J Med Genet 41:e104 doi:10.1136/jmg.2004.021139
  • Electronic letters

The congenital myasthenic syndrome mutation RAPSN N88K derives from an ancient Indo-European founder

  1. J S Müller1,*,
  2. A Abicht1,*,
  3. G Burke2,
  4. J Cossins2,
  5. P Richard3,
  6. S K Baumeister1,
  7. R Stucka1,
  8. B Eymard3,
  9. D Hantaï3,
  10. D Beeson2,
  11. H Lochmüller1
  1. 1Friedrich-Baur-Institute, Department of Neurology, and Gene Center, Ludwig-Maximilians-University, Munich, Germany
  2. 2Neurosciences Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK
  3. 3INSERM U.582, Institut de Myologie and Unité Fonctionnelle de Cardiogénétique et Myogénétique, Hôpital de la Salpêtrière, Paris, France
  1. Correspondence to:
 Dr Hanns Lochmüller
 Genzentrum München, Feodor-Lynen-Str. 25, 81377 München, Germany;
  • Received 4 May 2004
  • Accepted 4 May 2004

Only recently, mutations of the RAPSN gene have been recognised as causing acetylcholine receptor deficiency at the motor endplate resulting in early and late onset forms of congenital myasthenic syndromes (CMS).1–9 In most studies a single missense mutation of RAPSN (N88K) was detected either homozygously or compound heterozygously in numerous, unrelated patients of European and North American origin. Based on the analysis of a small number of intragenic single nucleotide polymorphisms (SNPs) and/or extragenic, polymorphic repeat markers, we hypothesised that RAPSN (N88K) may derive from a common founder.7 However, this hypothesis was disputed in a recent report in the Journal of Medical Genetics.10 In this study, 12 independent RAPSN (N88K) alleles from white North American CMS patients were compared to 37 wild type chromosomes. Five intragenic SNPs and two extragenic microsatellite markers appeared to be in linkage disequilibrium with the mutation, whereas four extragenic microsatellite markers failed to prove a significant association.10 To resolve this question we analysed 41 independent RAPSN (N88K) alleles using 21 SNPs flanking RAPSN on chromosome 11p11.11


We collected 21 CMS patients harbouring RAPSN (N88K) either homozygously (n = 20) or compound heterozygously (n = 1). Screening for the mutation N88K (264C→A) in exon 2 of the RAPSN gene was performed as described previously.7 Patients originated from Germany (n = 5), Austria (n = 1), Italy (n = 1), France (n = 2), the United Kingdom (n = 10), and the Indian subcontinent (n = 2). Consanguinity was not reported for any of the families. Most of the patients have been described, previously: patients G1–G4, Au1, UK10, and It1 (patients 1–7 in Müller et al7), patients UK1–7 (patients 3, 9, 11, 12, 13, 15, and 16 in Burke et al6), patient Ind2 (patient 1 in Burke et al6), patient Fr1 (patient 1 in Richard et al8), and patient Fr2 (in Yasaki …

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