Prof Yosef Shiloh
Identification of the gene responsible for a genetic disorder usually marks a turning point in the research of the disease. Knowing the gene's sequence and structure is essential for the construction of accurate and rapid diagnostic tools, and for understanding the physiological basis of the disease, without which no effective treatment can be designed. Manipulation of the corresponding gene in laboratory animals usually leads to animal models of the disorder that can be further studied and manipulated. A key step to learning the gene's mode of action is the identification of the protein that is defective or missing in the patients. Sometimes other proteins that regulate its activity or serve as targets of this activity also need to be identified.
Identification of the ATM gene indeed prompted extensive research in all of these directions. The gene's structure was elucidated, the entire gene was sequenced, and its regulatory elements were identified. While most of the mutations causing the typical form of A-T were found to eliminate the ATM protein, mutations causing somewhat milder forms of the disease leave a residual amount of the protein in patients' cells. The highly controversial question of possible cancer predisposition among A-T carriers is being extensively studied.
A mouse model of A-T was created in several laboratories by disrupting the Atm gene in this animal. While recapitulating the human clinical and cellular A-T phenotype, the neurological defects develop in these mice more slowly than in the human patients. Further manipulations of these animals is expected to enable them to live longer and develop the neurological signs of the disease to a full extent.
Artificial production of the ATM protein in A-T cells using genetic engineering methods corrected the disease features in these cells. While this indicates that the ATM gene is indeed responsible for the various aspects of A-T, it should be borne in mind that gene therapy may not be feasible in A-T due to its multi-system nature and the inaccessibility of most A-T affected tissues to such treatment.
We have learnt a great deal about the ATM protein. First, its sequence told us that it belongs to a family of large proteins, identified in various organisms, that play an important role in mediating various cellular stress responses, particularly the response to certain DNA damaging agents. Some of these proteins do so by controlling the progression of the cellular life cycle. These proteins are involved in intricate multi-protein pathways that transduce signals evoked by various stimuli to cellular regulatory systems. It is clear that ATM is involved in several different signal transduction pathways, which explains the multi-system nature of A-T. A common way proteins 'talk' to each other is by adding a phosphate group to their counterparts. Proteins with this activity are called 'protein kinases'. Several members of the ATM-like protein family exhibit this activity, and the ATM protein too has the hallmarks of a protein kinase. Attempts are being made to purify the ATM protein and demonstrate this activity in an unequivocal manner. This should allow us to identify the targets of this activity - namely the other proteins that receive the phosphate group via ATM activity. This will further elucidate the pathways in which ATM is involved.
Biochemical experiments have shown that ATM does not exist as a single, separate molecule, but rather as part of various protein complexes. Identification of the other members of these complexes should further disclose the functions in which ATM is involved. The mode of its interaction with the DNA or whole chromosomes is also being thoroughly investigated. Functional dissection is being done by individually expressing various portions of the big ATM protein and studying their effect on cellular metabolism, or by altering specific sequences in the complete ATM molecule.
The central direction of ATM research is thus still in its basic phase aimed at understanding how it functions. Once this goal is achieved, the next stage will follow: designing new treatment modalities for A-T patients based on this knowledge.
Prof Yosef Shiloh
Department of Human Genetics
Sackler School of Medicine
Tel Aviv University
Ramat Aviv 69978
Israel
OTHER PRESENTATIONS:
Ataxia Telangiectasia: 1926 - 1997 - An Introduction
Increased Radiation Sensitivity and Cancer Associated with Ataxia-Telangiectasia
The Neurological Aspects of Ataxia-Telangiectasia
Immunodeficiency and Infections Associated with Ataxia-Telangiectasia
Why it is Important to Identify Cases of Ataxia-Telangiectasia