title: Impaired receptor clustering in congenital myasthenic syndrome with novel RAPSN mutations.
abstract: OBJECTIVE
  Congenital myasthenic syndromes (CMS) with underlying RAPSN mutations turned out to be of high clinical relevance due to their worldwide frequency. To date, all reported patients with CMS with sequence variations in the translated region of RAPSN carry the mutation N88K on at least one allele. The authors report two patients lacking the common N88K allele but harboring differing novel mutations of the RAPSN gene on both alleles: one patient is homozygous for a missense mutation (R164C); the second patient is compound heterozygous for a splice (IVS1-15C>A) and another missense mutation (L283P).
  
  
  METHODS
  The authors analyzed the RAPSN gene for sequence variations and carried out in vitro studies in order to delineate the potential pathogenicity of the three novel RAPSN mutations.
  
  
  RESULTS
  For the putative splice mutation (IVS1-15C>A), the authors constructed wild-type and mutated RAPSN minigenes for transfection and subsequent RNA analysis. The mutation generates a novel acceptor splice site leading to retention of 13 nucleotides of intron 1 in the mature mRNA and subsequently to a frameshift transcript. Cotransfection of wild-type AChR subunits with RAPSN-constructs carrying R164C and L283P indicate that both mutations diminish coclustering of AChR with rapsyn.
  
  
  CONCLUSIONS
  Screening for the common mutation RAPSN N88K facilitates targeted genetic analysis in congenital myasthenic syndromes. However, absence of a N88K allele does not exclude underlying RAPSN mutations as cause of the congenital myasthenic syndromes. Sequencing of the entire gene may be considered in patients with joint contractures and respiratory problems even in the absence of the mutation N88K.
authors.affiliation: Friedrich-Baur-Institute, Department of Neurology, Munich, Germany.
authors.forename: J S
authors.initials: JS
authors.lastname: Müller
authors.forename: S K
authors.initials: SK
authors.lastname: Baumeister
authors.forename: V M
authors.initials: VM
authors.lastname: Rasic
authors.forename: S
authors.initials: S
authors.lastname: Krause
authors.forename: S
authors.initials: S
authors.lastname: Todorovic
authors.forename: K
authors.initials: K
authors.lastname: Kugler
authors.forename: W
authors.initials: W
authors.lastname: Müller-Felber
authors.forename: A
authors.initials: A
authors.lastname: Abicht
authors.forename: H
authors.initials: H
authors.lastname: Lochmüller
mesh_terms: D001483:Base Sequence; D002648:Child; D004252:DNA Mutational Analysis; D005060:Europe / Q000453:epidemiology; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation; D020294:Myasthenic Syndromes, Congenital / Q000453:epidemiology* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011978:Receptors, Nicotinic / Q000235:genetics*
chemical_list: D009124:Muscle Proteins; D011978:Receptors, Nicotinic; C051609:peripheral membrane protein 43K