A missense mutation in canine C1C-1 causes recessive myotonia congenita in the dog

FEBS Lett. 1999 Jul 30;456(1):54-8. doi: 10.1016/s0014-5793(99)00926-6.


Myotonia congenita is an inherited disorder of sarcolemmal excitation leading to delayed relaxation of skeletal muscle following contractions. Mutations in a skeletal muscle voltage-dependent chloride channel, CIC-1, have been identified as the molecular genetic basis for the syndrome in humans, and in two well characterized animal models of the disease: the myotonic goat, and the arrested development of righting (adr) mouse. We now report the molecular genetic and electrophysiological characterization of a canine CIC-1 mutation that causes autosomal recessive myotonia congenita in miniature Schnauzers. The mutation results in replacement of a threonine residue in the D5 transmembrane segment with methionine. Functional characterization of the mutation introduced into a recombinant CIC-1 and heterologously expressed in a cultured mammalian cell line demonstrates a profound effect on the voltage-dependence of activation such that mutant channels have a greatly reduced open probability at voltages near the resting membrane potential of skeletal muscle. The degree of this dysfunction is greatly diminished when heterodimeric channels containing a wild-type and mutant subunit are expressed together as a covalent concatemer strongly supporting the observed recessive inheritance in affected dog pedigrees. Genetic and electrophysiological characterization of the myotonic dog provides a new and potentially valuable animal model of an inherited skeletal muscle disease that has advantages over existing models of myotonia congenita.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Blotting, Northern
  • Chloride Channels / genetics*
  • Chloride Channels / metabolism
  • DNA Primers
  • Disease Models, Animal
  • Dogs
  • Electrophysiology / methods
  • Genes, Recessive
  • Homozygote
  • Methionine
  • Molecular Sequence Data
  • Muscle, Skeletal / pathology
  • Muscle, Skeletal / physiology
  • Mutation, Missense*
  • Myotonia Congenita / genetics*
  • Pedigree
  • Polymerase Chain Reaction / methods
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Threonine


  • CLC-1 channel
  • Chloride Channels
  • DNA Primers
  • Recombinant Proteins
  • Threonine
  • Methionine

Associated data

  • GENBANK/AF162445