Trem2*R47HHSS mice carry a CRISPR/Cas9-generated Trem2 mutant allele containing an R47H point mutation and the cryptic splice acceptor site in exon 2 corrected ("humanized"). The Trem2 R47H point mutation has been shown to increase Alzheimer's disease risk.
Mike Sasner, The Jackson Laboratory
This Trem2*R47HHSS strain has a mutant mouse Trem2 gene consisting of an R47H point mutation, along with 2 other silent mutations and a "humanized" (corrected) cryptic splice acceptor site in exon 2. The targeted Trem2 gene (triggering receptor expressed on myeloid cells 2) encodes a protein that is part of a receptor signaling complex with TYRO protein tyrosine kinase binding protein, and that activates macrophages and dendritic cells during immune responses. The TREM2 R47H mutation is a missense mutation in exon 2 that is one of the strongest genetic risk factors for late-onset Alzheimer's disease.
Unlike mice carrying the Trem2em1Adiuj allele (see Stock No. 027918) which expresses a novel truncated splice variant due to a cryptic splice acceptor site in exon 2, these Trem2em4Adiuj mice do not have a cryptic splice acceptor site in exon 2. Dr. Sasner and colleagues have now shown by RNA-seq that the Trem2*R47HHSS model does not express the truncated transcript and does express normal levels of transcript [July 2021].
Homozygous mice are viable and fertile. If additional characterization of these mice is performed, we may modify the strain description accordingly.
The Trem2*R47HHSS allele has the R47H point mutation, with two silent mutations and "humanized" cryptic splice acceptor site in exon 2. This allele was created by Dr. Michael Sasner (The Jackson Laboratory) using CRISPR/Cas9 endonuclease-mediated genome editing.
For the Trem2em4Adiuj allele (Trem2*R47HHSS): Plasmids encoding a single guide RNA designed to correct ("humanize") the cryptic splice acceptor site in exon 2 of the Trem2em1Adiuj allele (already having the R47H point mutation and two silent mutations) and the cas9 nuclease were introduced into the cytoplasm of C57BL/6J-congenic Apoetm1.1(APOE*4)Adiuj Trem2em1Adiuj (Stock No. 028709)-derived fertilized eggs with well recognized pronuclei. Correctly targeted embryos were transferred to pseudopregnant females. Correctly targeted pups were identified by sequencing and PCR and further bred together and/or to C57BL/6J (Stock No. 000664) mice to develop the colony. The Apoetm1.1(APOE*4)Adiuj and Trem2em1Adiuj alleles were bred away.
|Allele Name||endonuclease-mediated mutation 4, MODEL-AD Center|
|Allele Type||Endonuclease-mediated (Humanized sequence)|
|Gene Symbol and Name||Trem2, triggering receptor expressed on myeloid cells 2|
|Strain of Origin||B6(SJL)-Apoetm1.1(APOE*4)Adiuj Trem2em1Adiuj/J|
|Molecular Note||CRISPR/cas9 genome editing is used to create an R27H mutation with two silent mutations and "humanized" cryptic splice acceptor site in exon 2. The R27H mutation is one of the strongest genetic risk factors for late-onset Alzheimer's disease.|
When maintaining a live colony, homozygous mice may be bred together as they are viable and fertile.
When using the Trem2*R47HHSS mouse strain in a publication, please cite the originating article(s) and include JAX stock #033781 in your Materials and Methods section.