The autosomal recessive disorder, Ataxia Telangiectasia (AT), results in cerebellar ataxia, immunodeficiency and cancer. The defective gene, ATM, encodes a large protein which appears to be confined to the nucleus of most cells and plays a role in DNA repair which is defective in AT. The ATM protein product also contains a motif which resembles an enzyme, phosphatidylinositol-3-phosphokinase, that catayzes the conversion of phosphatidylinositol (ptdins) to Ptdins-3-P or Ptdins-4, 5-p2 to Ptdins-3, 4, 5-p3. Because these phosphoinositides play a role in signal transduction, it was suggested that the ATM protein is part of a novel nuclear signal transduction system which helps in certain cells to regulate proof reading of DNA during replication and somatic recombination as well as DNA repair. Lacking, however, is evidence that the levels of any of these phosphoinositides are perturbed in cells from patients with AT or that of their precursor, myo-inositol. The goals of this project are to: 1) characterize the cerebellar dysfunction in patients of different ages and with different ATM gene mutations; 2) characterize the T-cell abnormalities in patients; 3) measure the levels of the myo-inositol and the phosphoinositides in cells; 4) determine whether any of the clinical or laboratory abnormalities can be reversed by supplying for 1 month more of the phosphoinositide precursor, myo-inositol, to patients as part of their daily diet. This will be accomplished by performing a placebo controlled, double-blind crossover study in which at the beginning and end of each month the cerebellar and T-cell studies will be performed as well as the measurement of phosphoinositides and myo-inositol in cells.
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