title: Rapsyn mutations in humans cause endplate acetylcholine-receptor deficiency and myasthenic syndrome.
abstract: Congenital myasthenic syndromes (CMSs) stem from genetic defects in endplate (EP)-specific presynaptic, synaptic, and postsynaptic proteins. The postsynaptic CMSs identified to date stem from a deficiency or kinetic abnormality of the acetylcholine receptor (AChR). All CMSs with a kinetic abnormality of AChR, as well as many CMSs with a deficiency of AChR, have been traced to mutations in AChR-subunit genes. However, in a subset of patients with EP AChR deficiency, the genetic defect has remained elusive. Rapsyn, a 43-kDa postsynaptic protein, plays an essential role in the clustering of AChR at the EP. Seven tetratricopeptide repeats (TPRs) of rapsyn subserve self-association, a coiled-coil domain binds to AChR, and a RING-H2 domain associates with beta-dystroglycan and links rapsyn to the subsynaptic cytoskeleton. Rapsyn self-association precedes recruitment of AChR to rapsyn clusters. In four patients with EP AChR deficiency but with no mutations in AChR subunits, we identify three recessive rapsyn mutations: one patient carries L14P in TPR1 and N88K in TPR3; two are homozygous for N88K; and one carries N88K and 553ins5, which frameshifts in TPR5. EP studies in each case show decreased staining for rapsyn and AChR, as well as impaired postsynaptic morphological development. Expression studies in HEK cells indicate that none of the mutations hinders rapsyn self-association but that all three diminish coclustering of AChR with rapsyn.
authors.affiliation: Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Kinji
authors.initials: K
authors.lastname: Ohno
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Engel
authors.forename: Xin-Ming
authors.initials: XM
authors.lastname: Shen
authors.forename: Duygu
authors.initials: D
authors.lastname: Selcen
authors.forename: Joan
authors.initials: J
authors.lastname: Brengman
authors.forename: C Michel
authors.initials: CM
authors.lastname: Harper
authors.forename: Akira
authors.initials: A
authors.lastname: Tsujino
authors.forename: Margherita
authors.initials: M
authors.lastname: Milone
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002038:Bungarotoxins / Q000378:metabolism; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D018680:Cholinergic Antagonists / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008839:Microelectrodes; D008969:Molecular Sequence Data; D009045:Motor Endplate / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D009124:Muscle Proteins / Q000032:analysis / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D020294:Myasthenic Syndromes, Congenital / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011950:Receptors, Cholinergic / Q000032:analysis / Q000172:deficiency* / Q000378:metabolism; D016415:Sequence Alignment; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D002038:Bungarotoxins; D018680:Cholinergic Antagonists; D009124:Muscle Proteins; D011950:Receptors, Cholinergic; C051609:peripheral membrane protein 43K