title: Chromosome 17p-linked myasthenias stem from defects in the acetylcholine receptor epsilon-subunit gene.
abstract: OBJECTIVE
  To identify and to characterize functionally the mutational basis of congenital myasthenic syndromes (CMS) linked to chromosome 17p.
  
  
  BACKGROUND
  A total of 37 patients belonging to 13 CMS families, 9 of them consanguineous, were investigated. All patients were linked previously to the telomeric region of chromosome 17p. Two candidate genes in this region encode synaptobrevin 2, a presynaptic protein, and the epsilon-subunit of the acetylcholine receptor (AChR). Direct sequencing of the synaptobrevin 2 gene revealed no mutations. The authors thus searched for mutations in the epsilon-subunit gene of AChR.
  
  
  METHODS
  Direct sequencing of the AChR epsilon-subunit, restriction analysis, allele-specific PCR, and expression studies in human embryonic kidney cells were performed.
  
  
  RESULTS
  The authors identified two previously characterized and five novel epsilon-subunit gene mutations, all homozygous, in the 13 kinships. Two of the novel mutations are truncating (epsilon723delC and epsilon760ins8), one is a missense mutation in the signal peptide region (epsilonV-13D), one is a missense mutation in the N-terminal extracellular domain (epsilonT51P), and one is a splice donor site mutation in intron 10 (epsilonIVS10+2T-->G). Unaffected family members have no mutations or are heterozygous. Expression studies indicate that the four novel mutations in the coding region of the gene and the most likely transcript of the splice-site mutation, which skips exon 10, are low-expressor or null mutations.
  
  
  CONCLUSIONS
  Chromosome 17p-linked congenital myasthenic syndromes are caused by low-expressor/null mutations in the AChR epsilon-subunit gene. Mutations in this gene are a common cause of CMS in eastern Mediterranean countries.
authors.affiliation: Cyprus Institute of Neurology and Genetics, Nicosia.
authors.forename: L
authors.initials: L
authors.lastname: Middleton
authors.forename: K
authors.initials: K
authors.lastname: Ohno
authors.forename: K
authors.initials: K
authors.lastname: Christodoulou
authors.forename: J
authors.initials: J
authors.lastname: Brengman
authors.forename: M
authors.initials: M
authors.lastname: Milone
authors.forename: V
authors.initials: V
authors.lastname: Neocleous
authors.forename: P
authors.initials: P
authors.lastname: Serdaroğlu
authors.forename: F
authors.initials: F
authors.lastname: Deymeer
authors.forename: C
authors.initials: C
authors.lastname: Ozdemir
authors.forename: A
authors.initials: A
authors.lastname: Mubaidin
authors.forename: K
authors.initials: K
authors.lastname: Horany
authors.forename: A
authors.initials: A
authors.lastname: Al-Shehab
authors.forename: I
authors.initials: I
authors.lastname: Mavromatis
authors.forename: I
authors.initials: I
authors.lastname: Mylonas
authors.forename: M
authors.initials: M
authors.lastname: Tsingis
authors.forename: E
authors.initials: E
authors.lastname: Zamba
authors.forename: M
authors.initials: M
authors.lastname: Pantzaris
authors.forename: K
authors.initials: K
authors.lastname: Kyriallis
authors.forename: A G
authors.initials: AG
authors.lastname: Engel
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D002648:Child; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D008040:Genetic Linkage / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D011950:Receptors, Cholinergic / Q000235:genetics*
chemical_list: D011950:Receptors, Cholinergic