Cancer and Cardiac Deaths in Obligatory Ataxia-Telangiectasia Heterozygotes

Swift, Michael; Chase, Charles L.

doi:10.1016/s0140-6736(83)92678-8

Cited by 51 publications

(22 citation statements)

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“…These observations suggest that ATM is involved in an apoE-independent pathway to facilitate the catabolism of apoB-48-carrying remnants. Findings from this report might be clinically important because a heterozygous mutation at the ATM locus in humans might increase the risk of ischemic heart disease (6) and because heterozygous ATM carriers have been estimated to constitute ‫%2-1ف‬ of the general population (6).…”

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confidence: 99%

Heterozygous mutation of ataxia-telangiectasia mutated gene aggravates hypercholesterolemia in apoE-deficient mice

Hong

Wei

et al. 2005

Journal of Lipid Research

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Individuals with a heterozygous mutation at the ataxia-telangiectasia mutated gene ( ATM ) have been reported to be predisposed to ischemic heart disease. This report examined for the first time the effect of a heterozygous ATM mutation ( ATM ؉ / ؊ ) on plasma lipid levels and atherosclerosis intensity using, and ATM ؉ / ؊ / ApoE ؊ / ؊ mice. Our data demonstrated that the plasma cholesterol and triglyceride levels in ATM ؉ / ؊ and ATM ؉ / ؊ / LDLR ؊ / ؊ mice were approximately the same as those in ATM ؉ / ؉ and ATM ؉ / ؉ / LDLR ؊ / ؊ control mice, respectively. In contrast, the plasma cholesterol level was significantly higher in ATM ؉ / ؊ / ApoE ؊ / ؊ mice than in ATM ؉ / ؉ / ApoE ؊ / ؊ control mice. In addition, the ATM ؉ / ؊ / ApoE ؊ / ؊ mice showed higher plasma apoB-48 levels, slower clearance for plasma apoB-48-carrying lipoproteins, and more advanced atherosclerotic lesions in the aorta compared with the ATM ؉ / ؉ / ApoE ؊ / ؊ mice. These novel results suggest that the product of ATM is involved in an apoE-independent pathway for catabolism of apoB-48-carrying remnants; therefore, superimposition of a heterozygous ATM mutation onto an ApoE deficiency background reduces the clearance of apoB-48-carrying lipoproteins from the blood circulation and promotes the formation of atherosclerosis. The product of the ataxia-telangiectasia mutated gene ( ATM ) has been reported to be a nuclear protein and involved in several signaling pathways, including DNA damage recognition, cell cycle control, and meiotic recombination (for review, see 1). It is now known that a fraction of ATM is also present in the cytoplasm and associated with vesicular structures such as peroxisomes (2). Ataxiatelangiectasia patients [i.e., those individuals carrying mutations at both ATM alleles ( ATM Ϫ / Ϫ )] express a variety of progressive clinical symptoms, such as cerebellar ataxia, telangiectasias, and a high incidence of cancer (for review, see 3). Cells obtained from ataxia-telangiectasia patients are more sensitive to ionizing radiation and show increased chromosomal aberrations compared with those obtained from normal subjects (4). Individuals with an ATM mutation in one allele ( ATM ϩ / Ϫ ) are spared most of the symptoms of the disease but are predisposed to cancer (5). A close review of the literature suggests that heterozygous ATM deficiency might also increase the risk of atherosclerosis-related cardiovascular diseases. For example, Swift and Chase (6) reported that the age-related mortality of heterozygous ATM carriers was increased markedly compared with the general population and that ischemic heart disease was one of the underlying causes for the early death of these individuals. Ataxia-telangiectasia patients reportedly have increased plasma cholesterol and triglyceride levels (7), which are the two major risk factors for atherosclerosis. However, ataxia-telangiectasia patients do not usually live past 20 or 30 years of age, and atherosclerosis has not been studied in these individuals.More recently, a mouse mode...

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confidence: 99%

Heterozygous mutation of ataxia-telangiectasia mutated gene aggravates hypercholesterolemia in apoE-deficient mice

Hong

Wei

et al. 2005

Journal of Lipid Research

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“…18 " 20 The demonstration of an intermediate radiosensitivity of skin fibroblasts from the patients with atherosclerosis might suggest that some or most of these patients may have been carriers of the AT gene, supporting the epidemiological observations of Swift and Chase. 16 However, in view of the considerable interstrain differences in the level of radiosensitivity, particularly the response of patient 3, the possibility of other genes enhancing cellular sensitivity to genotoxic agents like radiation in patients with atherosclerosis cannot be ruled out. In this preliminary study, we also observed a moderate level of RDS in cells from the patients with atherosclerosis relative to those from the healthy subjects.…”

Section: Discussionmentioning

confidence: 99%

“…21 ' 22 Any alteration in these genes would also affect the cell cycle progression after exposure to genotoxic agents and may, in fact, contribute to cellular hypersensitivity to these agents. Whether some or most of the patients with ischemic heart disease are carriers of the AT gene, as may be predicted from the epidemiological findings of Swift and Chase, 16 can be confirmed only by using AT gene probes when they become available.…”

Section: Discussionmentioning

confidence: 99%

“…1215 As normal cells usually show G, arrest and, thus, an inhibition of DNA synthesis after irradiation, RDS is believed to be an indication of cell cycle deregulation. 15 Swift and Chase 16 and Swift et al 17 presented epidemiological data showing an increased rate of mortality for ischemic heart disease as well as for various malignant diseases among AT gene carriers (obligate heterozygotes). If the hypothesis linking the AT gene with predisposition to ischemic heart disease were valid, one would expect to find AT heterozygotelike characteristics in patients with atherosclerosis.…”

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Increased radiosensitivity and radioresistant DNA synthesis in cultured fibroblasts from patients with coronary atherosclerosis.

Hannan

Khougeer

Halees

et al. 1994

Arterioscler Thromb

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Cultured skin fibroblasts from five patients with atherosclerosis who underwent coronary artery bypass graft surgery were compared with those from one ataxia telangiectasia (AT) homozygote, three AT heterozygotes, and five healthy subjects to determine their sensitivity to gamma radiation as determined by a colony survival assay. Fibroblasts from four of these patients were also compared with those from two AT homozygotes, two AT heterozygotes, and three healthy subjects to determine postirradiation [ 3 H]thymidine incorporation, indicating the levels of radioresistant DNA synthesis (RDS). On the basis of colony survival assay, after long-term irradiation (at low dose rate, ie, 0.007 Gy/min), fibroblasts from all five patients with atherosclerosis exhibited radiosensitivity that was intermediate between that of the healthy subjects and that of patients with the known radiosensitive syndrome AT. However, there was a considerable interstrain difference in the radiosensitivity of fibroblasts from patients with atherosclerosis, with their mean D lo values C ardiovascular diseases and cancer are the major causes of morbidity and mortality in many countries. Several studies have suggested that multifactorial processes are involved in the origin of these diseases.1 ' 2 The evidence of monoclonality, somatic mutations, and a possible involvement of mutagen/carcinogen exposure in both atherosclerosis and carcinogenesis strongly indicated that at some stage the two diseases may follow a similar pathway and share common risk factors. 36 This would, inter alia, imply that genetic factors that increase susceptibility to malignancies may also enhance the risk of developing atherosclerosis. Among various carcinogenic factors, ionizing radiation has almost conclusively been shown to be atherogenic.811 Therefore, it is expected that individuals with increased sensitivity to radiation would be prone to develop atherosclerosis. The inherited disorder ataxia telangiectasia (AT), an autosomal recessive syndrome that is highly susceptible to malignancies, is characterized by its cellular hypersensitivity to ionizing radiation (showing reduced cell survival) as well as Received May 31, 1994; revision accepted August 19, 1994. © 1994 American Heart Association, Inc.(radiation dose resulting in 10% cell survival) varying between 2.3 and 6.2 Gy, whereas the mean D lo values for the cells from the AT homozygote, AT heterozygotes, and healthy subjects were 2.0, 3.8, and 9.0 Gy, respectively. One of the patients with atherosclerosis showed cellular radiosensitivity quite similar to that of the AT homozygote, up to 2% to 10% of survival levels after short-(at a dose rate of 8 Gy/min) and long-term irradiation, respectively. The results of [ 3 H]thymidine incorporation showed an AT heterozygote-like RDS in fibroblasts from patients with atherosclerosis that appeared to be intermediate between that of AT homozygotes and that of healthy subjects, suggesting a partial deregulation of cell cycle in the patients with atherosclerosis. Ove...

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“…Studies on DNA repair de fects and a cancer risk assessment in the heterozygous carriers of the genes for these disorders, particularly those of AT, led to the suggestion that they may re present a good percentage of the early adult cancer victims [6][7][8]. This hypothesis implied that many of the cancer patients would have an underlying defi ciency in DNA repair mechanisms [9].…”

Section: Introductionmentioning

confidence: 99%

Gamma-Radiation and Mitomycin C Sensitivity of Peripheral Blood Lymphocytes from Saudi Patients with Non-Hodgkin’s Lymphoma

Hannan

Al‐Sedairy²,

Gibson³

et al. 1990

Acta Haematol

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Peripheral blood lymphocytes (PBLs) from 28 patients with non-Hodgkin’s lymphoma (NHL) were compared with those of 28 healthy subjects (controls) for their responsiveness to the T cell mitogen phytohemagglutinin (PHA) before and after treatment with γ-radiation and mitomycin C. PBLs from 9 of the 28 patients with NHL exhibited almost a total failure to respond to PHA while mitogenic stimulation in the rest varied from 7 to 90% relative to the controls. PBLs from 19 NHL patients and 28 healthy subjects were compared for their radiosensitivity by measuring postirradiation uptake of [³H]-thymidine. Increased sensitivity to γ-radiation was observed in more than half of the NHL patients studied. Increased sensitivity to mitomycin C was also noted in 5 of the 7 patients analyzed compared to the respective controls. Poor mitogenic responsiveness and hypersensitivity of blood lymphocytes to the carcinogens (γ-rays and mitomycin C) are suggestive of a severe immunological abnormality and defective DNA repair in these Saudi NHL patients.

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Cancer and Cardiac Deaths in Obligatory Ataxia-Telangiectasia Heterozygotes

Cited by 51 publications

References 4 publications

Heterozygous mutation of ataxia-telangiectasia mutated gene aggravates hypercholesterolemia in apoE-deficient mice

Heterozygous mutation of ataxia-telangiectasia mutated gene aggravates hypercholesterolemia in apoE-deficient mice

Increased radiosensitivity and radioresistant DNA synthesis in cultured fibroblasts from patients with coronary atherosclerosis.

Gamma-Radiation and Mitomycin C Sensitivity of Peripheral Blood Lymphocytes from Saudi Patients with Non-Hodgkin’s Lymphoma

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