Species: Mouse
Genes: Trem2
Mutations: TREM2 R47H
Modification: Trem2: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: B6.Cg-Trem2^em4Adiuj/J
Genetic Background: C57BL/6J
Availability: Register interest at The Jackson Laboratory, Stock No. 033781.

Summary

R47H is a rare variant in TREM2 that triples the risk of Alzheimer’s disease in heterozygous carriers. In order to study the effects of this variant, several mouse models were created in which the R47H mutation was introduced into the mouse Trem2 gene (Trem2 R47H KI (JAX), Trem2 R47H KI (Haass), Trem2 R47H KI (Lamb/Landreth)). Unfortunately, these early R47H knock-in mice had decreased expression of Trem2, unlike human carriers of the R47H mutation. This difference in expression was traced to aberrant splicing of the mutant allele (Xiang et al., 2018; see Sep 2018 news): Introduction of the R47H point mutation into the mouse Trem2 sequence created a cryptic splice acceptor site in exon 2, generating a transcript with a premature stop codon subject to nonsense-mediated decay.

The Trem2*R47H^HSS line—for “humanized splice site”—was created to correct the problem of aberrant splicing of the mouse Trem2 gene. CRISPR/Cas9 was used to edit the mouse Trem2 gene, introducing the R47H point mutation and humanizing the cryptic splice acceptor site in exon 2. RNA-Seq confirmed that truncated transcripts were not expressed and that levels of Trem2 mRNA were normal.

Modification Details

CRISPR/Cas9 was used to edit the mouse Trem2 locus in the Trem2 R47H KI (JAX) model (JAX #27918), “humanizing” the cryptic splice acceptor site in exon 2 in the context of the existing R47H point mutation and two silent mutations.

Phenotype Characterization

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References

Research Models Citations

1. Trem2 R47H KI (JAX)
2. Trem2 R47H KI (Haass)
3. Trem2 R47H KI (Lamb/Landreth)

News Citations

1. Model Morass? R47H Mutation Scuttles TREM2 Expression in Mice, Not People 13 Sep 2018

Paper Citations

1. Xiang X, Piers TM, Wefers B, Zhu K, Mallach A, Brunner B, Kleinberger G, Song W, Colonna M, Herms J, Wurst W, Pocock JM, Haass C. The Trem2 R47H Alzheimer's risk variant impairs splicing and reduces Trem2 mRNA and protein in mice but not in humans. Mol Neurodegener. 2018 Sep 6;13(1):49. PubMed.

External Citations

1. The Jackson Laboratory, Stock No. 033781

Further Reading

No Available Further Reading