title: Functional consequences of chloride channel gene (CLCN1) mutations causing myotonia congenita.
abstract: OBJECTIVE
  To determine the functional consequences of missense mutations within the skeletal muscle chloride channel gene CLCN1 that cause myotonia congenita.
  
  
  BACKGROUND
  Myotonia congenita is a genetic muscle disease associated with abnormalities in the skeletal muscle voltage-gated chloride (ClC-1) channel. In order to understand the molecular basis of this inherited disease, it is important to determine the physiologic consequences of mutations found in patients affected by it.
  
  
  METHODS
  The authors used a mammalian cell (human embryonic kidney 293) expression system and the whole-cell voltage-clamp technique to functionally express and physiologically characterize five CLCN1 mutations.
  
  
  RESULTS
  The I329T mutation shifted the voltage dependence of open probability of ClC-1 channels to the right by 192 mV, and the R338Q mutation shifted it to the right by 38 mV. In addition, the I329T ClC-1 channels deactivated to a lesser extent than normal at negative potentials. The V165G, F167L, and F413C ClC-1 channels also shifted the voltage dependence of open probability, but only by +14 to +20 mV.
  
  
  CONCLUSIONS
  The functional consequences of these mutations form the physiologic argument that these are disease-causing mutations and could lead to myotonia congenita by impairing the ability of the skeletal muscle voltage-gated chloride channels to maintain normal muscle excitability. Understanding of genetic and physiologic defects may ultimately lead to better diagnosis and treatment of patients with myotonia congenita.
authors.affiliation: Department of Neurology, University of Utah, Salt Lake City 84112-5331, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: S
authors.initials: S
authors.lastname: Bendahhou
authors.forename: M C
authors.initials: MC
authors.lastname: Sanguinetti
authors.forename: L J
authors.initials: LJ
authors.lastname: Ptácek
mesh_terms: D018118:Chloride Channels / Q000235:genetics* / Q000502:physiology; D006801:Humans; D020125:Mutation, Missense / Q000235:genetics; D009224:Myotonia Congenita / Q000209:etiology* / Q000235:genetics* / Q000503:physiopathology
chemical_list: C086321:CLC-1 channel; D018118:Chloride Channels