title: [Anti-MuSK antibodies in myasthenia gravis block binding of collagen Q to MuSK].
abstract: In myasthenia gravis (MG), 5-15% of patients are positive for MuSK antibodies. MuSK binds to LRP4 and transmits an agrin-mediated signal for clustering of acetylcholine receptor (AChR). MuSK also anchors the collagenic tail subunit (ColQ) of acetylcholinesterase (AChE). MuSK-IgG is a blocking antibody, but its molecular targets remained elusive. As acetylcholine receptor (AChR) deficiency is typically mild and as cholinesterase inhibitors are generally ineffective in MuSK-MG patients, we asked if MuSK-IgG interferes with binding of ColQ to MuSK. The in vitro overlay assay showed that MuSK-IgG blocked binding of ColQ to the neuromuscular junction of Colq-/- mice. The in vitro plate-binding assay showed that MuSK-IgG blocked binding of ColQ to MuSK in a dose-dependent manner. Passive transfer of MuSK-IgG to wild-type mice reduced the size and density of ColQ to ～10% of controls and had a lesser effect on the size and density of AChR and MuSK. These data point to a notion that MuSK-IgG blocks binding of ColQ to MuSK. As lack of ColQ compromises agrin-mediated AChR clustering in Colq-/- mice, a similar mechanism may lead to AChR deficiency in MuSK-MG patients.
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine.
authors.forename: Kinji
authors.initials: K
authors.lastname: Ohno
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000328:Adult; D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D002675:Child, Preschool; D003094:Collagen / Q000378:metabolism*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009124:Muscle Proteins / Q000378:metabolism*; D009157:Myasthenia Gravis / Q000276:immunology* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology* / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000276:immunology* / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G; D009124:Muscle Proteins; D011950:Receptors, Cholinergic; D003094:Collagen; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000110:Acetylcholinesterase; C114027:COLQ protein, human