Related Experiment Videos
Atm knock-in mice harboring an in-frame deletion corresponding to the human ATM 7636del9 common mutation exhibit a
1Queensland Cancer Fund Research Laboratories, The Queensland Institute of Medical Research, P.O. Box Royal Brisbane Hospital, Herston, Brisbane, Queensland 4029, Australia.
Abstract:
ATM, the gene mutated in the human immunodeficiency disorder ataxia-telangiectasia (A-T), plays a central role in recognizing ionizing radiation damage in DNA and in controlling several cell cycle checkpoints. We describe here a murine model in which a nine-nucleotide in-frame deletion has been introduced into the Atm gene by homologous recombination followed by removal of the selectable marker cassette by Cre-loxP site-specific, recombination-mediated excision. This mouse, Atm-DeltaSRI, was designed as a model of one of the most common deletion mutations (7636del9) found in A-T patients. The murine Atm deletion results in the loss of three amino acid residues (SRI; 2556-2558) but produces near full-length detectable Atm protein that lacks protein kinase activity. Radiosensitivity was observed in Atm-DeltaSRI mice, whereas the immunological profile of these mice showed greater heterogeneity of T-cell subsets than observed in Atm(-/-) mice. The life span of Atm-DeltaSRI mice was significantly longer than that of Atm(-/-) mice when maintained under nonspecific pathogen-free conditions. This can be accounted for by a lower incidence of thymic lymphomas in Atm-DeltaSRI mice up to 40 weeks, after which time the animals died of other causes. The thymic lymphomas in Atm-DeltaSRI mice were characterized by extensive apoptosis, which appears to be attributable to an increased number of cells expressing Fas ligand. A variety of other tumors including B-cell lymphomas, sarcomas, and carcinomas not seen in Atm(-/-) mice were observed in older Atm-DeltaSRI animals. Thus, expression of mutant protein in Atm-DeltaSRI knock-in mice gives rise to a discernibly different phenotype to Atm(-/-) mice, which may account for the heterogeneity seen in A-T patients with different mutations.
Insights
A new mouse model with a specific Atm gene deletion shows radiosensitivity and a different tumor profile compared to Atm-null mice, offering insights into ataxia-telangiectasia (A-T) patient heterogeneity.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- The ATM gene is crucial for DNA damage response and cell cycle control, and its mutation causes ataxia-telangiectasia (A-T).
- Common ATM mutations in A-T patients include deletion mutations.
Purpose of the Study:
- To create and characterize a murine model (Atm-DeltaSRI) mimicking a common A-T deletion mutation (7636del9).
- To investigate the phenotypic consequences of expressing a kinase-inactive ATM protein in mice.
Main Methods:
- Homologous recombination was used to introduce a nine-nucleotide in-frame deletion into the mouse Atm gene.
- Cre-loxP recombination was employed to remove the selectable marker.
- Phenotypic analyses included radiosensitivity, immunological profiling, lifespan studies, and tumor incidence assessment.
Main Results:
- The Atm-DeltaSRI mice exhibited radiosensitivity and produced a near full-length ATM protein lacking kinase activity.
- These mice displayed greater T-cell subset heterogeneity and a longer lifespan than Atm(-/-) mice.
- Atm-DeltaSRI mice had a lower incidence of thymic lymphomas but developed other tumors (B-cell lymphomas, sarcomas, carcinomas) with age.
Conclusions:
- The Atm-DeltaSRI knock-in mouse model presents a distinct phenotype compared to Atm(-/-) mice, reflecting the impact of expressing a mutant ATM protein.
- This model provides valuable insights into the heterogeneity observed in ataxia-telangiectasia patients with different ATM mutations.