title: A missense mutation in canine C1C-1 causes recessive myotonia congenita in the dog.
abstract: 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.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: T H
authors.initials: TH
authors.lastname: Rhodes
authors.forename: C H
authors.initials: CH
authors.lastname: Vite
authors.forename: U
authors.initials: U
authors.lastname: Giger
authors.forename: D F
authors.initials: DF
authors.lastname: Patterson
authors.forename: C
authors.initials: C
authors.lastname: Fahlke
authors.forename: A L
authors.initials: AL
authors.lastname: George
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015152:Blotting, Northern; D018118:Chloride Channels / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers; D004195:Disease Models, Animal; D004285:Dogs; D004594:Electrophysiology / Q000379:methods; D005808:Genes, Recessive; D006720:Homozygote; D008715:Methionine; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000473:pathology / Q000502:physiology; D020125:Mutation, Missense; D009224:Myotonia Congenita / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction / Q000379:methods; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013912:Threonine
chemical_list: C086321:CLC-1 channel; D018118:Chloride Channels; D017931:DNA Primers; D011994:Recombinant Proteins; D013912:Threonine; D008715:Methionine