A missense mutation in canine C1C-1 causes recessive myotonia congenita in the dog.
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.
Rhodes
T H
TH
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Vite
C H
CH
Giger
U
U
Patterson
D F
DF
Fahlke
C
C
George
A L
AL
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
C086321:CLC-1 channel; D018118:Chloride Channels; D017931:DNA Primers; D011994:Recombinant Proteins; D013912:Threonine; D008715:Methionine