Genetic susceptibility to radiation.
In the context of space radiation, it is important to know whether the human population includes genetically predisposed radiosensitive subsets. One possibility is that haploinsufficiency for ATM confers radiosensitivity, and this defect involves 1-3% of the population. Using knock-out mice we chose to study cataractogenesis in the lens and oncogenic transformation in mouse embryo fibroblasts to assay for effects of ATM deficiency. Radiation induced cataracts appeared earlier in the heterozygous versus wild-type animals following exposure to either gamma rays or 1 GeV/nucleon iron ions. In addition, it was found that embryo fibroblasts of Atm heterozygotes showed an increased incidence of oncogenic transformation compared with their normal litter-matched counterparts. From these data we suggest that Ataxia Telangiectasia heterozygotes could indeed represent a societally significant radio sensitive subpopulation. Knock-out mice are now available for other genes including BRCA1 and 2, and Mrad9. An exciting possibility is the creation of double heterozygotes for pairs of mutated genes that function in the same signal transduction pathway, and consequently confer even greater radiosensitivity.
Hall
E J
EJ
Columbia University Medical Center, College of Physicians and Surgeons, Center for Radiological Research, New York, NY 10032-3795, USA. ejh1@columbia.edu
Brenner
D J
DJ
Worgul
B
B
Smilenov
L
L
D000337:Aerospace Medicine; D000818:Animals; D018480:Astronauts; D001260:Ataxia Telangiectasia / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D002386:Cataract / Q000209:etiology*; D018797:Cell Cycle Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004307:Dose-Response Relationship, Radiation; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009381:Neoplasms, Radiation-Induced / Q000453:epidemiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011832:Radiation Injuries / Q000235:genetics; D011836:Radiation Tolerance / Q000235:genetics*; D013026:Space Flight; D017356:Synchrotrons; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics; D014965:X-Rays
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases