Premium
A missense mutation in canine ClC‐1 causes recessive myotonia congenita in the dog 1
Author(s) -
Rhodes Thomas H.,
Vite Charles H.,
Giger Urs,
Patterson Donald F.,
Fahlke Christoph,
George Alfred L.
Publication year - 1999
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(99)00926-6
Subject(s) - myotonia , missense mutation , myotonia congenita , skeletal muscle , mutation , biology , congenital myasthenic syndrome , genetics , mutant , microbiology and biotechnology , endocrinology , gene , myotonic dystrophy
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, ClC‐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 ClC‐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 ClC‐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.