Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

From more than 500 tumours reported in human primary immune deficiencies a majority has been observed in two disorders: ataxia telangiectasia (A-T) and common variable immune deficiency (CVID). Since both diseases have an increased risk of lymphomas/leukaemias and gastrointestinal tumours, suggesting a common risk factor, and the cells derived from A-T patients exhibit an increased chromosomal radiosensitivity we analysed chromosome damage in the G2 lymphocytes of 24 CVID patients and 21 controls after X-irradiation in vitro. There was a significant difference in mean aberration yields between patients and controls. Three CVID patients had yields higher than the mean + 3SD of the controls. Six patients but only one control had yields higher than the mean + 2SD of controls. The patient with the highest chromosomal radiosensitivity subsequently developed a lymphoma. Repeat assays on the same blood sample, with a 24-h delay in setting up the second culture, showed as much variability for control donors as the variation between control donors although for CVID patients inter-individual variation was greater than the difference between results of repeat samples. There was a weak positive correlation between radiosensitivity and age of donor. Chromosomal radiosensitivity of five patients with X-linked hypogammaglobulinaemia was not different from healthy donors. The mean mitotic index (MI) for unirradiated samples from CVID patients was significantly lower than for controls and there was an inverse relationship between MI and aberration yields in the patients, but not in controls. We suggest that the defect in CVID patients that reduces response to mitogenic stimuli may have mechanism(s) in common with those involved in cellular repair processes.
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PMID:Chromosomal radiosensitivity in common variable immune deficiency. 769 17

Ataxia-telangiectasia is a complex syndrome that includes a very high cancer risk in children with a progressive cerebellar ataxia, the onset of which occurs in early infancy. Ocular telangiectasiae often do not appear until several years after the ataxia. The most common type of malignancy is lymphoma, usually of the B-cell type. Leukemias also occur. Failure to diagnose ataxia-telangiectasia in an infant with lymphoma or leukemia may result in radiation therapy with conventional dosages, which is contraindicated in ataxia-telangiectasia patients.
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PMID:Ataxia-telangiectasia. 771 35

It is well established that ataxia-telangiectasia (A-T) patients suffer a grossly elevated risk of cancer, particularly lymphoma and leukaemia, but the possibility of an excess cancer risk of cancer in heterozygotes carriers of A-T mutations is more controversial. A number of studies indicate that female relatives of A-T patients suffer excess risk of breast cancer; based on an overview of all currently available data the estimated relative risk of breast cancer to A-T heterozygotes is 3.9-fold (95% CI 2.1-7.2). There is some suggestion that relative risk declines with age. In contrast, there is no consistent evidence of a risk from any other cancer; the estimated risk from all studies is 1.9 (95% CI 1.5-2.5) but some studies show a larger effect whilst others show no excess risk. On the basis of these results and the likely frequency of the A-T gene, A-T heterozygotes would account for between 1 and 13% of breast cancer cases, with 3.8% being the best estimate. However, unless the breast cancer risk has been seriously underestimated, the A-T gene will make little contribution to familial breast cancer.
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PMID:Cancer risks in A-T heterozygotes. 783 45

Hereditary breast cancer (HBC) shows extant clinical and genetic heterogeneity. Clinically one finds the onset of breast cancer at an early age, an excess of bilaterality, and patterns of multiple primary cancer such as combinations of breast and ovarian carcinoma in the hereditary breast-ovarian cancer (HBOC) syndrome. In addition to HBOC, one sees a variety of putative breast cancer-prone genotypes inclusive of hereditary site-specific breast cancer, and the Li-Fraumeni (SBLA) syndrome that is characterized by cancers involving all three germinal layers including sarcomas, brain tumors, leukemia, lymphoma, and adrenal cortical carcinoma in addition to often markedly early-onset breast cancer. Breast cancer is also associated with autosomal dominantly inherited Cowden's disease and autosomal recessively inherited ataxia-telangiectasia. Examples of pedigrees depicting clinical examples of these several HBC syndromes are presented in order to describe HBC's heterogeneity. The recent identification of the BRCA1 gene in early-onset hereditary site-specific breast cancer and the HBOC syndrome has led to new challenges for the genetic counselor. We review genetic counseling, which embraces surveillance and management recommendations that are responsive to the natural history of HBC and address the concept for future development of centers of expertise for HBC in the interest of improving cancer control.
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PMID:Hereditary breast cancer and family cancer syndromes. 819 73

Patients with the recessively inherited disorder ataxia telangiectasia (A-T) have a high level of specific chromosome translocations which can be easily observed in peripheral T cells and show a greatly increased predisposition to leukaemia/lymphoma, mainly of T cell origin. Some translocation cells proliferate into a large clone and may develop into T cell prolymphocytic leukaemia (T-PLL). By the time of diagnosis of T-PLL, the clone contains many more genetic changes in the form of additional translocations. T-PLL is also seen in non-A-T individuals where expression of either TCL1 (at 14q32) or the c6.1B/MTCP1 A1 transcript (at-Xq28) has been demonstrated in just a few instances. We show here, that expression of TCL1 occurs in leukaemic T cells from A-T patients with chromosome 14 rearrangements. Expression of TCL1 also occurs in the preleukaemic clone cells of A-T patients containing the primary translocation alone. Some expression of TCL1 could also be detected in randomly selected A-T patients without large cytogenetic clones and without any evidence of leukaemic change. We also show that expression of the B1 transcript from a second gene, MTCP1, occurred at a relatively high level only in two T-PLL tumours from A-T patients with t(X;14) translocations whereas the MTCP1/A1 transcript is much more widely expressed in both tumour and non tumour cells of A-T and non-A-T individuals.
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PMID:Expression of either the TCL1 oncogene, or transcripts from its homologue MTCP1/c6.1B, in leukaemic and non-leukaemic T cells from ataxia telangiectasia patients. 857 Feb 15

Ataxia telangiectasia (AT) is characterized by neurological deterioration, immunodeficiency, spontaneous chromosomal instability, hypersensitivity to ionizing radiation, predisposition to cancer, particularly T cell leukaemia and lymphoma, and premature ageing. The most commonly observed defect affecting telomeres in humans is telomeric fusions, particularly in T lymphocytes in AT patients. Rarely, some tumour cells, like senescent cells, have dicentric chromosomes that may arise as a result of telomeric sequence loss. We show that the AT mutation in the homozygous state confers a predisposition to accelerated telomere shortening with increasing age in peripheral blood lymphocytes (PBLs), which may be linked to premature senescence. We also show that telomeric fusions are associated with large (> 90%) preleukaemic translocation clones in T cells. We propose that these fusions may result from a compound effect of accelerated telomere shortening, together with a growth advantage of cells in large clones which leads to further telomere loss. Fusions are not observed in leukaemic cells in these patients. There is no evidence that either accelerated telomere loss per se or telomeric fusions are important in tumourigenesis. Telomerase is present in both normal and AT lymphocytes and so neither telomere shortening nor telomeric fusions can be explained by the absence of telomerase.
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PMID:Accelerated telomere shortening in ataxia telangiectasia. 867 36

Ataxia telangiectasia is a recessive disorder in which patients show a progressive cerebellar degeneration leading to ataxia, abnormal eye movements and deterioration of speech. Other features include ocular telangiectasia, high serum AFP levels, immunodeficiency, growth retardation and an increased predisposition to some tumours, particularly T cell leukaemia and lymphoma. We report the 1348 amino acid sequence of the N-terminal half of the A-T gene product which, together with the previously published C-terminal half, completes the sequence of the A-T protein. No homologies with other genes have been found within the N-terminal half of the A-T protein. We have also identified six mutations affecting the N-terminal half of the protein. One of these mutations was found to be associated with a haplotype that is common to four apparently unrelated families of Irish descent. All the patients so far examined for both A-T alleles were shown to be compound heterozygotes. None of these mutations affected a putative promoter region which may direct divergent transcription of both the A-T gene and a novel gene E14. The ability to recognise mutations across the entire coding sequence of the A-T gene provides a practical advantage to A-T families since a DNA based prenatal diagnosis will be possible in families where the mutations are identified irrespective of the level of radiosensitivity in these families.
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PMID:Mutations revealed by sequencing the 5' half of the gene for ataxia telangiectasia. 878 52

A total of 734 serum specimens from various clinical disorders along with 100 control samples from healthy subjects were processed for estimation of serum IgG, IgA and IgM employing single radial immunodiffusion procedure. Immunoglobulin deficiency, either selective or combined was noted in 31 males and 24 females in all age groups. Of the 55 cases encountered it was secondary immunoglobulin deficiency which was seen on a larger scale and encountered in patients with Multiple myeloma (16 out of 32) followed by Leprosy (14 out of 250), Lymphoma (5 out of 43), Malaria (4 out of 137), Burns (4 out of 52), Rheumatoid arthritis (2 out of 69) and non lymphoreticular malignancies (1 out of 41) in decreasing order of frequency. Primary immunoglobulin deficiency was observed in nine cases comprising of six belonging to Idiopathic late onset immunoglobulin deficiency, two of dysgammaglobulineamia and a solitary case of Ataxia telangiectasia. Panimmunoglobulin deficiency was observed in six cases, 11 had a dual deficiency while 38 showed deficiency of an isolated class with selective IgA deficiency in 20 cases. Furthermore, one patient each had total absence of IgG or IgA while IgM was not detectable in seven patients. A high suspicion index along with a regular rapport between the clinician and the laboratory personnel is necessary in the diagnostic set up of immunoglobulin deficiency states.
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PMID:Analysis of immunoglobulin deficiency cases: a five year study. 935 99

We report the spectrum of 59 ATM mutations observed in ataxia-telangiectasia (A-T) patients in the British Isles. Of 51 ATM mutations identified in families native to the British Isles, 11 were founder mutations, and 2 of these 11 conferred a milder clinical phenotype with respect to both cerebellar degeneration and cellular features. We report, in two A-T families, an ATM mutation (7271T-->G) that may be associated with an increased risk of breast cancer in both homozygotes and heterozygotes (relative risk 12.7; P=. 0025), although there is a less severe A-T phenotype in terms of the degree of cerebellar degeneration. This mutation (7271T-->G) also allows expression of full-length ATM protein at a level comparable with that in unaffected individuals. In addition, we have studied 18 A-T patients, in 15 families, who developed leukemia, lymphoma, preleukemic T-cell proliferation, or Hodgkin lymphoma, mostly in childhood. A wide variety of ATM mutation types, including missense mutations and in-frame deletions, were seen in these patients. We also show that 25% of all A-T patients carried in-frame deletions or missense mutations, many of which were also associated with expression of mutant ATM protein.
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PMID:ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer. 946 14

The role of ataxia-telangiectasia (AT) heterozygotes in breast cancer has been controversial. We have found previously an overrepresentation (3.4%) of ATM mutations in a subset of 88 selected breast cancer patients with a family history of breast cancer, leukemia, and lymphoma. This prevalence is comparable to the estimated value (3.8%) from epidemiological study. To further examine the possibility that ATM is correlated to breast cancer, we screened for ATM germ-line mutations in another 100 breast cancer patients with a family history of breast cancer. We used the protein truncating test and found one new germ-line mutation. This figure (1%) is consistent with the observed 0.2-1% carrier frequency for AT. We also studied breast tumors from ATM mutants, and three showed retention of both alleles, whereas the fourth showed loss of the mutant allele. We conclude that the contribution of heterozygous ATM mutations to familial breast cancer is minimal. Even if the ATM gene were causative in these cases, it is not likely to act as a tumor suppressor.
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PMID:The role of ataxia-telangiectasia heterozygotes in familial breast cancer. 953 33


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