title: 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.
authors.affiliation: Department of Neurology, University of California, 1515 Newton Court, Room 510, Davis, California 95616, USA. ramaselli@ucdavis.edu
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Maselli
authors.forename: Vanessa
authors.initials: V
authors.lastname: Dunne
authors.forename: Samuel Ignacio
authors.initials: SI
authors.lastname: Pascual-Pascual
authors.forename: Constance
authors.initials: C
authors.lastname: Bowe
authors.forename: Mark
authors.initials: M
authors.lastname: Agius
authors.forename: Rochelle
authors.initials: R
authors.lastname: Frank
authors.forename: Robert L
authors.initials: RL
authors.lastname: Wollmann
mesh_terms: D000293:Adolescent; D002675:Child, Preschool; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008854:Microscopy, Electron; D009124:Muscle Proteins / Q000172:deficiency* / Q000235:genetics*; D018482:Muscle, Skeletal / Q000294:innervation / Q000473:pathology / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D020294:Myasthenic Syndromes, Congenital / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009469:Neuromuscular Junction / Q000235:genetics* / Q000473:pathology / Q000648:ultrastructure; D010375:Pedigree; D010641:Phenotype; D011950:Receptors, Cholinergic / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D013570:Synaptic Membranes / Q000235:genetics / Q000473:pathology / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000235:genetics
chemical_list: D009124:Muscle Proteins; D011950:Receptors, Cholinergic; C051609:peripheral membrane protein 43K