Rapsyn mutations in humans cause endplate acetylcholine-receptor deficiency and myasthenic syndrome

Kinji Ohno, Andrew G. Engel, Xin Ming Shen, Duygu Selcen, Joan Brengman, C. Michel Harper, Akira Tsujino, Margherita Milone

Research output: Contribution to journalArticlepeer-review

186 Scopus citations

Abstract

Congenital myasthenic syndromes (CMSs) stem from genetic defects in endplate (EP)-specific presynaptic, synaptic, and postsynaptic proteins. The postsynaptic CMSs identified to date stern 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 β-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.

Original languageEnglish (US)
Pages (from-to)875-885
Number of pages11
JournalAmerican journal of human genetics
Volume70
Issue number4
DOIs
StatePublished - 2002

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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