Congenital Myasthenic Syndromes – Molecular Bases of Congenital Defects of Proteins at the Neuromuscular Junction

Congenital myasthenic syndromes (CMS) are heterogeneous disorders caused by mutations in molecules expressed at the neuromuscular junction (NMJ) (Fig. 1). Each mutation affects the expression level or the functional properties or both of the mutant molecule. No fewer than 11 defective molecules at the NMJ have been identified to date. The mutant molecules include (i) acetylcholine receptor (AChR) subunits that forms nicotinic AChR and generate endplate potentials (Ohno et al., 1995; Sine et al., 1995), (ii) rapsyn that anchors and clusters AChRs at the endplate (Ohno et al., 2002; Milone et al., 2009), (iii) agrin that is released from nerve terminal and induces AChR clustering by stimulating the downstream LRP4/MuSK/Dok-7/rapsyn/AChR pathway (Huze et al., 2009), (iv) muscle-specific receptor tyrosine kinase (MuSK) that transmits the AChR-clustering signal from agrin/LRP4 to Dok-7/rapsyn/AChR (Chevessier et al., 2004; Chevessier et al., 2008), (v) Dok-7 that interacts with MuSK and exerts the AChR-clustering activity (Beeson et al., 2006; Hamuro et al., 2008), (vi) plectin that is an intermediate filament-associate protein concentrated at sites of mechanical stress (Banwell et al., 1999; Selcen et al., 2011), (vii) glutamine-fructose-6phosphate aminotransferase 1 encoded by GFPT1, the function of which at the NMJ has not been elucidated (Senderek et al., 2011), (viii) skeletal muscle sodium channel type 1.4 (NaV1.4) that spreads depolarization potential from endplate throughout muscle fibers (Tsujino et al., 2003), (ix) collagen Q that anchors acetylcholinesterase (AChE) to the synaptic basal lamina (Ohno et al., 1998; Ohno et al., 1999; Kimbell et al., 2004), (x) 2-laminin that forms a cruciform heterotrimeric lamins-221, -421, and -521 and links extracellular matrix molecules to the -dystroglycan at the NMJ (Maselli et al., 2009), (xi) choline acetyltransferase (ChAT) that resynthesizes acetylcholine from recycled choline at the nerve terminal (Ohno et al., 2001). AChR (Lang & Vincent, 2009), MuSK (Hoch et al., 2001; Cole et al., 2008), and LRP4 (Higuchi et al., 2011) are also targets of myasthenia gravis, in which autoantibody against each molecule impairs the neuromuscular transmission.