HYPERSENSITIVITY OF ATAXIA-TELANGIECTASIA FIBROBLASTS TO A NITRIC-OXIDE DONOR

Ataxia-telangiectasia (A-T) is a human autosomal recessive disease cha racterised by immunodeficiency, extreme sensitivity to ionising radiat ion and progressive cerebellar ataxia. The defective gene has recently been cloned and is a member of the phosphatidylinositol 3-kinase fami ly. We have investigated the possibility that the neurodegeneration in A-T might be induced by an endogenously formed mutagen causing radiat ion-like damage. Nitric oxide is known to be formed in the cerebellum and we present evidence that A-T fibroblasts are hypersensitive to kil ling by the nitric oxide donor S-nitrosoglutathione (GSNO), as are fib roblasts from a radiosensitive individual without ataxia. Killing was determined as loss of colony forming ability. GSNO induces dose-depend ent DNA strand breakage, but to no greater extent in A-T fibroblasts. Breakdown of GSNO to nitrite and nitrate appears to occur to the same extent in both normal and A-T fibroblasts. Cell killing by GSNO appear s to be associated in both types of cell with formation of nitrite, ra ther than nitrate, as the ultimate oxidation product of nitric oxide. Copyright (C) 1996 Elsevier Science Inc.