Silencing of Dok-7 in Adult Rat Muscle Increases Susceptibility to Passive Transfer Myasthenia Gravis

Alejandro M. Gomez*, Jo A. A. Stevens, Marina Mane-Damas, Peter Molenaar, Hans Duimel, Fons Verheyen, Judith Cossins, David Beeson, Marc H. De Baets, Mario Losen, Pilar Martinez-Martinez*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Myasthenia gravis (MG) is an autoimmune disease mediated by autoantibodies thattarget proteins at the neuromuscular junction, primarily the acetylcholine receptor (AChR) and the muscle-specific kinase. Because downstream of kinase 7 (Dok-7) is essential for the full activation of muscle-specific kinase and consequently for dense clustering of AChRs, we hypothesized that reduced levels of Dok-7 increase the susceptibility to passive transfer MG. To test this hypothesis, Dok-7 expression was reduced by transfecting shRNA-coding plasmids into the tibialis anterior muscle of adult rats by in vivo electroporation. Subclinical MG was subsequently induced with a Low dose of anti-AChR monoclonal antibody 35. Neuromuscular transmission was significantly impaired in Dok-7-siRNA-electroporated legs compared with the contralateral control legs, which correlated with a reduction of AChR protein levels at the neuromuscular junction (approximately 25 %) in Dok-7-siRNA electroporated muscles, compared with contralateral control muscles. These results suggest that a reduced expression of Dok-7 may play a role in the susceptibility to passive transfer MG, by rendering AChR clusters less resistant to the autoantibody attack.
Original languageEnglish
Pages (from-to)2559-2568
JournalAmerican Journal of Pathology
Issue number10
Publication statusPublished - Oct 2016


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