This Mthfr*C677T/APOE4/Trem2*R47H triple mutant strain carries an A262V point mutation of the Mthfr gene that models the human C677T polymorphism, a humanized ApoE knock-in allele, in which 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) and a knock-in of a point mutation into mouse Trem2 gene containing an R47H point mutation with two silent mutations.
The Mthfr A262V point mutation models the human MTHFR C677T polymorphism which is associated with an increased risk for Alzheimer's Disease. The targeted Apoe gene encodes apolipoprotein E, which is important in lipoprotein metabolism and cardiovascular disease as well as Alzheimer's disease, immunoregulation and cognition. 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.
Mice that are heterozygous for Mthfrem1Adiuj (Mthfr*C677T), homozygous for Apoetm1.1(APOE*4)Adiuj (APOE4) and homozygous for Trem2em1Adiuj (Trem2*R47H) are viable and fertile [March 2020]. If additional characterization of these Mthfr*C677T/APOE4/Trem2*R47H mice is performed, we may modify the strain description accordingly.
Of note, in brains of mice homozygous for the Trem2em1Adiuj allele (and not carrying any other mutant alleles), expression of both transcripts of Trem2 is decreased by about 50%. Mice expressing the Trem2 R47H mutation also express 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 (see Stock No. 027918).
