Species: Mouse
Genes: Kif21b, APOE, Trem2
Mutations: TREM2 R47H
Modification: Kif21b: Knock-In; APOE: Knock-In; Trem2: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: B6(SJL)-Kif21b^em1Adiuj Apoe^{tm1.1(APOE*4)Adiuj} Trem2^em1Adiuj/J
Genetic Background: C57BL/6J
Availability: The Jackson Laboratory, Stock# 031938. Cryopreserved.

Summary

The epsilon-4 allele of Apolipoprotein E and the R47H variant of TREM2 have each been found to confer an approximately threefold increased risk for Alzheimer’s disease in humans heterozygous for either allele. The motor protein KIF21B (Kinesin Family Member 21B) is enriched in dendrites (Marszalek et al., 1999) and appears to have a role in the development of dendritic morphology (Muhia et al., 2016). KIF21B has been identified as a susceptibility locus for multiple sclerosis (The International Multiple Sclerosis Genetics Consortium, 2010), and a synonymous variant in KIF21B, T82T, was found to be associated with AD risk in the Alzheimer’s Disease Sequencing Project (Sasner et al., poster at 2018 Society for Neuroscience meeting).

This triple-mutant line carries a humanized Apoe gene (ε4 allele), the R47H mutation knocked into mouse Trem2, and the T82T (ACG to ACA) mutation knocked into mouse Kif21b. This line may be useful for studying late-onset sporadic Alzheimer’s disease.

Mice that are homozygous for the humanized Apoe and Trem2 R47H knock-in alleles and heterozygous for the knock-in Kif21b allele are viable and fertile. Viability and fertility of mice homozygous for all three mutant alleles have not been tested.

Although levels of Trem2 transcripts have not been reported for Kif21b*T82T/APOE4/Trem2*R47H mice, Jackson Labs has noted that Trem2 expression is decreased by approximately 50 percent in the brains of its homozygous Trem2 R47H KI mice. Decreased Trem2 expression has also been observed in other Trem2 R47H knock-in lines (Trem2 R47H KI (Haass), Trem2 R47H KI (Lamb/Landreth)), and has been traced to aberrant splicing of the mutant mouse allele (Xiang et al., 2018). The R47H mutation does not, however, reduce expression of human TREM2 (Xiang et al., 2018). For discussion on extrapolating findings from R47H knock-in mice to humans, see Sep 2018 news.

Modification Details

CRISPR/cas9 was used to generate a knock-in T82T (ACG > ACA) mutation of the Kif21b gene of APOE4/Trem2*R47H mice—double-mutant mice with a humanized Apoe (ε4 allele) gene and the R47H point mutation knocked into the mouse Trem2 gene. To humanize the mouse Apoe gene, exons 2, 3, and most of exon 4 of the mouse Apoe gene were replaced by human APOE4 gene sequence including exons 2, 3, and 4, and some 3' UTR sequence.

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)
4. Trem2 R47H KI x APOE4 (LOAD1)

News Citations

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

Paper Citations

1. Marszalek JR, Weiner JA, Farlow SJ, Chun J, Goldstein LS. Novel dendritic kinesin sorting identified by different process targeting of two related kinesins: KIF21A and KIF21B. J Cell Biol. 1999 May 3;145(3):469-79. PubMed.
2. Muhia M, Thies E, Labonté D, Ghiretti AE, Gromova KV, Xompero F, Lappe-Siefke C, Hermans-Borgmeyer I, Kuhl D, Schweizer M, Ohana O, Schwarz JR, Holzbaur EL, Kneussel M. The Kinesin KIF21B Regulates Microtubule Dynamics and Is Essential for Neuronal Morphology, Synapse Function, and Learning and Memory. Cell Rep. 2016 May 3;15(5):968-977. Epub 2016 Apr 21 PubMed.
3. International Multiple Sclerosis Genetics Consortium (IMSGC). Comprehensive follow-up of the first genome-wide association study of multiple sclerosis identifies KIF21B and TMEM39A as susceptibility loci. Hum Mol Genet. 2010 Mar 1;19(5):953-62. Epub 2009 Dec 9 PubMed.
4. 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.

Other Citations

1. R47H variant of TREM2

External Citations

1. poster at 2018 Society for Neuroscience meeting
2. The Jackson Laboratory, Stock# 031938

Further Reading

No Available Further Reading