title: The CHRNE 1293insG founder mutation is a frequent cause of congenital myasthenia in North Africa.
abstract: OBJECTIVE
  Mutations in various genes of the neuromuscular junction cause congenital myasthenic syndrome (CMS). A single truncating mutation (epsilon1293insG) in the acetylcholine receptor epsilon subunit gene (CHRNE) was most often identified in CMS families originating from North Africa and was possibly a founder mutation.
  
  
  METHODS
  Twenty-three families were studied with an early onset form of CMS and originating from Tunisia, Algeria, Morocco, and Libya. Screening for the mutation epsilon1293insG was performed by direct sequencing. Haplotype analysis was done with 9 (CA)n repeat microsatellite markers and 6 SNPs flanking epsilon1293insG on chromosome 17p13-p12. Dating was calculated using the ESTIAGE method for rare genetic diseases.
  
  
  RESULTS
  The epsilon1293insG mutation was identified in 14 families (about 60% of the initial 23). The expression of the CMS in affected members of these families was relatively homogeneous, without fetal involvement or being life-threatening, with moderate hypotonia and oculobulbar involvement, mild and stable disease course, and good response to cholinesterase inhibitors. Haplotype analysis revealed a common conserved haplotype encompassing a distance of 63 kb. The estimated age of the founder event was at least 700 years.
  
  
  CONCLUSIONS
  These results strongly support the hypothesis that epsilon1293insG derives from an ancient single founder event in the North African population. Identification of founder mutations in isolated or inbred populations may have important implications in the context of molecular diagnosis and genetic counseling of patients and families by detection of heterozygous carriers.
authors.affiliation: AP-HP, UF Cardiogénétique et Myogénétique, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Richard
authors.forename: K
authors.initials: K
authors.lastname: Gaudon
authors.forename: H
authors.initials: H
authors.lastname: Haddad
authors.forename: A Ben
authors.initials: AB
authors.lastname: Ammar
authors.forename: E
authors.initials: E
authors.lastname: Genin
authors.forename: S
authors.initials: S
authors.lastname: Bauché
authors.forename: M
authors.initials: M
authors.lastname: Paturneau-Jouas
authors.forename: J S
authors.initials: JS
authors.lastname: Müller
authors.forename: H
authors.initials: H
authors.lastname: Lochmüller
authors.forename: D
authors.initials: D
authors.lastname: Grid
authors.forename: A
authors.initials: A
authors.lastname: Hamri
authors.forename: S
authors.initials: S
authors.lastname: Nouioua
authors.forename: M
authors.initials: M
authors.lastname: Tazir
authors.forename: M
authors.initials: M
authors.lastname: Mayer
authors.forename: C
authors.initials: C
authors.lastname: Desnuelle
authors.forename: A
authors.initials: A
authors.lastname: Barois
authors.forename: B
authors.initials: B
authors.lastname: Chabrol
authors.forename: J
authors.initials: J
authors.lastname: Pouget
authors.forename: J
authors.initials: J
authors.lastname: Koenig
authors.forename: N
authors.initials: N
authors.lastname: Gouider-Khouja
authors.forename: F
authors.initials: F
authors.lastname: Hentati
authors.forename: B
authors.initials: B
authors.lastname: Eymard
authors.forename: D
authors.initials: D
authors.lastname: Hantaï
mesh_terms: D000352:Africa, Northern / Q000208:ethnology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004252:DNA Mutational Analysis; D005260:Female; D018703:Founder Effect; D005787:Gene Frequency; D005817:Genetic Counseling / Q000592:standards; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D008297:Male; D008967:Molecular Biology / Q000592:standards; D009154:Mutation / Q000235:genetics*; D020294:Myasthenic Syndromes, Congenital / Q000208:ethnology / Q000235:genetics* / Q000503:physiopathology; D011978:Receptors, Nicotinic / Q000235:genetics*
chemical_list: C504423:CHRNE protein, human; D002800:Cholinesterase Inhibitors; D005819:Genetic Markers; D011978:Receptors, Nicotinic