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URMC / Labs / Mayer-Pröschel Lab / Projects / Genetic Insults/Ataxia Telangiectasia (AT)


Genetic Insults/Ataxia Telangiectasia (AT)

A-T cerebellar atrophy.

A-T cerebellar atrophy.
(Tavani, F. et al., Neuroradiology, 2003)

As an example of a genetic insult that affects brain development, we study Ataxia-telangiectasia (A-T), which is a rare, systemic disease characterized by immunodeficiency, increased incidence of cancer, and progressive cerebellar neurodegeneration resulting in loss of gross motor control and death. Individuals with A-T harbor homozygous recessive mutations in the Atm gene, resulting in truncation, inactivation, or loss of ATM protein. Despite common underlying genetic defects, significant heterogeneity exists in the manifestation of symptoms.

A number of mouse models have been generated that harbor mutations in the distal region of the gene, and recent studies suggest the presence of residual Atm protein in such cases. As a result, these models may not reflect a all aspects of the pathology since patients with little or no residual protein expression are thought to be associated with a more neurological sequaele. In order to study whether mutations in the ATM gene the eliminates a large part of the open reading frame hence minimizing the opportunity for generating residual truncated proteins, we generated a novel inducible Atm mutant mouse model that results in a truncating null mutation in the proximal region of the Atm gene (A-T [M]).

Cells from the A-T [M] mutant mice exhibited reduced proliferation and an altered DNA damage response. Although the A-T [M] animals have an altered immunophenotype, they fail to develop thymic lymphomas, resulting in a significant increase in survival as compared to other mouse models of A-T. Morphological analyses of A-T [M] cerebella revealed more substantial abnormalities than those seen in other mouse models, suggesting that amino-terminal truncating mutations exhibit a different phenotype from mice with mutations in the carboxy-terminal half of Atm, thus providing a new model that recapitulates new aspects of this heterogeneous disease.

We are currently characterizing this new mouse model for A-T in respect of the neuronal impairments we have identified.