title: Three novel COLQ mutations and variation of phenotypic expressivity due to G240X.
abstract: OBJECTIVE
  To determine the molecular basis and consequences of endplate (EP) acetylcholinesterase (AChE) deficiency.
  
  
  BACKGROUND
  The EP species AChE is an asymmetric enzyme consisting of a tail subunit composed of three collagenic strands (ColQ), each attached to a tetramer of catalytic subunits. The tail subunit is essential for insertion of AChE into the synaptic basal lamina. Human EP AChE deficiency is caused by mutations in COLQ. The authors report three novel COLQ mutations in eight kinships.
  
  
  METHODS
  Immunocytochemistry, electron microscopy, microelectrode recordings, mutation analysis, and expression studies in COS cells were employed.
  
  
  RESULTS
  Two mutations (275insC and Q211X) were heterozygous in one patient. EP studies in this patient revealed no EP AChE, small nerve terminals, reduced presynaptic membrane length, as well as abnormally low-evoked quantal release. The third mutation (G240X) was homozygous in six Palestinian Arab families of the same tribe and in an Iraqi Jewish patient. Expression studies of the three mutations in COS cells indicate that each abrogates formation of insertion competent asymmetric AChE. Although the three mutations have identical predicted consequences at the EP, their phenotypic expressivity varies as regards age at onset, rate of progression, and severity of symptoms.
  
  
  CONCLUSIONS
  1) After mutations in the AChR epsilon subunit, mutations in COLQ are emerging as second most common cause of congenital myasthenic syndromes. 2) A founder effect is likely for G240X in the Palestinian Arab families. 3) That mutations predicting total absence of AChE from the EP have variable phenotypic expressivity suggests that modifying genes or environmental factors can partially compensate for EP AChE deficiency.
authors.affiliation: Pediatric Neurology Unit, Hadassah University Hospital, Jerusalem.
authors.forename: Y A
authors.initials: YA
authors.lastname: Shapira
authors.forename: M E
authors.initials: ME
authors.lastname: Sadeh
authors.forename: M P
authors.initials: MP
authors.lastname: Bergtraum
authors.forename: A
authors.initials: A
authors.lastname: Tsujino
authors.forename: K
authors.initials: K
authors.lastname: Ohno
authors.forename: X M
authors.initials: XM
authors.lastname: Shen
authors.forename: J
authors.initials: J
authors.lastname: Brengman
authors.forename: S
authors.initials: S
authors.lastname: Edwardson
authors.forename: I
authors.initials: I
authors.lastname: Matoth
authors.forename: A G
authors.initials: AG
authors.lastname: Engel
mesh_terms: D000110:Acetylcholinesterase / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D000200:Action Potentials / Q000235:genetics; D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics*; D000818:Animals; D019556:COS Cells / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003094:Collagen / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D005998:Glycine / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009045:Motor Endplate / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009124:Muscle Proteins; D009154:Mutation / Q000235:genetics*; D020294:Myasthenic Syndromes, Congenital / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D010641:Phenotype
chemical_list: D009124:Muscle Proteins; D003094:Collagen; D000110:Acetylcholinesterase; C114027:COLQ protein, human; D005998:Glycine