Identification of pathogenic mutations in the human rapsyn gene

Vanessa Dunne, Ricardo A Maselli

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Rapsyn, a complex postsynaptic protein of the striated muscle, assembles acetylcholine receptors (AChR) at high density at the motor endplate (EP). Neuromuscular junctions of mice lacking rapsyn show no clusters of AChRs or other structural postsynaptic proteins such as β-dystroglycan and utrophin. Humans with mutations in the rapsyn gene (RAPSN) are affected with a postsynaptic form of congenital myasthenic syndrome (CMS) characterized by impairment of the morphologic development of the postsynaptic region. We have identified four patients from four different families with RAPSN mutations and CMS, confirmed in two cases by microelectrode and electron microscopy studies. The N88K mutation was present in all patients. One patient who was homozygous for N88K was only mildly affected, while the other three patients who were heterozygous for N88K and a second mutation (either L14P, 46insC, or Y269X) were severely affected. Mutations 46insC and Y269X predicts truncation of the protein. L14P predicts a conformational change at the N-terminus that may disrupt membrane association. N88K occurs within the putative leucine zipper motif potentially important for AChR clustering. These findings may explain the severe clinical involvement of compound heterozygous patients.

Original languageEnglish (US)
Pages (from-to)204-207
Number of pages4
JournalJournal of Human Genetics
Volume48
Issue number4
DOIs
StatePublished - 2003

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Congenital Myasthenic Syndromes
Mutation
Genes
Cholinergic Receptors
Utrophin
Dystroglycans
Motor Endplate
Leucine Zippers
Proteins
Striated Muscle
Neuromuscular Junction
Microelectrodes
Cluster Analysis
Electron Microscopy
peripheral membrane protein 43K
Membranes

Keywords

  • Acetylcholine receptor clustering
  • Congenital myasthenic syndrome
  • Endplate
  • Postsynaptic
  • Rapsyn

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Identification of pathogenic mutations in the human rapsyn gene. / Dunne, Vanessa; Maselli, Ricardo A.

In: Journal of Human Genetics, Vol. 48, No. 4, 2003, p. 204-207.

Research output: Contribution to journalArticle

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