International Mammalian Genome Society

The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

F51 Mapping of the SCNM1 Modifier Locus Responsible for Dystonia in Sodium Channel Deficient Mice and Development of SCN8A Congenic Strains

Leslie K. Sprunger and Miriam H. Meisler. Dept. of Human Genetics, University of Michigan, Ann Arbor, MI 48109-0618

Dystonia is a heterogeneous neurological disorder characterized by involuntary muscle contractions that produce sustained twisting movements and abnormal posturing of the affected body segment(s). In humans, mutations in the torsin A (DYT1) gene and in two enzymes in the dopamine synthesis pathway have been associated with inherited dystonia. We described dystonia in mice homozygous for the medJ allele of the sodium channel gene Scn8a (Sprunger, et al. Hum.Mol.Gen. 8:471-9, 1999). On a hybrid B6C3H background, 60% of medJ homozygotes survive to adulthood and exhibit severe generalized dystonia, ataxia, and tremor. We have mapped a major modifier of the medJ allele to a region on mouse chromosome 3, flanked by D3Mit40 proximally and D3Mit101 distally. Mice that are homozygous C57BL/6J for this interval exhibit the paralytic, juvenile lethal phenotype. One or two copies of a C3H allele in this interval rescues the lethality and results in dystonia. We have generated over 400 affected (C57BL/6J x C3HeB/FeJ)F2-medJ/medJ mice in order to map the modifier gene. We are developing additional markers that are polymorphic between C57BL/6J and C3H to generate a higher resolution map of the modifier interval, using sequences from public databases to design PCR primers for CSGE analysis.

The medJ allele has been maintained at the Jackson Laboratory on a hybrid B6C3H background. We have developed two congenic lines by backcrossing medJ onto C57BL/6J and C3HeB/FeJ, respectively. N10 animals are currently available for each of these lines. These two congenic lines are particularly useful for functional studies. F1 animals can be generated that are homozygous for the medJ allele. Unaffected littermates constitute excellent experimental control animals, since they are genetically homogeneous and identical to the homozygotes except at the Scn8a locus. The F1 medJ homozgyotes are more uniform in size than their F2 counterparts, and survival beyond 4 months of age approaches 100%. The neurologic phenotype of the homozygous medJ F1 mice is identical to that described for F2 dystonic animals.


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