C57BL/6-Isr(HSA17;MAPT*L266V)6Mdk/J

Stock number: 040834
Product name: MAPT(H1.0*)L266V-GR
Strain synonyms: MAPT-GR*L266V
Research areas: Mouse/Human Gene Homologs, Neurobiology Research

Description

MAPT(H1.0*)L266V-GR mice express the human MAPT (H1 haplotype) with the L266V risk variant, MAPT-AS1 transcripts, and the typical MAPT protein isoforms. The L266V mutation is closely linked to Pick's disease.

Detailed description

The interspecies replacement (Isr) MAPT(H1.0*)L266V-GR (Gene Replacement) mice contain a syntenic 190 kb region from human chromosome 17 (HSA17) that includes SPPLC2 (signal peptide peptidase 2C) and MAPT (microtubule-associated protein tau), specifically, the H1 MAPT haplotype modified to express the L266V mutation. The region replaces 157 kb on mouse chromosome 11 stretching from, but not including, Crhr1 to Kansl1. The SPPL2C sequence is included because it is embedded entirely in the MAPT-AS1 transcribed region.

Human MAPT (microtubule-associated protein tau) is found within a 900 kb inversion on Chr 17q21 that defines two haplotypes, H1 and H2, found in Caucasians. The haplotypes are distinguished by a series of polymorphisms found in the MAPT sequence. A227A (GCA to GCG), is a silent point mutation in exon 9 of the MAPT isoform 441. The minor G allele is carried by the H2 haplotype, while the A allele is found in the more common H1 haplotype. H1 is linked with late onset Alzheimer's disease (AD) risk, progressive supranuclear palsy, Parkinson's disease, and corticobasal degeneration. MAPT(H1.0*)L266V-GR mice carry a leucine to valine (L266V) amino acid substitution, which is more closely linked to Pick's disease. H2 is associated with decreased risk of late onset AD, and lower MAPT levels in the cerebellum and temporal cortex. Homozygous mice are viable and fertile, no overt health or behavioral phenotype have been observed. These mice express the human MAPT (H1 haplotype) with the L266V risk variant, MAPT-AS1 transcripts and the typical MAPT protein isoforms.

Other strains from this set include: The H1 haplotype is distributed as Stock No. 035398 B6J.B6N-Isr(HSA17)2Mdk/J. A modified H1 haplotype carrying the pathogenic N279K mutation is distributed as Stock No. 035794. The H2 haplotype is distributed as Stock No. 033668 B6J.B6N(CBA)-Isr(HSA17)1Mdk/J. MAPT IVS10+16 C>T mice, distributed as Stock No. 036664, express the H1 haplotype and contain a non-coding C to T (rs63751011) mutation in intron 10. A modified H1 haplotype carrying the pathogenic L266V mutation is distributed as Stock No. 040834. A modified H1 haplotype carrying the pathogenic G272V mutation is distributed as Stock No. 040835.

Development

A 157 kb deletion on mouse chromosome 11 (Chr11:104,066,949-104,223,491) stretching from, but not including, Crhr1 to Kansl1 is replaced by a syntenic 190 kb region from human chromosome 17 (HSA17; Chr17:45,838,648-46,029,144). The genomic sequences are from mouse assembly GRCm39 and human assembly GRCh38.p14 [PMID:38343132 Benzow et al., 2024 Alzheimers Dement. 20:3080]. In this interspecies replacement (Isr) strain, the mouse Sppl2c (signal peptide peptidase 2C) and Mapt (microtubule-associated protein tau) genes are replaced by human SPPL2C and MAPT (H1 haplotype) genes. The human MAPT gene was modified to include the L266V (leucine to valine; Ctg to Gtg) mutation located in exon 9 and identified in patients with Pick's disease. The deletion/insertion was made using C57BL/6N-PRX-B6N embryonic stem cells (ES) and a loxN-flanked neomycin resistance cassette that was removed by transient cre expression prior to establishing the mouse line. Correctly targeted ES cells were injected into blastocysts. The resulting chimeric animals were crossed to C57BL/6J females. Upon arrival, mice were bred to C57BL/6J to establish the colony.