Congenital Myasthenic Syndromes and the Formation of the Neuromuscular Junction

Abstract

The congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders affecting neuromuscular transmission. Underlying mutations have been identified in at least 11 different genes. The majority of CMS patients have disorders due to mutations in postsynaptic proteins. Initial studies focused on dysfunction of the acetylcholine receptor (AChR) itself as the major cause of CMS. However, it is becoming apparent that mutations of proteins involved in clustering the AChR and maintaining neuromuscular junction structure form important subgroups. Analysis of the mutations in the AChR-clustering protein, rapsyn, show diverse causes for defective AChR localization and suggest that the common mutation rapsyn-N88K results in AChR clusters that are less stable than those generated by wild-type rapsyn. More recently, mutations in the newly identified endplate protein Dok-7 have been shown to affect AChR clustering and the generation and maintenance of specialized structures at the endplate. Dok-7 binds MuSK and many of the mutations of DOK7 impair the MuSK signaling pathway. Components of this pathway will provide attractive gene candidates for additional forms of CMS. The phenotypic characteristics of the different CMS in which muscle groups may be differentially affected not only provide clues for targeted genetic screening, but also pose further intriguing questions about underlying molecular mechanisms.

Rapsyn mediates subsynaptic anchoring of PKA type I and stabilisation of acetylcholine receptor in vivo

“…There is a wealth of studies showing a direct correlation between the amount of rapsyn present at NMJs and the abundance or the metabolic stability of synaptic AChRs (Brockhausen et al, 2008;Gervasio et al, 2007;Gervasio and Phillips, 2005;Luo et al, 2008;Martinez-Martinez et al, 2009;Wang et al, 1999). Furthermore, mutations in the RAPSN gene are amongst the most frequent causes for myasthenic syndromes, which are characterised by activity-dependent muscle weakness (Beeson et al, 2008;Müller et al, 2007). Together, these findings place rapsyn in the centre of regulatory processes that mediate stabilisation of synaptic AChRs.…”

Lrp4 Is a Receptor for Agrin and Forms a Complex with MuSK

“…The signals and mechanisms responsible for this process are poorly understood but require the neurally derived ligand Agrin, and MuSK, a receptor tyrosine kinase expressed in muscle (Glass and Yancopoulos, 1997). Defects in this signaling pathway, which lead to a reduced number of AChRs at synapses, are responsible for a variety of congenital neuromuscular disorders, termed CMS (Beeson et al, 2008; Engel et al, 2008; Engel and Sine, 2005). …”

The Cytoplasmic Adaptor Protein Dok7 Activates the Receptor Tyrosine Kinase MuSK via Dimerization

“…MuSK, LRP4, Rapsyn, and AChRs are pre-clustered in the muscle endplate prior to innervation, and their clustering is refined and sharpened upon release of Agrin from the developing nerve terminal (Kummer et al, 2006). Failure to properly cluster AChRs is responsible for multiple disorders in neuromuscular transmission, including myasthenia gravis and congenital myasthenic syndromes (CMS) (Beeson et al, 2008; Engel and Sine, 2005). …”