Are MuSK antibodies the primary cause of myasthenic symptoms?

Selcen, Duygu; Fukuda, Toyoki; Shen, Xin Ming; Engel, Andrew G.

doi:10.1212/01.wnl.0000128048.23930.1d

Cited by 107 publications

(109 citation statements)

References 29 publications

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“…Although our results predict endplate AChE deficiency in MuSK-MG patients, we found no AChE deficiency in intercostal muscles of one reported 33 and two unreported cases of MuSK-MG. In vitro microelectrode studies showed a normal EPP decay time constant.…”

Section: In Vitro Plate-binding Assay Shows That Musk-igg Blocks Bindcontrasting

confidence: 97%

“…In vitro microelectrode studies showed a normal EPP decay time constant. 34 In the 3 MuSK-MG patients observed by us, the MEPC decay times were shorter than normal, normal, and 2-fold prolonged 33 compared to controls. Thus, our biopsy findings do not indicate that MuSK-MG patients have endplate AChE deficiency.…”

Section: In Vitro Plate-binding Assay Shows That Musk-igg Blocks Bindmentioning

confidence: 62%

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Anti-MuSK autoantibodies block binding of collagen Q to MuSK

Kawakami¹,

Ito²,

Hirayama³

et al. 2011

Neurology

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Objective: Muscle-specific receptor tyrosine kinase (MuSK) antibody-positive myasthenia gravis (MG) accounts for 5%-15% of autoimmune MG. MuSK mediates the agrin-signaling pathway and also anchors the collagenic tail subunit (ColQ) of acetylcholinesterase (AChE). The exact molecular target of MuSK-immunoglobulin G (IgG), however, remains elusive. As acetylcholine receptor (AChR) deficiency is typically mild and as cholinesterase inhibitors are generally ineffective, we asked if MuSK-IgG interferes with binding of ColQ to MuSK. Methods:We used 3 assays: in vitro overlay of the human ColQ-tailed AChE to muscle sections of ColqϪ/Ϫ mice; in vitro plate-binding assay to quantitate binding of MuSK to ColQ and to LRP4; and passive transfer of MuSK-IgG to mice.

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Section: In Vitro Plate-binding Assay Shows That Musk-igg Blocks Bindcontrasting

confidence: 97%

Section: In Vitro Plate-binding Assay Shows That Musk-igg Blocks Bindmentioning

confidence: 62%

Anti-MuSK autoantibodies block binding of collagen Q to MuSK

Kawakami¹,

Ito²,

Hirayama³

et al. 2011

Neurology

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110

116

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“…Sparing of selected muscles can occur in both autoimmune and congenital myasthenias and is indicated by absence of muscle weakness or a decremental EMG response from some muscles in either disorder. For example, in MuSK antibody-positive myasthenia, EPs in intercostal and biceps brachii muscles have a normal AChR content, generate normal MEPP amplitudes, and have well preserved junctional folds (27,28). Analysis of Musk and Lrp4 expressions in mouse muscles by quantitative RT -PCR revealed that expressions of Musk in omohyoid and trapezius muscles were less than those in the other muscles (Supplementary Material, Fig.…”

Section: Lrp4 Mutations Cause a Novel Cmsmentioning

confidence: 99%

LRP4 third β-propeller domain mutations cause novel congenital myasthenia by compromising agrin-mediated MuSK signaling in a position-specific manner

Ohkawara¹,

Cabrera‐Serrano

Nakata³

et al. 2013

Human Molecular Genetics

114

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Congenital myasthenic syndromes (CMS) are heterogeneous disorders in which the safety margin of neuromuscular transmission is compromised by one or more specific mechanisms. Using Sanger and exome sequencing in a CMS patient, we identified two heteroallelic mutations, p.Glu1233Lys and p.Arg1277His, in LRP4 coding for the postsynaptic low-density lipoprotein receptor-related protein 4. LRP4, expressed on the surface of the postsynaptic membrane of the neuromuscular junction, is a receptor for neurally secreted agrin, and LRP4 bound by agrin activates MuSK. Activated MuSK in concert with Dok-7 stimulates rapsyn to concentrate and anchor AChR on the postsynaptic membrane and interacts with other proteins implicated in the assembly and maintenance of the neuromuscular junction. LRP4 also functions as an inhibitor of Wnt/beta-catenin signaling. The identified mutations in LRP4 are located at the edge of its 3rd beta-propeller domain and decrease binding affinity of LRP4 for both MuSK and agrin. Mutations in the LRP4 3rd beta-propeller domain were previously reported to impair Wnt signaling and cause bone diseases including Cenani -Lenz syndactyly syndrome and sclerosteosis-2. By analyzing naturally occurring and artificially introduced mutations in the LRP4 3rd beta-propeller domain, we show that the edge of the domain regulates the MuSK signaling whereas its central cavity governs Wnt signaling. We conclude that LRP4 is a new CMS disease gene and that the 3rd beta propeller domain of LRP4 mediates the two signaling pathways in a position-specific manner.

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“…There also seems to be a paradox in the pathophysiology; on the one hand, symptoms in MuSK-MG can be very severe while on the other hand the laboratory findings are ambiguous, with abnormalities that seem relatively innocuous, such as slightly subnormal MEPP amplitudes with normal AChR numbers. [47][48][49] In summary, the present results in mice suggest the possibility that MuSK MG autoantibodies indeed influence the molecular function of MuSK, possibly by hampering the interaction between lrp4 and MuSK, 21 with the capability thereby to diminish the size of endplates and the functioning of the AChRs without reducing their number. Obviously, such effects might be much larger in patients than in the present experimental mice because antibodies would circulate at a higher concentration and for a very much longer period than could be tested in our mice.…”

Section: Implications For the Pathophysiology Of Musk-mgmentioning

confidence: 60%

The Effect of Plasma From Muscle-Specific Tyrosine Kinase Myasthenia Patients on Regenerating Endplates

Beek

Martínez‐Martínez

Losen

et al. 2009

The American Journal of Pathology

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Muscle-specific tyrosine kinase (MuSK) is essential for clustering of acetylcholine receptors (AChRs) at embryogenesis and likely also important for maintaining synaptic structure in adult muscle. In 5 to 7% of myasthenia gravis (MG) cases, the patients' blood contains antibodies to MuSK. To investigate the effect of MuSK-MG antibody on synapse regeneration, notexin was used to induce damage to the flexor digitorum brevis muscle. We administered aliquots of MuSK-MG patients' plasma to the flexor digitorum brevis twice daily for a period up to 21 days, and muscles were investigated ex vivo in contraction experiments. AChR levels were measured with 125 I-␣-bungarotoxin, and endplates were studied with quantitative immunohistochemistry. In normal muscles and in 14-day regenerated muscles, MuSK plasma caused impairment of nerve stimulus-induced contraction in the presence of 0.35 and 0.5 mmol/L Ca 2؉ with or without 100 to 400 nmol/L tubocurarine. Endplate size was decreased in regenerated muscles relative to controls; however, we did not observe such differences in muscle not treated with notexin. MuSK plasma had no effect on the amount and turnover rate of AChRs. Our results suggest that anti-MuSK anti-

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Are MuSK antibodies the primary cause of myasthenic symptoms?

Cited by 107 publications

References 29 publications

Anti-MuSK autoantibodies block binding of collagen Q to MuSK

Anti-MuSK autoantibodies block binding of collagen Q to MuSK

LRP4 third β-propeller domain mutations cause novel congenital myasthenia by compromising agrin-mediated MuSK signaling in a position-specific manner

The Effect of Plasma From Muscle-Specific Tyrosine Kinase Myasthenia Patients on Regenerating Endplates

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