B6.129S4(SJL)-Grn^tm2.1Far/J

Stock number: 029919
Product name: Grn^R493X
Research areas: Developmental Biology Research, Neurobiology Research

Description

This Grn^R493X/R493X mouse model is useful for studying frontotemporal dementia (FTD).

Detailed description

Grn^R493X/R493X mice contain a R504X mutation, homologous to the GRN^R493X mutation observed in genetic studies of frontotemporal dementia (FTD). The Grn (granulin) gene encodes a secreted protein (progranulin) expressed by many cell types including neurons, microglia, macrophages, epithelial cells, and adipocytes. It is involved in tumorigenesis, angiogenesis, wound healing, neuronal outgrowth and survival, and inflammation. Mutations in progranulin are causative for FTD, a neurological disease characterized by atrophy of the frontal and anterior temporal brain lobes. Individuals with FTD display personality, behavior, and language abnormalities.

Grn^R493X/R493X mice are viable and fertile. mRNA levels are 90% reduced in these mice, and truncated progranulin R493X protein is not detectable. Mice exhibit central nervous system microgliosis and lipofuscinosis, hyper-inflammatory macrophages, excessive grooming behavior, and 30% reduced mean survival.

Development

A targeting construct was designed to insert a loxP- and frt-flanked neomycin (neo) resistance cassette downstream of coding region of the granulin (Grn) gene. A point mutation was introduced in exon 11 resulting in a nonsense mutation, R504X, analogous to the human mutation R493X, commonly associated with frontotemporal dementia (FTD). This targeting construct was electroporated into 129S4/SvJae-derived RF8 embryonic stem (ES) cells and correctly targeted ES cells were injected into C57BL/6J blastocysts. Chimeric mice were bred to C57BL/6J mice for 8 generatiosn, and offspring were bred to B6.Cg-Tg(ACTFLPe)9205Dym/J mice (Stock No. 005703) to remove the neo cassette. Resulting Grn^R493X mice were bred together to remove the Flp-expressing transgene. 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 oocytes (Stock No. 000664).

Allele

Symbol: Grn^tm2.1Far
Name: targeted mutation 2.1, Bob Farese
MGI accession ID: MGI:5811645
Generation method: Targeted
Attributes: Humanized sequence
Synonyms: Grn^R493X
Marker symbol: Grn
Marker name: granulin
Marker synonyms: acrogranulin; CLN11; epithelin; GEP; GP88; PC cell-derived growth factor; PCDGF; PEPI; Pgrn; progranulin
Chromosome: 11
Strain of origin: 129S4/SvJae
Molecular note: The targeting construct is designed to insert a loxP- and an FRT-flanked neomycin (neo) resistance cassette downstream of coding region of the gene. Additionally, a nonsense mutation, R504X, is introduced in to exon 11. The mutation is analogous to the human mutation, R493X, and is commonly associated with frontotemporal dementia (FTD). Flp-mediated recombination removed the FRT-flanked neo cassette.