B6.Cg-Scn8a^em2Mm/J

Stock number: 041752
Product name: Scn8a^R1872W conditional
Strain synonyms: Scn8a^cond
Research areas: Cell Biology Research, Mouse/Human Gene Homologs, Neurobiology Research, Research Tools

Description

Scn8a^R1872W conditional mice express a Cre-inducible clinical mutation (R1872W) in the Scn8a gene. These mice may be useful for studying epileptic encephalopathy.

Detailed description

Scn8a encodes the alpha subunit of the voltage-gated, type VIII sodium channel (SCN8A) involved in generation and propagation of action potentials in neurons. Gain of function mutations are associated with epileptic encephalopathy, while loss of function mutations may lead to developmental delay, tremor and ataxia. Scn8a^R1872W conditional knock-in (KI) mice have endogenous exon 26 of the Scn8a gene replaced with a loxP-flanked wild-type exon 26 (26a) followed by a modified exon 26 (26b) harboring the clinical gain-of-function R1872W mutation. Prior to Cre-mediated recombination, these mice will express wildtype Snc8a, while after exposure to Cre recombinase they will express the mutant Scn8a^R1872W allele.

Heterozygous and homozygous Scn8a^R1872W conditional KI mice are viable and fertile with no overt phenotype. When bred to mice that express tissue-specific Cre recombinase, resulting offspring will have wildtype exon26a deleted and only the mutant exon 26b, carrying the R1872W mutation, expressed in the cre-expressing tissues. When these Scn8a^R1872W conditional KI mice are bred to an EIIa-Cre mouse line (Stock No. 003724), resulting Scn8a^R1872W/+;E2a-Cre progeny demonstrated severe early onset seizures with a median survival of ~2 weeks (P15). The donating laboratory also bred these Scn8a^R1872W conditional KI mice to an Emx1-Cre mouse line (Stock No. 005628) and found that expression of the mutant Scn8a^R1872W allele in excitatory neurons lead to seizure activity and median survival between 1-2 months of age (PMID: 30601941). These mice may be useful for studying epileptic encephalopathy and respective therapies, as well as neuron-specific expression of the mutant gain-of-function allele.

Of note, sequence analysis completed by The Jackson Laboratory (July 2026) indicates that the mutation in this allele is R1870W based on the Ensembl canonical transcript (ENSMUST00000201549.5 Scn8a-213).

Development

Scn8a^R1872W conditional knock-in (KI) allele was generated by TALEN-based genome editing, replacing endogenous exon 26 of the sodium channel, voltage-gated, type VIII, alpha (Scn8a) gene with a loxP-flanked wild-type exon 26 (26a) followed by a modified exon 26 (26b) with the amino acid substitution of arginine to tryptophan at position 1872 (R1872W, CGG>TGG). The knocked-in exons 26a and 26b also contain eight synonymous nucleotide substitutions for protection against TALEN digestion. TALEN mRNAs were introduced by pronuclear injection into (C57BL/6JXSJL)F2 blastocysts. Resulting founder mice were screened for the targeted mutation by Southern blotting and long range junction PCR. Correctly targeted founder mice were crossed to C57BL/6 mice to confirm germline transmission and the line was further backcrossed to C57BL/6J for more than 20 generations by the donating laboratory. Upon arrival at The Jackson Laboratory, sperm was cryopreserved. To establish our live colony, an aliquot of frozen sperm was used to fertilize C57BL/6J (Stock No. 000664) oocytes.

Of note, sequence analysis completed by The Jackson Laboratory (July 2026) indicates that the mutation in this allele is R1870W based on the Ensembl canonical transcript (ENSMUST00000201549.5 Scn8a-213).

Allele

Symbol: Scn8a^em2Mm
Name: endonuclease-mediated mutation 2, Miriam Meisler
MGI accession ID: MGI:5910126
Generation method: Endonuclease-mediated
Attributes: Conditional ready (e.g. floxed)
Synonyms: Scn8a^Arg1872Trp; Scn8a^cond; Scn8a^R1872W
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: (C57BL/6J x SJL/J)F2
Molecular note: TALEN-targeting replaced exon 26 with a floxed wild-type exon 26 and a modified exon 26 with the amino acid substitution of arginine to tryptophan at position 1872 (R1872W).