B6C3Fe a/a-Krt71^Ca Scn8a^med-J/J

Stock number: 000304
Product name: motor end plate disease Jackson
Research areas: Cell Biology Research, Dermatology Research, Immunology, Inflammation and Autoimmunity Research, Neurobiology Research

Description

These mice carry a spontaneous mutation at the Scn8a locus characterized by progressive skeletal muscle weakness, progressive atrophy of skeletal muscle, and terminal sprouting of motor nerves. The strain also carries Krt71^Ca (caracul) that produces curved vibrissae and wavy hair in young mice.

Detailed description

Mice homozygous for the motor end plate disease-Jackson spontaneous mutation (Scn8a^med-J) have a phenotype that resembles the original mutation (Scn8a^med). Homozygous motor end plate disease mutant mice show progressive skeletal muscle weakness beginning 8 to 10 days postnatally and usually die within 2 weeks of onset. Other disease characteristics include progressive atrophy of skeletal muscle, marked terminal sprouting of motor nerves along with slower conduction velocity and prolonged refraction, and eventually failure of muscle fibers to show end-plate potentials or action potentials in response to nerve stimulation. Heterozygotes may show mild manifestations of the disease during the first 2 weeks of life but symptoms disappear with age. Both homozygotes and heterozygotes exhibit immunological aberrations.

Allele

Symbol: a
Name: nonagouti
MGI accession ID: MGI:1855937
Generation method: Spontaneous
Marker symbol: a
Marker name: nonagouti
Marker synonyms: agouti; agouti signal protein; AGSW; AGTI; AGTIL; As; ASP; SHEP9
Chromosome: 2
Strain of origin: old mutant of the mouse fancy
Molecular note: Characterization of this allele shows an insertion of DNA comprised of a 5.5kb virus-like element, VL30, into the first intron of the agouti gene. The VL30 element itself contains an additional 5.5 kb sequence, flanked by 526 bp of direct repeats (beta4 retroviral sequence). The host integration site is the same as for a^t-2Gso and A^w-38J and includes a duplication of four nucleotides of host DNA and a deletion of 2 bp from the end of each repeat. Northern analysis of mRNA from skin of homozygotes shows a smaller agouti message and levels 8 fold lower than found in wild-type.
General note: Insertion of the LV30 retrotransposon without the beta4 retrovirus sequence does not cause the nonagouti phenotype. J:278039

Allele

Symbol: Krt71^Ca
Name: caracul
MGI accession ID: MGI:1855990
Generation method: Spontaneous
Synonyms: Ca
Marker symbol: Krt71
Marker name: keratin 71
Marker synonyms: Ca; Cal4; Cu; HYPT13; K6IRS1; Krt2-6g; KRT6IRS; KRT6IRS1; mK6irs; mK6irs1
Chromosome: 15
Strain of origin: Swiss stock
Molecular note: Sequence analysis identified the transversion of an C-to-A at coding nucleotide 1292, resulting in an alanine to aspartic acid missense mutation at codon 431 (p.A431D).

Allele

Symbol: Scn8a^med-J
Name: motor end plate disease Jackson
MGI accession ID: MGI:1856079
Generation method: Spontaneous
Synonyms: med^J; seal
Marker symbol: Scn8a
Marker name: sodium channel, voltage-gated, type VIII, alpha
Marker synonyms: ataxia 3; BFIS5; C630029C19Rik; CERIII; CIAT; DEE13; EIEE13; med; mnd2; mnd-2; motor end-plate disease; MYOCL2; NaCh6; Nav1.6; nmf2; nmf335; nmf58; nur14; PN4; seal
Chromosome: 15
Strain of origin: STOCK Krt71^Ca
Molecular note: A 4-base pair deletion within the 5' donor site of exon 3 results in splicing from exon 1 to exon 4. The mutant transcript has an altered reading frame with premature stop codon close to the N terminus of the protein. A very low level of correctly spliced transcripts has been detected.
General note: This Scn8a^med remutation occurred at The Jackson Laboratory on the same chromosome as the very closely linked gene Krt71 in a stock carrying a mutation in that gene (J:6191). Homozygotes resemble Scn8a^med homozygotes. Heterozygotes may show mild manifestations of the disease during the first 2 weeks but they recover. Both homozygotes and heterozygotes exhibit immunological aberrations: reduced PFC response to sheep red blood cells in 14- to 16-day old mice, with reduced suppressor cell function and precocious maturation of the cytotoxic response to allogeneic cells at 21 to 23 days. The reduction in the PFC response disappears in older heterozygotes but remains in the few homozygotes that survive beyond 6 weeks of age (J:6824). The molecular defect in Scn8a is a 4 bp deletion in the splice donor site of exon 3 that causes exon skipping and protein truncation (J:34154). A very low level of correctly spliced transcripts has been detected, indicating that Scn8a^med-J is a severe hypomorph (J:53340). The modifier locus Scnm1 on chromosome 3 influences the phenotype of homozygotes for the Scn8a^med-J allele (J:53340). C57BL/6J mice carry the susceptible allele of Scnm1 which results in juvenile death. Other inbred strains carry a resistant allele and on these strains, homozygotes exhibit muscle weakness and dystonia.