B6129S-Syngap1^em1Rlh/Mmjax

Stock number: 038460
Product name: Syngap1^L813Rfsx22
Research areas: Developmental Biology Research, Neurobiology Research, Research Tools

Description

Syngap1^L813RfsX22 mice have a frameshift mutation resulting in a premature stop codon in the Syngap1 [synaptic Ras GTPase activating protein 1 homolog (rat)] gene. Heterozygous mice display impaired synaptic plasticity, hyperactivity, and impaired working memory. This strain may be useful in studies of SRID (SYNGAP1-related intellectual disability).

Of note, mice with another patient-derived Syngap1 mutation (c.3583-9G>A) is distributed as B6;129-Syngap1^em2Rlh/Mmjax, MMRRC No. 071392).

Detailed description

Syngap1 [synaptic Ras GTPase activating protein 1 homolog (rat)] encodes a synaptic RasGAP (SynGAP) that is largely localized to dendritic spines in neocortical pyramidal neurons, where it suppresses signaling pathways linked to NMDA receptor (NMDAR)-mediated synaptic plasticity and AMPA receptor (AMPAR) membrane insertion. Syngap1 has alternative transcriptional start sites and several alternatively spliced C-terminal exons that result in many possible SynGAP isoforms. Mutations in SYNGAP1 are associated with neurodevelopmental disorders, specifically SRID (SYNGAP1-related intellectual disability). SRID is characterized by cognitive impairment, social deficits, early-onset seizures and sleep disturbances.

The Syngap1^L813RfsX22 allele has a 1 bp deletion in codon 813 resulting in a frameshift mutation leading to a premature stop codon. The L813RfsX22 mutation was identified in a human patient with developmental delays, intellectual disability and epilepsy. Mice heterozygous for the mutation have a 50% reduction in SYNGAP protein. In addition, heterozygous Syngap1^L813RfsX22 mice exhibit deficits in theta-burst stimulated induced long term potentiation and decreased spontaneous alternations and increased repetitive arm visits in the Y maze. Heterozygous mice are viable and fertile, the donating investigator indicates that in homozygotes postnatal lethality occurs in 3-5 days.

Of note, mice with another patient-derived Syngap1 mutation (c.3583-9G>A) is distributed as B6;129-Syngap1^em2Rlh/Mmjax, MMRRC No. 071392).

Development

CRISPR/cas9 endonuclease-mediated genome editing was used to delete a single base at c.2438 (T) creating a frameshift mutation, L813Rfsx22, in exon 15 of the Syngap1 [synaptic Ras GTPase activating protein 1 homolog (rat)] on chromosome 17. gRNA (GAGCTGCTCGTGCAGTATGC), homology directed repair DNA oligos and cas9 endonuclease were introduced into C57BL/6-EZ-derived one cell stage zygotes. Embryos were transferred to pseudopregnant females, and correctly targeted pups were bred to C57BL/6J mice for germline transmission. The deletion was confirmed by sequencing and Southern blot. Mice were backcrossed to C57BL/6J for at least three generations and then crossed with 129 mice. The colony is maintained as a cross to B6129SF1/J. Upon arrival, sperm was cryopreserved. To establish our live colony, an aliquot of frozen sperm was used to fertilize B6129SF1/J (Stock No. 101043) oocytes.

Allele

Symbol: Syngap1^em1Rlh
Name: endonuclease-mediated mutation 1, Richard Huganir
MGI accession ID: MGI:7514997
Generation method: Endonuclease-mediated
Attributes: Null/Knockout
Synonyms: Syngap1^L813Rfsx22
Marker symbol: Syngap1
Marker name: synaptic Ras GTPase activating protein 1 homolog (rat)
Marker synonyms: MRD5; RASA5; SYNGAP
Chromosome: 17
Strain of origin: C57BL/6
Molecular note: CRISPR/cas9 endonuclease-mediated genome editing is used to delete a single base at c.2438 (T) creating a frameshift mutation, L813Rfsx22, in exon 15. The deletion was confirmed by sequencing and Southern blot.