Abnormal myo-inositol and phospholipid metabolism in cultured fibroblasts from patients with ataxia telangiectasia.
Ataxia telangiectasia (AT) is a complex autosomal recessive disorder that has been associated with a wide range of physiological defects including an increased sensitivity to ionizing radiation and abnormal checkpoints in the cell cycle. The mutated gene product, ATM, has a domain possessing homology to phosphatidylinositol-3-kinase and has been shown to possess protein kinase activity. In this study, we have investigated how AT affects myo-inositol metabolism and phospholipid synthesis using cultured human fibroblasts. In six fibroblast lines from patients with AT, myo-inositol accumulation over a 3-h period was decreased compared to normal fibroblasts. The uptake and incorporation of myo-inositol into phosphoinositides over a 24-h period, as well as the free myo-inositol content was also lower in some but not all of the AT fibroblast lines. A consistent finding was that the proportion of 32P in total labeled phospholipid that was incorporated into phosphatidylglycerol was greater in AT than normal fibroblasts, whereas the fraction of radioactivity in phosphatidic acid was decreased. Turnover studies revealed that AT cells exhibit a less active phospholipid metabolism as compared to normal cells. In summary, these studies demonstrate that two manifestations of the AT defect are alterations in myo-inositol metabolism and phospholipid synthesis. These abnormalities could have an effect on cellular signaling pathways and membrane production, as well as on the sensitivity of the cells to ionizing radiation and proliferative responses.
Yorek
M A
MA
Department of Internal Medicine, Diabetes-Endocrinology Research Center and Veterans Affairs Medical Center, University of Iowa, Iowa City, IA 52246, USA.
Dunlap
J A
JA
Manzo-Fontes
A
A
Bianchi
R
R
Berry
G T
GT
Eichberg
J
J
D001260:Ataxia Telangiectasia / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division; D002460:Cell Line; D002478:Cells, Cultured; D002794:Choline / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D020404:Glycerophospholipids / Q000378:metabolism*; D006801:Humans; D007294:Inositol / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism*; D010761:Phosphorus Radioisotopes
D020404:Glycerophospholipids; D010716:Phosphatidylinositols; D010761:Phosphorus Radioisotopes; D007294:Inositol; D002794:Choline