The Role of MuSK in Synapse Formation and Neuromuscular Disease

Burden, Steven J.; Yumoto, Norihiro; Zhang, Wei

doi:10.1101/cshperspect.a009167

Cited by 157 publications

(145 citation statements)

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“…As such, antibodies that inhibit MuSK function would be expected to disrupt the architecture of the neuromuscular synapse as well as perturb neurotransmitter release and reception (9,18,19,34,(41)(42)(43)(44). Because the synaptic accumulation of acetylcholinesterase (AChE), like all other postsynaptic proteins, depends on MuSK (10,42), IgG4 antibodies to MuSK are likely to lower AChE expression at the synapse, which may explain the hypersensitivity of MuSK MG patients to AChE inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…MuSK is essential for all known aspects of presynaptic and postsynaptic differentiation (9,10,17). As such, antibodies that inhibit MuSK function would be expected to disrupt the architecture of the neuromuscular synapse as well as perturb neurotransmitter release and reception (9,18,19,34,(41)(42)(43)(44).…”

Section: Discussionmentioning

confidence: 99%

“…complement and cell damage in MuSK MG, the structural and functional deficits of synapses are extensive in MuSK MG, which highlights the key role that MuSK plays in organizing all aspects of synaptic differentiation (9,17).…”

mentioning

confidence: 99%

“…A hydrophobic surface on the opposite side of the first Ig-like domain mediates MuSK homodimerization, which is essential for MuSK transphosphorylation (24). Although MuSK is expressed by muscle and not by motor neurons, MuSK is critical for presynaptic as well as postsynaptic differentiation (9).…”

mentioning

confidence: 99%

“…The extracellular region of MuSK contains three Ig-like domains and a Frizzled-like domain (9). The first Ig-like domain in MuSK is required for MuSK to bind Lrp4.…”

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confidence: 99%

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MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4

Huijbers¹,

Zhang

Klooster³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

246

207

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Myasthenia gravis (MG) is a severely debilitating autoimmune disease that is due to a decrease in the efficiency of synaptic transmission at neuromuscular synapses. MG is caused by antibodies against postsynaptic proteins, including (i) acetylcholine receptors, the neurotransmitter receptor, (ii) muscle-specific kinase (MuSK), a receptor tyrosine kinase essential for the formation and maintenance of neuromuscular synapses, and (iii)

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

“…The extracellular region of MuSK contains three Ig-like domains and a Frizzled-like domain (9). The first Ig-like domain in MuSK is required for MuSK to bind Lrp4.…”

mentioning

confidence: 99%

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MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4

Huijbers¹,

Zhang

Klooster³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

246

207

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Impaired Synaptic Development, Maintenance, and Neuromuscular Transmission in LRP4-Related Myasthenia

et al. 2015

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IMPORTANCE Congenital myasthenic syndromes (CMS) are heterogeneous disorders. Defining the phenotypic features, genetic basis, and pathomechanisms of a CMS is relevant to prognosis, genetic counseling, and therapy.OBJECTIVES To characterize clinical, structural, electrophysiologic, and genetic features of a CMS and to search for optimal therapy. DESIGN, SETTINGS, AND PARTICIPANTS Two sisters with CMS affecting the limb-girdle muscles were investigated between 2012 and 2014 at an academic medical center by clinical observation, in vitro analysis of neuromuscular transmission, cytochemical and electron microscopy studies of the neuromuscular junction, exome sequencing, expression studies in HEK293 and COS7 cells, and for response to therapy, and they were compared with 15 historical control participants. MAIN OUTCOMES AND MEASURESWe identified the disease gene and mutation, confirmed pathogenicity of the mutation by expression studies, and instituted optimal pharmacotherapy. RESULTS Quantitative analysis of single EP regions was done for all 15 control participants and microelectrode studies of neuromuscular transmission and α-bgt binding sites per EP was conducted for 13 control participants. Examination of the older sister's intercostal muscle end plates (EPs) showed them to be abnormally small, with attenuated reactivities for the acetylcholine receptor and acetylcholinesterase. Most EPs had poorly differentiated or degenerate junctional folds, and some appeared denuded of nerve terminals. The amplitude of the EP potential (EPP), the miniature EPP, and the quantal content of the EPP were all markedly reduced. Exome sequencing identified a novel homozygous p.Glu1233Ala mutation in low-density lipoprotein receptor-related protein 4 (LRP4), a coreceptor for agrin to activate muscle-specific tyrosine kinase (MuSK), which is required for EP development and maintenance. Expression studies indicate that the mutation compromises the ability of LRP4 to bind to, phosphorylate, and activate MuSK. Treatment with albuterol sulfate improved the patients' symptoms. A previously identified patient harboring 2 heterozygous mutations in LRP4 had structurally abnormal intercostal EPs but no identifiable defect of neuromuscular transmission at these EPs. CONCLUSIONS AND RELEVANCEWe identified a second CMS kinship harboring mutations in LRP4, identified the mechanisms that impair neuromuscular transmission, and mitigated the disease by appropriate therapy.

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Molecular Genetics of Congenital Myasthenic Syndromes

Ohno

Ohkawara

Ito

et al. 2014

Encyclopedia of Life Sciences

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Congenital myasthenic syndromes (CMS) are heterogeneous disorders caused by congenital defects of molecules expressed at the neuromuscular junctions. Clinical features include fatigable muscle weakness, amyotrophy and minor facial anomalies. Mutations have been identified in 18 genes encoding acetylcholine receptor (AChR) subunits ( CHRNA1 , CHRNB1 , CHRND and CHRNE ); skeletal muscle sodium channel ( SCN4A ); signalling molecules driving AChR clustering and subserving maintenance and differentiation of the postsynaptic region ( AGRN, LRP4, MUSK and DOK7 ); postsynaptic structural proteins ( RAPSN and PLEC ); synaptic β2 laminin, which promotes presynaptic differentiation, and synaptic collagen Q; presynaptic choline acetyltransferase and enzymes in subserving protein glycosylation ( GFPT1 , DPAGT1 , ALG14 , and ALG2 ). The CMS are caused by recessive mutations except for the slow‐channel CMS. The recent development of the exome sequencing has speeded identification of causative mutations. Mutations in glycosylation genes were recently discovered, but the mechanisms by which they impair neuromuscular signal transmission have not been fully elucidated. Key Concepts: Congenital myasthenic syndromes are caused by germline mutations in molecules expressed at the neuromuscular junction (NMJ). Muscle nicotinic acetylcholine receptor (AChR) is a pentameric ligand‐gated ion channel in the stoichiometry of α 2 βδϵ subunits. Missense mutations in AChR subunit genes can cause abnormally long and brief ion channel openings resulting in slow‐ and fast‐channel myasthenic syndromes, respectively. Primary endplate AChR deficiency can be due to low‐expressor or null mutations in the AChR ϵ subunit. The phenotype in case of biallelic low‐expressor or null mutations in the ϵ subunit is rescued by expression of the foetal γ subunit. Biallelic null mutations in non‐ϵ are embryonic lethal mutations. A second group of endplate AChR deficiency is caused by mutations in signalling molecules including agrin, LRP4, MuSK, Dok‐7, which drive AChR clustering. The third group of endplate AChR deficiency stems from mutations in the postsynaptic structural proteins of rapsyn or plectin. Mutations in enzymes subserving the N ‐glycosylation pathway of GFPT1, DPAGT1, ALG14 and ALG2 cause limb‐girdle CMS with tubular aggregates. Endplate acetylcholinesterase (AChE) deficiency is caused by mutations in collagen Q (ColQ), which anchors AChE to the synaptic basal lamina. Protein‐anchoring therapy, in which ectopically expressed AChE/ColQ complex is specifically anchored to the neuromuscular junction using the proprietary binding motifs, markedly ameliorates myasthenic symptoms of Colq ‐knockout mice. Mutations in choline acetyltransferase (ChAT) cause defective resynthesis of ACh at the nerve terminal and a CMS associated with frequent episodic apnoea.

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The Role of MuSK in Synapse Formation and Neuromuscular Disease

Cited by 157 publications

References 68 publications

MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4

MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4

Impaired Synaptic Development, Maintenance, and Neuromuscular Transmission in LRP4-Related Myasthenia

Molecular Genetics of Congenital Myasthenic Syndromes

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