Scn8a9J offers a viable model for study of SCN8A involved diseases. This single amino acid deletion causes a less severe phenotype than the Scn8amed-J allele and much less severe than a targeted null allele. Approximately half of homozygotes survive to six months of age.Read More +
This hypomorphic allele is less severe than the Scn8amed-J allele. Homozygotes develop an early onset tremor, lurching gait, muscle weakness, dystonia, and premature death, but disease progression is slower than in Scn8amed-J homozygotes. Although this allele arose spontaneously on the BALB/cJ background it was characterized most extensively on a C57BL/6J congenic background, which permitted direct comparison with other alleles of this gene. On the C57BL/6J congenic background homozygotes develop tremor and ataxia between 2 and 3 weeks of age. The body weight is approximately 30% less than normal, and grip strength reduced by approximately 50%. Although convulsive seizures have not been observed in either heterozygotes or homozygotes, homozygotes have an unsteady, spread-legged, trembling gait. Dystonia is evident by approximately 6 months of age and becomes more severe with age. Nearly half of homozygotes are dead before 6 months of age, only 10% live beyond 8 months, only 5% live beyond 11 months, and a few homozygotes have lived up to 18 months. This is distinct from homozygotes of a null allele, which causes pre-wean death, and therefore Scn8a9J offers a viable model for study of SCN8A involved diseases. Heterozygotes are viable and fertile and appear to behave normally in the open field test in a familiar environment, but display reduced distance traveled in an unfamiliar environment.
This mutant SCN8A protein has severely reduced channel activity and altered localization. Cerebellar Purkinje neurons from homozygotes assessed at five weeks of age showed diminished spontaneous and induced repetitive firing. The conduction velocity of the sciatic-tibial nerve and sural nerve were both found to be reduced by approximately 50% in homozygotes. Immunohistochemistry found that SCN8A in homozygotes has reduced expression at nodes of Ranvier in optic nerves, and is not detectable at the axon initial segment of cortical neurons. However, immunohistochemistry of the neuromuscular junctions of the extensor digitalis longus muscle of the hind limb and the diaphragm muscle at one year of age found no abnormalities; the number of neuromuscular junctions, proportion normally innervated, proportion denervated, and morphology were comparable to those of wild type controls.
The Scn8a9J mutation arose spontaneously on the BALB/cJ inbred background at The Jackson Laboratory and was maintained coisogenic on this background. Sperm was cryopreserved from heterozygous males after 10 generations of sibling intercrossing.
|Allele Name||9 Jackson|
|Allele Type||Spontaneous (Hypomorph)|
|Gene Symbol and Name||Scn8a, sodium channel, voltage-gated, type VIII, alpha|
|Strain of Origin||BALB/cJ|
|Molecular Note||Failed complementation test proved this an allele of Scn8a. A 3 base pair deletion c.5248_5250delATC was identified in the final exon of the gene. This in-frame deletion removes isoleucine codon 1750 in transmembrane segment DIVS6. Deletion of isoleucine 1750 alters the secondary structure of the distal half of the alpha-helix in transmembrane segment DIVS6. Glycosylation of the mutant protein is limited to core glycosylation for a molecular weight of 240 kDa instead of the wild type 260 kDa.|
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