This targeted mutation of the sodium channel, voltage-gated, type IV, alpha (Scn4a) gene displays myotonia, muscle fiber type switching and potassium-sensitive weakness and may be useful in studies of myotonia, vacuolar myopathy and hyperkalemic periodic paralysis (HyperKPP).
Lawrence J Hayward, University of Massachusetts Medical School
Most homozygous mice die before 30 days, although a few live longer. Homozygotes appear smaller, have difficulty feeding, and exhibit an accelerated myopathy characterized by increased fiber size variation and vacuolar structures within muscle fibers. Mice heterozygous for the mutation exhibit continuous myotonia of skeletal muscles, progressive age-related myopathy, reduced contractile force, delayed relaxation and potassium sensitive skeletal muscle weakness. A switch from a mixture of glycolytic and oxidative muscle fibers to an increased number of oxidative fibers is observed in multiple muscle types. The donating investigator reports that the Scn4atm1.1Ljh allele (neo out) has the same phenotype as the Scn4atm1Ljh allele (neo in) reported in Hayward et al, 2009. This mutant strain may be useful in studies of myotonia, vacuolar myopathy and hyperkalemic periodic paralysis (HyperKPP).
In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. It should be noted that the phenotype could vary from that originally described. We will modify the strain description if necessary as published results become available.
A targeting vector was designed to create a missense substitution corresponding to the human HyperKPP mutation in the murine Scn4a cDNA sequence. The mutation changes a methionine to a valine at amino acid position 1592 in exon 24 (M1592V). A loxP-flanked PGKneo cassette was also inserted within intron 23. The construct was electroporated into 129S4/SvJae-derived J1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. The neomycin cassette was removed by transient transfection with a Cre recombinase expressing plasmid leaving a single loxP site downstream of exon 23. The resulting chimeric animals were crossed to C57BL/6 mice for several generations and then to FVB for a minimum of 10 generations.
|Allele Name||targeted mutation 1.1, Lawrence J Hayward|
|Gene Symbol and Name||Scn4a, sodium channel, voltage-gated, type IV, alpha|
|Promoter||Scn4a, sodium channel, voltage-gated, type IV, alpha, mouse, laboratory|
|Strain of Origin||129S4/SvJae|
|Molecular Note||The targeting vector inserts a missense substitution changing a methionine to a valine at amino acid position 1592 (M1592V) in exon 24 and a loxP flanked neo cassette in intron 23. The neo cassette is removed by transient infection with a Cre recombinase expressing plasmid leaving a single loxP site downstream of exon 23.|
|Mutations Made By|| |
Lawrence Hayward, University of Massachusetts Medical School
While maintaining a live colony, these mice are bred as heterozygotes. Mice homozygous for the mutation die by two months of age.
When using the FVB.129S4(B6)-Scn4atm1.1Ljh/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #011033 in your Materials and Methods section.
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