Rapsyn mutations in myasthenic syndrome due to impaired receptor clustering

Abstract

Rapsyn, a 43-kDa postsynaptic protein, is essential for anchoring and clustering acetylcholine receptors (AChRs) at the endplate (EP). Mutations in the rapsyn gene have been found to cause a postsynaptic congenital myasthenic syndrome (CMS). We detected six patients with CMS due to mutations in the rapsyn gene (RAPSN). In vitro studies performed in the anconeus muscle biopsies of four patients showed severe reduction of miniature EP potential amplitudes. Electron microscopy revealed various degrees of impaired development of postsynaptic membrane folds. All patients carried the N88K mutation. Three patients were homozygous for N88K and had less severe phenotypes and milder histopathologic abnormalities than the three patients who were heterozygous and carried a second mutation (either L14P, 46insC, or Y269X). Surprisingly, two N88K homozygous patients had one asymptomatic relative each who carried the same genotype, suggesting that additional genetic factors to RAPSN mutations are required for disease expression.

Myasthenic syndrome due to defects in rapsyn

“…N88K occurred with high frequency, as observed in other series. 9,18,26,32 Six mutations reported here are novel and family analysis indicates they are recessive.…”

The congenital myasthenic syndrome mutation RAPSN N88K derives from an ancient Indo-European founder

“…[1][2][3][4][5][6][7][8][9] In most studies a single missense mutation of RAPSN (N88K) was detected either homozygously or compound heterozygously in numerous, unrelated patients of European and North American origin. Based on the analysis of a small number of intragenic single nucleotide polymorphisms (SNPs) and/or extragenic, polymorphic repeat markers, we hypothesised that RAPSN (N88K) may derive from a common founder.…”

Silencing rapsyn in vivo decreases acetylcholine receptors and augments sodium channels and secondary postsynaptic membrane folding

“…Indeed, mutations within the RAPSN gene have been shown to underlie a high proportion of AChR deficiency syndromes (Burke et al, 2003;Dunne and Maselli, 2003;Ioos et al, 2004;Maselli et al, 2003a;Muller et al, 2003;Ohno et al, 2002Ohno et al, , 2003. Endplates of patients with the N88K rapsyn mutation contain a reduced number of postsynaptic folds (Ohno et al, 2002(Ohno et al, , 2003, which could lead to a reduction of the safety factor of the neuromuscular transmission Lennon, 1998, 2008).…”

“…Decreased recruitment of AChR to rapsyn clusters, as well as decreased rapsyn expression at the endplate is likely to account for the endplate AChR deficiency (Cossins et al, 2006;Engel and Sine, 2005;Hantai et al, 2004;Maselli et al, 2003a;Ohno et al, 2002) resulting in an impaired neuromuscular transmission. In patients with the N88K rapsyn mutation (either homozygous or heteroallelic with other missense or promoter mutations) simplified postsynaptic membranes with few folds were found (Ohno et al, 2002(Ohno et al, , 2003.…”