International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)

Oral Presentation

Monday 18 November

09:45 - 10:00 HRS


DA Buchner
University of Michigan

Co-Authors: de Haan G, Kearney JA, Adamska M, Meisler MH
Institutions: Department of Human Genetics, University of Michigan

The voltage-gated sodium channel Scn8a is expressed in neurons of the brain and spinal cord and is concentrated at the nodes of Ranvier in myelinated axons. The hypomorphic allele medJ has a 4 bp deletion within the splice donor site of intron 3. Using a quantitative RT-PCR/Primer extension assay, we determined that 12% of Scn8a transcripts are correctly spliced in medJ brain. medJ homozygotes exhibit a dystonic phenotype and a normal life span. C57BL/6J mice (B6) show an increased susceptibility to the medJ mutation. medJ homozygotes on the B6 background do not survive beyond one month. Only 6% of Scn8a transcripts are correctly spliced in these mice. The molecular mechanism of B6 susceptibility is thus a two-fold reduction in the splicing efficiency of Scn8a. This subtle splicing deficiency may affect the expression of other genes and the severity of other mutants on the B6 background. The inter-strain phenotypic variation was mapped in > 2,000 meioses to a 950 kb interval on mouse chromosome 3. One gene in this interval, designated Htm, has homology to a U1-like zinc finger domain, often found in splice factors, and contains a nuclear localization signal. Strain B6 has a nonsense mutation in Htm that truncates the C-terminal 42 amino acids. Transgenic rescue experiments are in progress to test whether Htm is the sodium channel modifier gene.

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