These Mre11ATLD1/ATLD1 mice contain a mutation in the Mre11 gene, similar to that found in humans with ataxia-telangiectasia like disorder.
John Petrini, Memorial Sloan-Kettering Cancer Center
These Mre11ATLD1/ATLD1 mice contain an A to T point mutation at nucleotide 1894, corresponding to human codon 633, of the meiotic recombination 11 homolog A (Mre11) gene. MRE11 is a component of a trimeric protein complex also containing Nbs1 and Rad50 which is involved in DNA double-strand break repair, cell cycle checkpoint activation, telomere maintenance, and meiotic recombination. This mutation introduces a premature stop codon, resulting in the truncation of 75 amino acids which produces a hypomorphic protein. This mutation is commonly found in human ataxia-telangiectasia like disorder (A-TLD) and Nijmegen Breakage Syndrome (NBS). A-TLD is characterized by defects in movement, coordination, and immune responses due to chromosomal instability. NBS is characterized by short stature, microcephaly, distinctive facial features, recurrent respiratory tract infections, an increased risk of cancer, and intellectual disability. Homozygous Mre11ATLD1/ATLD1 females have severely reduced fertility, with decreased embryonic viability due to genome instability and cell cycle checkpoint defects. Homozygous males are viable and fertile. These mice, and cells derived from these mice, exhibit DNA double strand break repair defects, cell-cycle checkpoint defects, and chromosomal instability. These mice are not prone to malignancy including lymphomagenesis.
A targeting construct was designed to introduce an A to T point mutation at nucleotide 1894, corresponding to human codon 633, resulting in a premature STOP codon in the meiotic recombination 11 homolog A (Mre11) gene, commonly found in human ataxia-telangiectasia like disorder (A-TLD). A neomycin resistance cassette was placed downstream of the mutation. This targeting construct was electroporated into 129S7/SvEvBrd-Hprtb-m2-derived AB2.2 embryonic stem (ES) cells and correctly targeted ES cells were injected into C57BL/6 blastocysts. The resulting chimeric males were bred to C57BL/6 females. These Mre11ATLD1/ATLD1 mice were maintained on a mixed background. Upon arrival at The Jackson Laboratory, mutant mice were bred to C57BL/6J mice (Stock No. 000664) for at least one generation to establish the colony.
|Allele Name||targeted mutation 1, John H J Petrini|
|Allele Type||Targeted (Humanized sequence)|
|Gene Symbol and Name||Mre11a, MRE11A homolog A, double strand break repair nuclease|
|Strain of Origin||129S7/SvEvBrd-Hprtb-m2|
|Molecular Note||An A-to-T transversion point mutation was engineered at nucleotide 1894 of the coding sequence to recapitulate a nonsense mutation identified in human patients (codon 633). This mutation results in the truncation of 75 amino acids.|
When maintaining a live colony, heterozygous females may be bred to homozygous males. Homozygous females are extremely subfertile.
When using the B6;129S7-Mre11atm1Jpt/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #024172 in your Materials and Methods section.