Possible founder effect of rapsyn N88K mutation and identification of novel rapsyn mutations in congenital myasthenic syndromes

Congenital myasthenic syndromes (CMS) constitute a group of rare diseases heterogeneous both in terms of their mode of hereditary transmission (recessive and dominant forms) and their pathophysiology (with presynaptic, synaptic, and postsynaptic defects). They are responsible for dysfunction of neuromuscular transmission giving rise to a condition of muscle weakness which is accentuated by exertion. In most cases, CMS begin in early childhood but later onset in adulthood is possible. Severity also varies from severe with respiratory failure to mild expression.1,2 The majority of CMS primarily affect postsynaptic function and are the result of mutations located in the muscle acetylcholine receptor (AChR) subunit genes that lead to kinetic abnormalities or to AChR deficiency. For example, an increased response occurs in the slow channel syndromes associated with dominant mutations in AChR subunits delaying channel closure or increasing the affinity of the receptor for acetylcholine. However, the most commonly encountered CMS is a deficiency in AChR which occurs with recessive mutations. Most of these mutations are located in the AChR e subunit.3,4 Recent advances have shown that mutations in rapsyn are also involved in recessive forms of postsynaptic CMS and cause AChR deficiency.5 Rapsyn is a 43 kDa postsynaptic protein involved in development and maintenance of the molecular architecture of the postsynaptic membrane by participating in the clustering of AChR after binding of neural agrin to its muscle specific receptor tyrosine kinase, MuSK.6,7 The rapsyn gene ( RAPSN ) has been mapped to chromosome 11p11.2 p11.1 and comprises eight exons.8 The primary structure of rapsyn is predicted to contain several functional domains such as an N-terminus myristoylation signal, seven tetratricopeptide repeats (residues 6-279), a coiled-coiled domain (298-331), a cysteine rich RING-H2 domain (363-402), and a serine phosphorylation site at codon 406.9,10 The aim of this …