These mice carry an ENU-induced mutation shown to be a new allele of Scn8a and characterized by bilateral hind limb paralysis and early mortality.
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Mice develop bilateral hind limb paralysis between 14-22 days (average onset 16.9 +/- 2.1 days) followed by death between 3-4 weeks of age. Mutants of either gender have been produced.
A complementation test between NMF5 and C3HeB/FeJ-Scn8med-J (JR#3798) revealed that the motor phenotype of NMF5 represents a new allele of Scn8a, which encodes a type VIII voltage-gated sodium channel alpha polypeptide. Affected mice were found in each of 3 litters from heterozygote matings (NMF5 x Scn8med-J). Of the 25 mice born, 28% were affected (4/8, 1/9, 2/8, litters 1-3, respectively). Additional complementation tests showed NMF5 to be an allele of NMF58, and recent sequencing data confirmed the allelic relationship of NMF58 and Scn8a, and therefore of NMF5 and Scn8a (Mammalian Genome, 15,4, 2004).
However, we note that the retinal phenotype detected in NMF5 has not been reported for any Scn8a allele. To determine whether the retinal phenotype was caused by a closely-linked but independent recessive mutation, we attempted to separate the two mutations by genetic recombinantion. Nineteen F2 intercross progeny from C57BL/6J-Scn8anmf5 and A.B6-Tyr+ mice were genotyped for Scn8a and two flanking markers, D15Mit43 and D15Mit246, to detect mice carrying recombinant chromosomes in the Scn8a region. Individual recombinants were subsequently analyzed histologically. Although the two phenotypes were concordant in an Scn8anmf5/+ mouse carrying a recombination event between D15Mit43 and Scn8a, the retinal layer defect was detected in a mouse carrying a recombination event between Scn8a (heterozygous) and the telomeric marker D15Mit246 (homozygous B6-Scn8anmf5-like). These data suggest that the retinal phenotype is caused by a recessive mutation that maps approximately 3.0cM telomeric to Scn8a.
Standard pathology work-up on 6 mutants and 2 unaffected mice (12-40 days of age) showed no apparent defects in PNS or muscle. The ventricles of the brain were enlarged; mild hydrocephalus was observed in 7 of 8 mice examined. A paucity of granule cells was observed in small areas of the cerebellum. Additional muscle histology showed no evidence of atrophy, regeneration or abnormalities in the neuromuscular junction. The outer layer of the retina was thin (normal retina), consisting of 6-7 rather than the expected 11 cell layers in all 8 mice.
Homozygotes are not viable so that a colony has to be maintained through heterozygote matings and ovarian transplants.
This phenotypic deviant was generated by ethylnitrosourea (ENU) mutagenesis in C57BL/6J males (Stock No. 000664), in the Neuroscience Mutagenesis facility at The Jackson Laboratory. Mutagenized males were crossed to C57BL/6J females; G3 descendants of the mutagenized males were selected for neurological impairment.
|Allele Name||5 Jackson|
|Allele Type||Chemically induced (ENU)|
|Allele Synonym(s)||neuroscience mutagenesis facility, 5; NMF5; Scn8anmf5|
|Gene Symbol and Name||Scn8a, sodium channel, voltage-gated, type VIII, alpha|
|Strain of Origin||C57BL/6J|
|Molecular Note||This phenotypic mutant was identified in an ENU mutagenesis screen. A complementation test between nmf5 and C3HeB/FeJ-Scn8amed-J revealed that nmf5 is a new allele of Scn8a. Molecular sequence analysis revealed that an A-to-T transversion mutation had occurred that is predicted to change the amino acid isoleucine 1392 to phenylalanine in the encoded protein. This conserved residue is within the S5-S6 pore loop of transmembrane domain 3.|