MYOTONIA CONGENITA IN MINIATURE SCHNAUZERS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In the Miniature Schnauzer dog, a mutation in the CIC-I chloride channel is responsible for autosomal recessive myotonia congenita. The mutation results in replacement of a threonine residue in the D5 transmembrane segment with methionine. A colony of affected and heterozygote dogs has been established and eight affected dogs have been examined. Affected dogs exhibited a delay in skeletal muscle relaxation following stimulation, diffuse skeletal muscle hypertrophy, stridor, an abnormal bark, and a stiff, stilted gait that improves with exercise. Dental abnormalities including disoclusion, delayed dental eruption of both deciduous and permanent dentitions, delayed dental exfoliation of the primary teeth, and unenipted or partially erupted permanent teeth have been documented. In no other animals affected with myotonia congenita have such dental abnormalities been described. Clinical and electrophysiological signs are first apparent at 5 weeks of age. Heterozygous dogs showed no clinical or electrophysiological signs of disease. Two affected dogs were treated with procainamide from 4 weeks of age onward; treated dogs showed amelioration of muscle stiffness and of dental abnormalities as adults. We have developed a PCR-based DNA test for myotonia congenita in collaboration with Dr. Alfred L. George, Jr , Director, Division of Genetic Medicine, Vanderbilt University. Either blood or cheek swabs from miniature schnauzers were obtained from the various states in the US, Canada, and other countries. DNA was extracted and the segment around the site of the mutation was amplified with species-specific primers. The 340 by PCR product was digested then with Hpy CH4 III, a restriction enzyme that cuts the normal allele twice resulting in fragments of 175, 135, and 30 bp., while the mutant allele is cut only once resulting in 175 and 165 by fragments. A total of 354 dogs were screened, and 79.1% were found normal, 19.8% were carriers, and L 1% (4 dogs) were affected. The male to female ratio was 1'2 among carriers as well as normal dogs tested. In this biased group of dogs, the mutant allele frequency was 1 1 ¿% Pedigrees were available from 59 carriers and all four affected dogs. One popular sire known to be a carrier was identified as a common ancestor to all of the dogs with a mutant allele. Our recent studies have identified electrical myotonia is present in carrier dogs indicating that heterozygotes show some evidence of disease.