Disease relevance of Scn8a

• Mice with different mutant alleles of Scn8a provide models of the movement disorders ataxia, dystonia, tremor and progressive paralysis [1].
• The mouse neurological mutant 'motor endplate disease' (med) is characterized by early onset progressive paralysis of the hind limbs, severe muscle atrophy, degeneration of Purkinje cells and juvenile lethality [2].
• Motor end-plate disease (med), in the mouse, is a hereditary neuromuscular defect, caused by a single gene mutation and characterized by a progressive muscle weakness. +Med/+med mice die 21-23 days after birth and the neurobiological abnormalities already reported are nerve terminal sprouting and swelling and neurotransmission failures [3].
• At 7 months of age, however, Plp/- mice exhibit severe demyelination and oligodendrocyte cell death, leading to a profound reduction in Nav1.6 clusters, loss of the paranodal axoglial apparatus, and a marked increase in Nav1 [4].
• In most type I ganglion cells, Nav1.6 was present at the first nodes flanking the myelinated bipolar cell body and at subsequent nodes of Ranvier [5].

High impact information on Scn8a

• Mutation of a new sodium channel gene, Scn8a, in the mouse mutant 'motor endplate disease' [2].
• Scn8a is expressed in brain and spinal cord but not in skeletal muscle or heart, and encodes a predicted protein of 1,732 amino acids [2].
• Expression of CD69, an early activation marker, is first observed on a minority of cells at the T cell receptor (TCR)lo/med double-positive stage, is maximal (50-90%) on heat-stable antigen (HSA)hi TCRhi double-positive, HSAhi TCRmed CD4+8lo, and HSAhi TCRhi CD4+8- cells, and is downmodulated at the mature HSAlo CD4+8- stage [6].
• Sodium currents and action potentials were characterized in Purkinje neurons from ataxic mice lacking expression of the sodium channel Scn8a [7].
• In jolting mice, with a missense mutation in Scn8a, steady-state and resurgent current were also reduced, with altered voltage dependence and kinetics [7].

Biological context of Scn8a

• We previously reported that the phenotype of the hypomorphic allele of Scn8a, medJ, is dependent upon an unlinked modifier locus, Scnm1 [1].
• Dystonia associated with mutation of the neuronal sodium channel Scn8a and identification of the modifier locus Scnm1 on mouse chromosome 3 [8].
• Our results suggest that at least a portion of the dmu phenotype is caused by a down-regulation of Scn8a, making dmu a new allele of Scn8a [9].
• The generation of three independent Scn8a mutations among 1100 tested G3 families demonstrates that the Scn8a locus is highly susceptible to ENU mutagenesis [10].
• We also recorded non-sodium currents from Purkinje cells of both genotypes to test whether the Scn8a mutation induced changes in other ion channels [11].

Anatomical context of Scn8a

• Scn8a encodes an abundant, widely distributed voltage-gated sodium channel found throughout the central and peripheral nervous systems [1].
• A shift in the threshold of the Scn8a channel could account for the reduced spontaneous activity of Purkinje cells, reduced inhibitory output from the cerebellum, and loss of motor control observed in jolting mice [12].
• To examine the functional characteristics of this channel, we constructed a full-length cDNA clone encoding the mouse Scn8a sodium channel and expressed it in Xenopus oocytes [13].
• Reduced spontaneous activity in the dorsal cochlear nucleus of Scn8a mutant mice [14].
• Our data supports the hypothesis that the lack of expression of Nav1.6 in Schwann cells at neuromuscular junctions might play a role in the med phenotype [15].

Associations of Scn8a with chemical compounds

• Intron 2 of Scn8a is flanked by minor class AT-AC splice sites [16].
• A mutation of alanine to threonine in the III S4-S5 linker of the mouse Scn8a sodium channel has previously been identified as causing the ataxia in med(jo) mice [17].
• Paranodal axoglial junction is required for the maintenance of the Nav1.6-type sodium channel in the node of Ranvier in the optic nerves but not in peripheral nerve fibers in the sulfatide-deficient mice [18].
• 1. Experiments using intracellular recording, stimulation, and microionophoretic techniques were performed on extensor digitorum longus nerve-muscle preparations excised from mice having hereditary 'motor end-plate disease'. Control experiments were performed on normal innervated and chronically denervated nerve-muscle preparations [19].
• Is resurgent Na+ current an alpha-subunit-specific property? Maybe not. Focus on "Sodium currents in subthalamic nucleus neurons from Nav1.6-null mice" [20].

Other interactions of Scn8a

• Using fluorescence in situ hybridization (FISH), the Mgat3 gene was regionally mapped to chromosome 15E11, near the Scn8a sodium channel gene at 15F1 [21].
• Analysis of a transgene-induced mutation at the mouse med locus led to the identification of the novel voltage-gated sodium channel gene Scn8a (Burgess, D. L., Kohrman, D. C., Galt, J., Plummer, N. W., Jones, J. M., Spear, B., and Meisler, M. H.(1995) Nat. Genet. 10, 461-465) [16].
• This reduction was not an unspecific consequence of muscle disease, as it was not observed in two other neuromuscular mouse mutants, "wobbler" (wr) and "motor endplate disease" (med or medjo) [22].
• Synaptotagmin 1 and contactin 1 were eliminated as candidate genes for the med mutation [23].
• Coexpression of the beta1 and beta2 subunits modulated the properties of Scn8a channels, but to a lesser extent than for the Rat1 or Rat2 channels [13].

Analytical, diagnostic and therapeutic context of Scn8a

• Denervation was functional, rather than structural, since the Scn8a mutation was not accompanied by retraction of neuromuscular contacts, motoneuron death, or decreased motoneuron soma diameter [24].
• Using fluorescent in situ hybridization (FISH), immunofluorescence, and confocal microscopy, we detected the neuronal Nav1.6 sodium channel transcripts and proteins in TSCs in normal adult rats and mice [15].
• Nerve transplantation shows that motor end-plate disease is not a primary Schwann cell defect [25].
• NaCh6 mRNA and protein were not detected in either brain or spinal cord at E15 and E18 by in situ hybridization and immunohistochemistry [26].

References