129S1;B6J-Syngap1^em1Syngp/Mmjax

Stock number: 039443
Product name: Syngap1-Q503*
Research areas: Developmental Biology Research, Neurobiology Research

Description

Syngap1-Q503* mice express the equivalent of the Q503X patient-derived SYNGAP1-related intellectual disability (SRID) pathogenic variant of the mouse Syngap1 (synaptic Ras GTPase activating protein 1 homolog) gene. The phenotype has not yet been described, but it is anticipated that this knock-in will phenocopy other Syngap1 knock-out model phenotypes (e.g. B6;129-Syngap1^tm1Rlh/J, Stock No. 008890).

Detailed description

SYNGAP1 is a Ras-GTPase activating protein, enriched at excitatory synapses in the brain. Loss-of function de novo mutations in SYNGAP1 (synaptic Ras GTPase activating protein 1) cause SYNGAP1-related intellectual disability (SRID). SRID is considered a spectrum disorder with symptoms that can include seizure, intellectual disability (mild to severe), severe behavioral problems, high pain threshold, hypotonia, eating problems, autism spectrum disorder, and ataxia/gait abnormalities.

Syngap1-Q503* mice carry the equivalent of the patient-derived pathogenic variant p.Q503*. The phenotype of these mice has not yet been described, but it is anticipated that this knock-in will phenocopy other Syngap1 knock-out model phenotypes (e.g. B6;129-Syngap1^tm1Rlh/J, Stock No. 008890). This strain is on a mixed genetic background composed of C57BL/6J and 129S1/SvImJ. The mutation was originally created using C57BL/6J embryos, but animals on the inbred background were found to be very difficult to breed naturally.

Heterozygotes on the mixed background are viable and fertile. Homozygotes exhibit postnatal lethality. By postnatal day 3-4 (P3-P4), homozygotes have reduced body and brain size, show reduced movement, and do not feed.

Development

The equivalent of the human p.Q503*, C>t mutation (Q503X, nucleotide change CAG to TAG) and three upstream silent mutations (TATATGAGACTG > TACATGAGGCTC) were introduced to exon 9 of the mouse Syngap1 gene (ENSMUST00000194598.6) using CRISPR/Cas9 methodologies in C57BL/6J embryos. A 2 bp deletion alters the amino acid sequence at L500 and is predicted to create a stop codon 18 amino acids later in the next exon (Y518X). Resultant mice were backcrossed to C57BL/6J for 2 generations. Due to breeding difficulties on the inbred background, the strain was then backcrossed to 129S1/SvImJ for 1 generation to create a mixed genetic background. Sperm was cryopreserved at The Jackson Laboratory. To establish a live colony, an aliquot of frozen sperm was used to fertilize B6129SF1/J (Stock No. 101043) oocytes. This is founder line 1914.

Allele

Symbol: Syngap1^em1Syngp
Name: endonuclease-mediated mutation 1, SynGAP Research Fund
MGI accession ID: MGI:7705033
Generation method: Endonuclease-mediated
Attributes: Humanized sequence
Marker symbol: Syngap1
Marker name: synaptic Ras GTPase activating protein 1 homolog (rat)
Marker synonyms: MRD5; RASA5; SYNGAP
Chromosome: 17
Strain of origin: C57BL/6J
Molecular note: The equivalent of the human p.Q503*, C>t mutation (Q503X, nucleotide change CAG to TAG) and three upstream silent mutations (TATATGAGACTG > TACATGAGGCTC) were introduced to exon 9 of the mouse Syngap1 gene using CRISPR/Cas9 methodologies in C57BL/6J embryos.