Home About us Contact
|
Home About us Contact | ||
|
|
||
ATM Gene (atm + gene)
Selected AbstractsEvaluation and management of pulmonary disease in ataxia-telangiectasiaPEDIATRIC PULMONOLOGY, Issue 9 2010Sharon A. McGrath-Morrow MD Abstract Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder caused by mutations in the ATM gene, resulting in faulty repair of breakages in double-stranded DNA. The clinical phenotype is complex and is characterized by neurologic abnormalities, immunodeficiencies, susceptibility to malignancies, recurrent sinopulmonary infections, and cutaneous abnormalities. Lung disease is common in patients with A-T and often progresses with age and neurological decline. Diseases of the respiratory system cause significant morbidity and are a frequent cause of death in the A-T population. Lung disease in this population is thought to exhibit features of one or more of the following phenotypes: recurrent sinopulmonary infections with bronchiectasis, interstitial lung disease, and lung disease associated with neurological abnormalities. Here, we review available evidence and present expert opinion on the diagnosis, evaluation, and management of lung disease in A-T, as discussed in a recent multidisciplinary workshop. Although more data are emerging on this unique population, many recommendations are made based on similarities to other more well-studied diseases. Gaps in current knowledge and areas for future research in the field of pulmonary disease in A-T are also outlined. Pediatr. Pulmonol. 2010; 45:847,859. © 2010 Wiley-Liss, Inc. [source] Down-regulation of ATM protein in HRS cells of nodular sclerosis Hodgkin's lymphoma in children occurs in the absence of ATM gene inactivation,THE JOURNAL OF PATHOLOGY, Issue 3 2007S Bose Abstract The tumour component of classical Hodgkin's lymphoma (cHL), Hodgkin Reed,Sternberg (HRS) cells, are believed to be derived from germinal centre (GC) B cells but intriguingly display a characteristic loss of B cell receptor (BCR) expression. The precise mechanisms by which BCR-negative HRS cell progenitors survive negative selection during the GC reaction remain obscure. Individuals with ataxia telangiectasia, caused by biallelic inactivation of the DNA damage response gene, ataxia telangiectasia mutated (ATM), have a higher risk of cHL development. Here we show that, in contrast to normal GC B cells that expressed low but detectable ATM protein, ATM protein was not detected in HRS cells of 17/18 cases of paediatric cHL, all but one with nodular sclerosis (NS) subtype. A comprehensive analysis of the ATM gene in microdissected HRS cells of nine representative tumours showed no evidence of either loss of heterozygosity or consistent pathogenic mutations. Furthermore, bisulphite sequencing of the ATM promoter from HRS cells of five tumours also revealed the absence of hypermethylation. Since our microarray data suggested significantly reduced ATM transcription in HRS cells compared to GC B cells, we conclude that loss of ATM expression could be the result of alterations in upstream regulators of ATM transcription. Importantly, ATM loss in paediatric cHLs has clinical implications and could be potentially exploited to guide future, less toxic, tumour-specific treatments. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Founder Effects for ATM Gene Mutations in Italian Ataxia Telangiectasia FamiliesANNALS OF HUMAN GENETICS, Issue 5 2009Luciana Chessa Summary We screened ATM gene mutations in 104 Italian Ataxia-Telangiectasia patients from 91 unrelated families (detection rate 90%) and found 21 recurrent mutations in 63 families. The majority (67%) of patients were compound heterozygotes, while 33% were homozygotes. To determine the existence of common haplotypes and potential founder effects, we analyzed five microsatellite markers within and flanking the ATM gene. Haplotype analysis was carried out in 48/63 families harbouring 16 of the 21 recurrent mutations. Forty different haplotypes were detected in the 48 A-T families studied. We found that the majority of patients with the same recurrent mutation originated from the same geographical area. All but one recurrent mutation analyzed displayed a common haplotype suggesting a single origin that then spread to different geographical areas. The high number of different haplotypes does not allow the screening of ATM mutations by haplotype analysis alone in the Italian population. The finding of recurrent public mutations without founder effect suggests the existence of ,mild' hot spots of mutation located along the sequence of the ATM gene. [source] Pathogenic ATM mutations occur rarely in a subset of multiple myeloma patientsBRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2008Belinda Austen Summary Ataxia Telangiectasia (A-T) patients have biallelic inactivation of the ATM gene and exhibit a 200-fold-increased frequency of lymphoid tumours. ATM mutations have been found in a number of adult lymphoid malignancies but there is no data on the occurrence of ATM mutations in multiple myeloma tumours. The purpose of our work was to investigate the occurrence of ATM mutations in multiple myeloma and to this end we screened 45 sporadic cases for ATM mutations using denaturing high-performance liquid chromatography analysis and DNA sequencing. Pathogenic ATM mutations were identified in 2/45 of the myelomas compared with a published estimate of ATM mutant allele frequency in the UK population of 2/521 (P = 0·033). One was the missense mutation 7181C>T which was then modelled in an expression system and the S2394L protein shown to have no ATM kinase activity. The second myeloma had the pathogenic ATM splice site mutation IVS40-1G>C leading to loss of exon 41. We also report a 48-year-old ataxia telangiectasia patient who developed multiple myeloma. Taken together our study suggests that ATM mutation may play a role in the pathogenesis of a subset of multiple myelomas. [source] Expression patterns of the ATM gene in mammary tissues and their associations with breast cancer survivalCANCER, Issue 9 2007Chuanzhong Ye MD Abstract BACKGROUND. The ataxia-telangiectasia mutated (ATM) gene plays a critical role in cell-cycle arrest, apoptosis, and DNA repair. However, to date, no study has directly investigated the association between ATM gene expression and breast cancer survival. METHODS. ATM gene expression levels were evaluated in tumor and adjacent normal tissue from patients diagnosed with primary breast cancer or BBD using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) assays. Cox regression models were used to evaluate the association of ATM gene expression and survival in a cohort of 471 breast cancer patients. RESULTS. In breast cancer cases, ATM expression in cancer tissues was decreased by approximately 50% compared with adjacent normal tissues from the same patients. In BBD cases, the expression level of the ATM gene was similar in benign tumor tissue and adjacent normal tissues. No apparent difference was found in ATM gene expression levels in adjacent normal tissues obtained from cancer patients or BBD controls. Compared with patients with the lowest tertile of the ATM mRNA, patients in the upper 2 tertiles had more favorable disease-free survival (hazard ratio [HR] = 0.46, 95% confidence interval [CI]: 0.30,0.73 and HR = 0.52, 95% CI: 0.33,0.81, respectively) and overall survival (HR = 0.56, 95% CI: 0.35,0.92 and HR = 0.70, 95% CI: 0.43,1.13, respectively). CONCLUSIONS. The ATM gene expression was down-regulated in breast cancer tissues and a high ATM gene expression level in breast cancer tissue was associated with a favorable prognosis. Cancer 2007. © 2007 American Cancer Society. [source] X-Irradiation Induces Up-regulation of ATM Gene Expression in Wild-type Lymphoblastoid Cell Lines, but Not in Their Heterozygous or Homozygous Ataxia-telangiectasia CounterpartsCANCER SCIENCE, Issue 6 2001Yuko Hirai Ataxia-telangiectasia (AT) is an autosomal recessive disease. The relevant gene has been cloned and designated ATM. We studied the expression of both ATM mRNA and the ATM protein in unirradi-ated and X-irradiated EBV (Epstein-Barr virus)-transformed lymphoblastoid cell lines (LCLs) derived from donors who were normal (ATM+/+), AT heterozygotes (ATM+/,), or AT homozy-gotes (ATM,/,), respectively. In ATM+/+ LCLs, the levels of ATM mRNA were found to have increased by approximately 1.5-fold within 1 h of exposure to 10 Gy of X-rays, while the ATM protein levels had increased by 1.5- to 2.0-fold within 2 to 3 h of irradiation. The wild-type mRNA and protein levels both returned to their basal values fairly quickly after this tune. The results obtained with the ATM+/, LCLs were quite different, however: neither the mRNA nor protein levels were found to have increased as a consequence of X-irradiation in any ATM+/, LCL. Twelve of the mutations in the ATM,/, LCLs we used were truncating mutations, and we suspected that the corresponding truncated ATM proteins would be too labile to be detected by western blot analysis. However, five of the ATM,/, LCLs produced mutant ATM proteins that were identical in molecular weight to the wild-type ATM protein. When cells from three of these five clones were exposed to X-rays, transcription of the mutant ATM genes appeared to reduce somewhat, as were the levels of protein being produced. These results suggest that the normal ATM gene responds to ionizing radiation by up-regulating its activity, whereas none of the mutant ATM genes we studied were able to respond in this way. [source] Lung disease in ataxia-telangiectasiaACTA PAEDIATRICA, Issue 7 2007L Bott Abstract Ataxia-telangiectasia (AT) is a multi-systemic disease caused by mutational inactivation of the ATM gene. We report a retrospective study of lung disease in 15 patients. Patients and methods: A diagnosis of AT was made if the patient met the following criteria: neurological features and at least one the following: oculo-cutaneous telangiectasia, elevated serum ,-feto-protein level. Results: Recurrent sino-pulmonary infections were usually present in 11 of the cases and occurred during the first 2 years of life. Other lung injuries noted were bronchiectasis, obstruction and restriction of the airways, fibrosis, pneumothorax and haemoptysis. Eleven children had immunodeficiencies. Discussion: Recurrent sino-pulmonary manifestations precede neurological complications, but the severity of neuro-degeneration and pulmonary disease were not correlated. Pulmonary status was a prognosis factor. Immunodeficiency was the main, but not the only, aetiology for lung disease in AT. Conclusion: There is little dispute over the role of ATM in lung and respiratory epithelium. To reduce the morbidity associated with AT, there needs to be greater awareness of respiratory complications. Early management and monitoring lung function is necessary to minimize lung damage. [source] ATM germline mutations in Spanish early-onset breast cancer patients negative for BRCA1/BRCA2 mutationsCLINICAL GENETICS, Issue 5 2008J Brunet Heterozygous carriers of ATM (ataxia telangiectasia mutated gene) mutations have increased risk of breast cancer (BC). We have estimated the prevalence of mutations in the ATM gene among Spanish patients with early-onset BC. Forty-three patients diagnosed with BC before the age of 46 years, and negative for BRCA1 and BRCA2 mutations, were analysed for the presence of ATM mutations. A total of 34 ATM sequence variants were detected: 1 deleterious mutation, 10 unclassified variants and 23 polymorphisms. One patient (2.3%) carried the ATM deleterious mutation (3802delG that causes ataxia telangiectasia in the homozygous state) and 13 patients carried the 10 ATM unclassified variants. The truncating mutation 3802delG and eight of the rare variants were not detected in a control group of 150 individuals. Different bioinformatic sequence analysis tools were used to evaluate the effects of the unclassified ATM changes on RNA splicing and function protein. This in silico analysis predicted that the missense variants 7653 T>C and 8156 G>A could alter the splicing by disrupting an exonic splicing enhancer motif and the 3763 T>G, 6314 G>C, and 8156 G>A variants would affect the ATM protein function. These are the initial results concerning the prevalence of germline mutations in the ATM gene among BC cases in a Spanish population, and they suggest that ATM mutations can confer increased susceptibility to early-onset BC. [source] X-Irradiation Induces Up-regulation of ATM Gene Expression in Wild-type Lymphoblastoid Cell Lines, but Not in Their Heterozygous or Homozygous Ataxia-telangiectasia CounterpartsCANCER SCIENCE, Issue 6 2001Yuko Hirai Ataxia-telangiectasia (AT) is an autosomal recessive disease. The relevant gene has been cloned and designated ATM. We studied the expression of both ATM mRNA and the ATM protein in unirradi-ated and X-irradiated EBV (Epstein-Barr virus)-transformed lymphoblastoid cell lines (LCLs) derived from donors who were normal (ATM+/+), AT heterozygotes (ATM+/,), or AT homozy-gotes (ATM,/,), respectively. In ATM+/+ LCLs, the levels of ATM mRNA were found to have increased by approximately 1.5-fold within 1 h of exposure to 10 Gy of X-rays, while the ATM protein levels had increased by 1.5- to 2.0-fold within 2 to 3 h of irradiation. The wild-type mRNA and protein levels both returned to their basal values fairly quickly after this tune. The results obtained with the ATM+/, LCLs were quite different, however: neither the mRNA nor protein levels were found to have increased as a consequence of X-irradiation in any ATM+/, LCL. Twelve of the mutations in the ATM,/, LCLs we used were truncating mutations, and we suspected that the corresponding truncated ATM proteins would be too labile to be detected by western blot analysis. However, five of the ATM,/, LCLs produced mutant ATM proteins that were identical in molecular weight to the wild-type ATM protein. When cells from three of these five clones were exposed to X-rays, transcription of the mutant ATM genes appeared to reduce somewhat, as were the levels of protein being produced. These results suggest that the normal ATM gene responds to ionizing radiation by up-regulating its activity, whereas none of the mutant ATM genes we studied were able to respond in this way. [source] | |||||||||||||