B6(Cg)-Isr(HSA17;rs63751011-T)3Mdk/J

Stock number: 036664
Product name: MAPT 10IVS+16 C>T
Strain synonyms: B6(Cg)-Tc(HSA17*)1Mdk/J
Research areas: Mouse/Human Gene Homologs, Neurobiology Research

Description

MAPT IVS10+16 C>T mice express the human MAPT (H1 haplotype), contain a non-coding C to T (rs63751011) mutation in intron 10, MAPT-AS1 transcripts and the typical MAPT protein isoforms. The mutation is associated with early onset frontotemporal dementia (FTD).

Detailed description

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.

The interspecies replacement (Isr) MAPT IVS10+16 C>T 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 and is modified to contain a non-coding C to T substitution in intron 10. 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.

The IVS10+16 C>T mutation, originally identified in four families located in Australia, the United States and the United Kingdom, is associated with early onset frontotemporal dementia (FTD), Alzheimer's disease, progressive supranuclear palsy, progressive subcortical gliosis and FTD with parkinsonism. The mutation is believed to destabilize a stem-loop structure that regulates alternative splicing on exon 10, increasing the inclusion of exon 10 and the proportion of four-repeat (4R) tau isoforms (See Alzforum MAPT IVS10+16 C>T). Homozygous mice are viable and fertile.

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 stretching from, but not including, Crhr1 to Kansl1 is replaced by a syntenic 190 kb region from human chromosome 17 (HSA17). 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 contain a non-coding C to T (rs63751011-T) substitution at position 44087784 (GRCh37/hg19) in intron 10. The substitution was made using C57BL/6N-PRX-B6N embryonic stem cells (ES) and a loxN-flanked neomycin resistance cassette 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 B6(Cg)-Tyr^c-2J/J females. Upon arrival, mice were bred to C57BL/6J to establish the colony.

In 2021, a 48 SNP (single nucleotide polymorphism) panel analysis, with 43 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the males sent to The Jackson Laboratory Repository. Four of the 5 markers that determine C57BL/6J from C57BL/6N were found to be segregating. These data suggest the mice sent to The Jackson Laboratory Repository were on a mixed C57BL/6N;C57BL/6J genetic background.

Allele

Symbol: Isr(HSA17;rs63751011-T)3Mdk
Name: interspecies replacement, human Chr 17, Michael Koob 3
MGI accession ID: MGI:6729680
Generation method: Targeted
Attributes: Inserted expressed sequence; Humanized sequence
Synonyms: MAPT 10IVS+16 CT; Tc(HSA17*)1Mdk
Marker symbol: Isr(HSA17;rs63751011-T)3Mdk
Marker name: interspecies replacement, human Chr 17, Michael Koob 3
Marker synonyms: Isr(HSA17*)1Mdk; Isr(HSA17;MAPT*rs63751011)3Mdk; Tc(HSA17*)1Mdk
Chromosome: 11
Strain of origin: C57BL/6NTac
Molecular note: A 157 kb deletion on mouse chromosome 11 stretching from, but not including, Crhr1 to Kansl1 is replaced by a syntenic 190 kb region from human chromosome 17 (HSA17). 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 contain a non-coding C to T (rs63751011) substitution at position 44087784 (GRCh37/hg19) in intron 10. The mutation is identified in early onset frontotemporal dementia (FTD) patients. A loxN-flanked neomycin resistance cassette that was removed by transient cre expression.