. and Martin S. Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016.

Key genes, such as , , and , are required for the initial formation, subsequent maturation, and long-term stabilization of mammalian neuromuscular synapses. Additional molecules are thought to function selectively during the evolution and stabilization of these synapses, but these molecular players are largely unknown. Here, we used mass spectrometry to identify vezatin, a two-pass transmembrane protein, as an acetylcholine receptor (AChR)-associated protein, and we provide evidence that vezatin binds directly to AChRs. Read More

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September 2019

Conditional Inactivation of and in Schwann Cells Results in Abnormal Neuromuscular Junction Maturation.

G3 (Bethesda) 2019 01 9;9(1):297-303. Epub 2019 Jan 9.

Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR

The neuromuscular junction (NMJ) consists of three components, namely presynaptic motor neurons, postsynaptic muscle fibers and perisynaptic Schwann cells (PSCs). The role of Schwann cells (SCs) in regulating NMJ structural and functional development remains unclear. In this study, mice with conditional inactivation of () and (), specifically in SCs, resulted in delayed NMJ maturation that led to delayed muscle growth, recapitulating the muscular dystrophy condition observed in human neurofibromatosis type I syndrome (NF1) patients. Read More

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January 2019

Adeno-Associated Virus-Mediated Mini-Agrin Delivery Is Unable to Rescue Disease Phenotype in a Mouse Model of Limb Girdle Muscular Dystrophy Type 2I.

Am J Pathol 2017 Feb;187(2):431-440

McColl-Lockwood Laboratory for Muscular Dystrophy Research, Cannon Research Center, Carolinas Medical Center, Carolinas Healthcare System, Charlotte, North Carolina. Electronic address:

Agrin is a basement membrane-specific proteoglycan that can regulate orientation of cytoskeleton proteins and improve function of dystrophic skeletal muscle. In skeletal muscle, agrin binds with high affinity to laminin(s) and α-dystroglycan (α-DG), an integral part of the dystrophin-glycoprotein complex. Miniaturized forms of agrin (mAgrin) have been shown to ameliorate disease pathology in a laminin-α2 knockout mouse model of muscular dystrophy, acting as a link between α-DG and laminin(s). Read More

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February 2017

MuSK Kinase Activity is Modulated By A Serine Phosphorylation Site in The Kinase Loop.

Sci Rep 2016 09 26;6:33583. Epub 2016 Sep 26.

Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090 Vienna, Austria.

The neuromuscular junction (NMJ) forms when a motor neuron contacts a muscle fibre. A reciprocal exchange of signals initiates a cascade of signalling events that result in pre- and postsynaptic differentiation. At the centre of these signalling events stands muscle specific kinase (MuSK). Read More

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September 2016

Lrp4 in astrocytes modulates glutamatergic transmission.

Nat Neurosci 2016 08 13;19(8):1010-8. Epub 2016 Jun 13.

Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Georgia, USA.

Neurotransmission requires precise control of neurotransmitter release from axon terminals. This process is regulated by glial cells; however, the underlying mechanisms are not fully understood. We found that glutamate release in the brain was impaired in mice lacking low-density lipoprotein receptor-related protein 4 (Lrp4), a protein that is critical for neuromuscular junction formation. Read More

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Functional analysis of matriptase-2 mutations and domains: insights into the molecular basis of iron-refractory iron deficiency anemia.

Am J Physiol Cell Physiol 2015 Apr 14;308(7):C539-47. Epub 2015 Jan 14.

Membrane Transport Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia; Faculty of Medicine and Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia

Mutations in the TMPRSS6 gene are associated with severe iron-refractory iron deficiency anemia resulting from an overexpression of hepcidin, the key regulator of iron homeostasis. The matriptase (MT)-2 protein (encoded by the TMPRSS6 gene) regulates hepcidin expression by cleaving hemojuvelin [HJV/hemochromatosis type 2 (HFE2)], a bone morphogenetic protein (BMP) coreceptor in the hepcidin regulatory pathway. We investigated the functional consequences of five clinically associated TMPRSS6 variants and the role of MT-2 protein domains by generating epitope-tagged mutant and domain-swapped MT-2-MT-1 (encoded by the ST14 gene) chimeric constructs and expressing them in HepG2/C3A cells. Read More

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Synaptic plasticity and cognitive function are disrupted in the absence of Lrp4.

Elife 2014 Nov 19;3:e04287. Epub 2014 Nov 19.

Graduate Program in Developmental Genetics, Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, NYU Medical Center, New York, United States.

Lrp4, the muscle receptor for neuronal Agrin, is expressed in the hippocampus and areas involved in cognition. The function of Lrp4 in the brain, however, is unknown, as Lrp4-/- mice fail to form neuromuscular synapses and die at birth. Lrp4-/- mice, rescued for Lrp4 expression selectively in muscle, survive into adulthood and showed profound deficits in cognitive tasks that assess learning and memory. Read More

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November 2014

LRP4 is critical for neuromuscular junction maintenance.

J Neurosci 2014 Oct;34(42):13892-905

Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, Department of Neurology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, and Charlie Norwood Veterans Administration Medical Center, Augusta, Georgia 30904

The neuromuscular junction (NMJ) is a synapse between motor neurons and skeletal muscle fibers, and is critical for control of muscle contraction. Its formation requires neuronal agrin that acts by binding to LRP4 to stimulate MuSK. Mutations have been identified in agrin, MuSK, and LRP4 in patients with congenital myasthenic syndrome, and patients with myasthenia gravis develop antibodies against agrin, LRP4, and MuSK. Read More

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October 2014

Acetylcholine receptor (AChR) clustering is regulated both by glycogen synthase kinase 3β (GSK3β)-dependent phosphorylation and the level of CLIP-associated protein 2 (CLASP2) mediating the capture of microtubule plus-ends.

J Biol Chem 2014 Oct 17;289(44):30857-30867. Epub 2014 Sep 17.

Department of Cell Biology, Erasmus Medical Center, 3015 GE, Rotterdam, Netherlands,. Electronic address:

The postsynaptic apparatus of the neuromuscular junction (NMJ) traps and anchors acetylcholine receptors (AChRs) at high density at the synapse. We have previously shown that microtubule (MT) capture by CLASP2, a MT plus-end-tracking protein (+TIP), increases the size and receptor density of AChR clusters at the NMJ through the delivery of AChRs and that this is regulated by a pathway involving neuronal agrin and several postsynaptic kinases, including GSK3. Phosphorylation by GSK3 has been shown to cause CLASP2 dissociation from MT ends, and nine potential phosphorylation sites for GSK3 have been mapped on CLASP2. Read More

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October 2014

APP interacts with LRP4 and agrin to coordinate the development of the neuromuscular junction in mice.

Elife 2013 Aug 20;2:e00220. Epub 2013 Aug 20.

Department of Molecular Genetics , University of Texas Southwestern Medical Center , Dallas , United States.

ApoE, ApoE receptors and APP cooperate in the pathogenesis of Alzheimer's disease. Intriguingly, the ApoE receptor LRP4 and APP are also required for normal formation and function of the neuromuscular junction (NMJ). In this study, we show that APP interacts with LRP4, an obligate co-receptor for muscle-specific tyrosine kinase (MuSK). Read More

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Podocyte-specific deletion of NDST1, a key enzyme in the sulfation of heparan sulfate glycosaminoglycans, leads to abnormalities in podocyte organization in vivo.

Kidney Int 2014 Feb 7;85(2):307-18. Epub 2013 Aug 7.

1] Department of Cell Biology and Anatomy, LSU Health Sciences Center, Shreveport, Louisiana, USA [2] Department of Pathology, LSU Health Sciences Center, Shreveport, Louisiana, USA.

Heparan sulfate proteoglycans have been shown to modulate podocyte adhesion to--and pedicel organization on--the glomerular basement membrane. Recent studies showed that foot process effacement developed in a mutant mouse model whose podocytes were unable to assemble heparan sulfate glycosaminoglycan chains. This study, a further refinement, explored the role of heparan N-sulfation on podocyte behavior. Read More

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February 2014

Synaptic basal lamina-associated congenital myasthenic syndromes.

Ann N Y Acad Sci 2012 Dec;1275:36-48

Department of Neurology, University of California, Davis, California, USA.

Proteins associated with the basal lamina (BL) participate in complex signal transduction processes that are essential for the development and maintenance of the neuromuscular junction (NMJ). Most important junctional BL proteins are collagens, such as collagen IV (α3-6), collagen XIII, and ColQ; laminins; nidogens; and heparan sulfate proteoglycans, such as perlecan and agrin. Mice lacking Colq (Colq(-/-)), laminin β2 (Lamb2(-/-)), or collagen XIII (Col13a1(-/-)) show immature nerve terminals enwrapped by Schwann cell projections that invaginate into the synaptic cleft and decrease contact surface for neurotransmission. Read More

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December 2012

The Onecut transcription factor HNF-6 regulates in motor neurons the formation of the neuromuscular junctions.

PLoS One 2012 5;7(12):e50509. Epub 2012 Dec 5.

Laboratory of Neural Differentiation, Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium.

The neuromuscular junctions are the specialized synapses whereby spinal motor neurons control the contraction of skeletal muscles. The formation of the neuromuscular junctions is controlled by a complex interplay of multiple mechanisms coordinately activated in motor nerve terminals and in their target myotubes. However, the transcriptional regulators that control in motor neurons the genetic programs involved in neuromuscular junction development remain unknown. Read More

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Agrin and synaptic laminin are required to maintain adult neuromuscular junctions.

PLoS One 2012 3;7(10):e46663. Epub 2012 Oct 3.

Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, Massachusetts, United States of America.

As synapses form and mature the synaptic partners produce organizing molecules that regulate each other's differentiation and ensure precise apposition of pre- and post-synaptic specializations. At the skeletal neuromuscular junction (NMJ), these molecules include agrin, a nerve-derived organizer of postsynaptic differentiation, and synaptic laminins, muscle-derived organizers of presynaptic differentiation. Both become concentrated in the synaptic cleft as the NMJ develops and are retained in adulthood. Read More

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Genetic suppression of agrin reduces mania-like behavior in Na+ , K+ -ATPase α3 mutant mice.

Genes Brain Behav 2012 Jun 11;11(4):436-43. Epub 2012 May 11.

Samuel Lunenfeld Research Institute, Mount Sinai Hospital Institute of Medical Science, University of Toronto, Toronto, ON, Canada.

Myshkin mice heterozygous for an inactivating mutation in the neuron-specific Na(+) ,K(+) -ATPase α3 isoform show behavior analogous to mania, including an abnormal endogenous circadian period. Agrin is a proteoglycan implicated as a regulator of synapses that has been proposed to inhibit activity of Na(+) ,K(+) -ATPase α3. We examined whether the mania-related behavior of Myshkin mice could be rescued by a reduction in the expression of agrin through genetic knockout. Read More

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Agrin-signaling is necessary for the integration of newly generated neurons in the adult olfactory bulb.

J Neurosci 2012 Mar;32(11):3759-64

Aix-Marseille University, IBDML, 13288, Marseille, France, CNRS, UMR7288, 13288 Marseille, France.

In the adult forebrain, new interneurons are continuously generated and integrated into the existing circuitry of the olfactory bulb (OB). In an attempt to identify signals that regulate this synaptic integration process, we found strong expression of agrin in adult generated neuronal precursors that arrive in the olfactory bulb after their generation in the subventricular zone. While the agrin receptor components MuSK and Lrp4 were below detection level in neuron populations that represent synaptic targets for the new interneurons, the alternative receptor α3-Na(+)K(+)-ATPase was strongly expressed in mitral cells. Read More

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The formation of complex acetylcholine receptor clusters requires MuSK kinase activity and structural information from the MuSK extracellular domain.

Mol Cell Neurosci 2012 Apr 23;49(4):475-86. Epub 2011 Dec 23.

Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090 Vienna, Austria.

Efficient synaptic transmission at the neuromuscular junction (NMJ) requires the topological maturation of the postsynaptic apparatus from an oval acetylcholine receptor (AChR)-rich plaque into a complex pretzel-shaped array of branches. However, compared to NMJ formation very little is known about the mechanisms that regulate NMJ maturation. Recently the process of in vivo transformation from plaque into pretzel has been reproduced in vitro by culturing myotubes aneurally on laminin-coated substrate. Read More

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LG2 agrin mutation causing severe congenital myasthenic syndrome mimics functional characteristics of non-neural (z-) agrin.

Hum Genet 2012 Jul 29;131(7):1123-35. Epub 2011 Dec 29.

Department of Neurology, University of California Davis, Davis, CA 95616, USA.

We describe a severe form of congenital myasthenic syndrome (CMS) caused by two heteroallelic mutations: a nonsense and a missense mutation in the gene encoding agrin (AGRN). The identified mutations, Q353X and V1727F, are located at the N-terminal and at the second laminin G-like (LG2) domain of agrin, respectively. A motor-point muscle biopsy demonstrated severe disruption of the architecture of the neuromuscular junction (NMJ), including: dispersion and fragmentation of endplate areas with normal expression of acetylcholinesterase; simplification of postsynaptic membranes; pronounced reduction of the axon terminal size; widening of the primary synaptic cleft; and, collection of membranous debris material in the primary synaptic cleft and in the subsynaptic cytoplasm. Read More

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Current status of the congenital myasthenic syndromes.

Authors:
Andrew G Engel

Neuromuscul Disord 2012 Feb 21;22(2):99-111. Epub 2011 Nov 21.

Department of Neurology, Mayo Clinic, Rochester, MN 55905, United States.

Congenital myasthenic syndromes (CMS) are heterogeneous disorders in which the safety margin of neuromuscular transmission is compromised by one or more specific mechanisms. Clinical, electrophysiologic, and morphologic studies have paved the way for detecting CMS-related mutations in proteins residing in the nerve terminal, the synaptic basal lamina, and in the postsynaptic region of the motor endplate. The disease proteins identified to date include choline acetyltransferase (ChAT), the endplate species of acetylcholinesterase (AChE), β2-laminin, the acetylcholine receptor (AChR), rapsyn, plectin, Na(v)1. Read More

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February 2012

The extracellular region of Lrp4 is sufficient to mediate neuromuscular synapse formation.

Dev Dyn 2011 Dec 28;240(12):2626-33. Epub 2011 Oct 28.

Molecular Neurobiology Program, Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, NYU Medical School, 540 First Avenue, New York, NY 10016, USA.

Neuromuscular synapse formation requires an exchange of signals between motor neurons and muscle. Agrin, supplied by motor neurons, binds to Lrp4 in muscle, stimulating phosphorylation of MuSK and recruitment of a signaling complex essential for synapse-specific transcription and anchoring of key proteins in the postsynaptic membrane. Lrp4, like the LDLR and other Lrp-family members, contains an intracellular region with motifs that can regulate receptor trafficking, as well as assembly of an intracellular signaling complex. Read More

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December 2011

Congenital myasthenic syndromes in 2012.

Authors:
Andrew G Engel

Curr Neurol Neurosci Rep 2012 Feb;12(1):92-101

Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.

Congenital myasthenic syndromes (CMS) represent a heterogeneous group of disorders in which the safety margin of neuromuscular transmission is compromised by one or more specific mechanisms. Clinical, electrophysiologic, and morphologic studies have paved the way for detecting CMS-related mutations in proteins residing in the nerve terminal, the synaptic basal lamina, or in the postsynaptic region of the motor endplate. The disease proteins identified to date include the acetylcholine receptor, acetylcholinesterase, choline acetyltransferase, rapsyn, and Na(v)1. Read More

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February 2012

A valid mouse model of AGRIN-associated congenital myasthenic syndrome.

Hum Mol Genet 2011 Dec 1;20(23):4617-33. Epub 2011 Sep 1.

The Jackson Laboratory, Bar Harbor, ME 04609, USA.

Congenital myasthenic syndromes (CMS) are inherited diseases affecting the neuromuscular junction (NMJ). Mutations in AGRIN (AGRN) and other genes in the AGRIN signaling pathway cause CMS, and gene targeting studies in mice confirm the importance of this pathway for NMJ formation. However, these mouse mutations are complete loss-of-function alleles that result in an embryonic failure of NMJ formation, and homozygous mice do not survive postpartum. Read More

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December 2011

Nestin is not essential for development of the CNS but required for dispersion of acetylcholine receptor clusters at the area of neuromuscular junctions.

J Neurosci 2011 Aug;31(32):11547-52

Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5T 3H7 Canada.

Nestin is expressed in many different progenitors during development including those of the CNS, heart, skeletal muscle, and kidney. The adult expression is mainly restricted to the subependymal zone and dentate gyrus of the brain, the neuromuscular junction, and renal podocytes. In addition, this intermediate filament protein has served as a marker of neural stem/progenitor cells for close to 20 years. Read More

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The function of cortactin in the clustering of acetylcholine receptors at the vertebrate neuromuscular junction.

PLoS One 2009 Dec 29;4(12):e8478. Epub 2009 Dec 29.

Department of Biology, The Hong Kong University of Science and Technology, Kowloon, Hong Kong, China.

Background: Postsynaptic enrichment of acetylcholine receptors (AChRs) at the vertebrate neuromuscular junction (NMJ) depends on the activation of the muscle receptor tyrosine MuSK by neural agrin. Agrin-stimulation of MuSK is known to initiate an intracellular signaling cascade that leads to the clustering of AChRs in an actin polymerization-dependent manner, but the molecular steps which link MuSK activation to AChR aggregation remain incompletely defined.

Methodology/principal Findings: In this study we used biochemical, cell biological and molecular assays to investigate a possible role in AChR clustering of cortactin, a protein which is a tyrosine kinase substrate and a regulator of F-actin assembly and which has also been previously localized at AChR clustering sites. Read More

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December 2009

Impaired blood-brain and blood-spinal cord barriers in mutant SOD1-linked ALS rat.

Brain Res 2009 Dec 11;1301:152-62. Epub 2009 Sep 11.

Université Libre de Bruxelles, Brussels, Belgium.

Blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) impairment is an additional accident occurring during the amyotrophic lateral sclerosis (ALS) progression. In this work, we aimed to decipher if BBB/BSCB leakage appeared before critical detrimental events and could serve as a marker preceding clinical symptoms. Three different BBB leakage markers: Evans blue, IgG and hemosiderin, were used to look at the SOD1-linked ALS rat model at presymptomatic and symptomatic stages. Read More

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December 2009

Identification of an agrin mutation that causes congenital myasthenia and affects synapse function.

Am J Hum Genet 2009 Aug 23;85(2):155-67. Epub 2009 Jul 23.

Equipe Différenciation Neuromusculaire, UMR 5239, Ecole Normale Supérieure Lyon, CNRS, Université Lyon 1, Lyon, France.

We report the case of a congenital myasthenic syndrome due to a mutation in AGRN, the gene encoding agrin, an extracellular matrix molecule released by the nerve and critical for formation of the neuromuscular junction. Gene analysis identified a homozygous missense mutation, c.5125G>C, leading to the p. Read More

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Rapsyn interacts with the muscle acetylcholine receptor via alpha-helical domains in the alpha, beta, and epsilon subunit intracellular loops.

Neuroscience 2009 Sep 29;163(1):222-32. Epub 2009 May 29.

Department of Anesthesiology and Physiology and Membrane Biology, University of California Davis, One Shields Avenue, Davis, CA 95616, USA.

At the developing vertebrate neuromuscular junction, the acetylcholine receptor becomes aggregated at high density in the postsynaptic muscle membrane. Receptor localization is regulated by the motoneuron-derived factor, agrin, and requires an intracellular, scaffolding protein called rapsyn. However, it remains unclear where rapsyn binds on the acetylcholine receptor and how their interaction is regulated. Read More

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September 2009