This CRISPR/Cas9-generated mutant of the Trem2 gene carries a R47H point mutation which has been shown to increase Alzheimer's disease risk. This model expresses about half as much Trem2 as wildtype controls.
Mike Sasner, The Jackson Laboratory
This CRISPR/Cas9-generated knock-out mutant of the Trem2, triggering receptor expressed on myeloid cells 2, gene introduces a R47H point mutation, as well as two silent mutations (lysine AAG>AAA and alanine GCC>GCA). The targeted Trem2 gene 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.
Homozygous TREM2 R47H mice are viable and fertile. As the mice are characterized, we will modify the strain description and add phenotype data.
Mice expressing this TREM2 R47H allele exhibit a novel splice variant with a deletion of 119bp at the 5' end of exon 2, due to a cryptic splice acceptor site in exon 2 (Xiang et al. 2018 Mol Neurodegener 13:49). This leads to a ~50% decrease in expression in the brain in homozygotes.
Please note, other Trem2R47H models do not exhibit this aberrant splicing and have normal levels of expression - see Trem2*R47HHSS [Stock No. 033781] and Trem2*R47HNSS [Stock No. 034036].
Plasmids encoding cas9 nuclease and a single guide RNA designed to introduce a R47H point mutation, with two silent mutations (lysine AAG>AAA and alanine GCC>GCA), into the Trem2 gene were introduced into the cytoplasm C57BL/6J-derived fertilized eggs with well recognized pronuclei. Correctly targeted embryos were transferred to pseudopregnant females. Pups containing the engineered mutations were identified by sequencing and PCR and further bred to C57BL/6J (Stock No. 000664) to develop the colony.
|Allele Name||endonuclease-mediated mutation 1, MODEL-AD Center|
|Allele Type||Endonuclease-mediated (Humanized sequence)|
|Allele Synonym(s)||Jax R27H ki; Trem2 R47H KI|
|Gene Symbol and Name||Trem2, triggering receptor expressed on myeloid cells 2|
|Strain of Origin||C57BL/6J|
|Molecular Note||The allele was generated by injecting cas9 nuclease and a single guide RNA designed to introduce a R47H point mutation with two silent mutations (lysine AAG>AAA and alanine GCC>GCA) into the gene.|
When maintaining a live colony, these mice can be bred as homozygotes. Homozygotes are viable and fertile.
When using the Trem2 R47H KI (Trem2*R47H) mouse strain in a publication, please cite the originating article(s) and include JAX stock #027918 in your Materials and Methods section.