Mutations: TREM2 R47H
Modification: Trem2: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: B6.Cg-Trem2em4Adiuj/J
Genetic Background: C57BL/6J
Availability: Register interest at The Jackson Laboratory, Stock No. 033781.
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*R47HHSS 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.
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.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Neuronal Loss
- Synaptic Loss
- Changes in LTP/LTD
- Cognitive Impairment
Changes in LTP/LTD
Last Updated: 22 Jul 2021
Research Models Citations
- 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.
No Available Further Reading