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)

To further pinpoint the location of the genes for ataxia-telangiectasia on the long arm of chromosome 11, we performed linkage analysis and analysis of recombinants of genetic haplotypes on 14 Turkish families with ataxia-telangiectasia, 12 of which were consanguineous. These studies used more than 25 polymorphic genetic markers spanning a region of the long arm of chromosome 11 that is larger than 50 cM. Seven markers gave significant LOD scores to AT: CJ5, DRD2, CJ208, S144, CD3E, PBGD, and S147, as did haplotypes created with pairs of markers DRD2/CJ5 and S144/CJ208, giving recombination fractions (theta) of 0.00, 0.00, 0.05, 0.08, 0.03, 0.09, 0.07, 0.00, and 0.06, respectively. Monte Carlo analysis of these 14 Turkish families indicated the best location for a single AT gene to be within a 6 cM sex-averaged (3 cM male-specific) interval defined by STMY and CJ77; this was three times more likely than the next most likely location (peak III) at the DRD2 locus. The analysis also revealed a peak (peak II) between S147 and S133, which may represent the complementation group D gene. Recombinant analysis of haplotypes also localized an AT locus to the STMY-CJ77 interval. Taken together, these results suggest that at least two distinct AT loci exist (ATA and ATD) at 11q22-23, with perhaps a third locus, ATC, located very near to the ATA gene. This genetic heterogeneity further complicates plans to isolate the major ATA and ATC genes and to begin identifying AT carriers in the general population.
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PMID:Ataxia-telangiectasia: linkage analysis of chromosome 11q22-23 markers in Turkish families. 163 48

The multisystem autosomal recessive disease ataxia-telangiectasia (A-T) is determined by several genes, as evidenced by the existence of four complementation groups in this disorder. Using linkage analysis, the ATA (A-T complementation group A) gene was previously localized to chromosome 11, region q22-q23. Analysis of the segregation of RFLP markers from this region in a Jewish-Moroccan family assigned to group C indicates that the ATC (A-T complementation group C) gene localizes to chromosome 11q22-q23 as well.
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PMID:The ATC (ataxia-telangiectasia complementation group C) locus localizes to 11q22-q23. 167 97

Ataxia-telangiectasia (AT) is an autosomal recessive disorder resulting from a single defective gene in each family. Complementation studies suggest that the same syndrome is associated with defects of at least four AT genes (ATA, ATC, ATD and ATE). The syndrome is multifaceted and involves the cerebellum, skin, immunological system, chromosomes, cancer susceptibility, radiosensitivity, premature ageing and serum alphafetoprotein levels. In order to further develop understanding of how these seemingly unrelated physiological systems interact in this disease, we attempted to localize the gene by linkage analysis, using a single large Group A AT family to screen 171 genetic markers and 30 additional AT families to confirm any positive linkages. We found a linkage to AT (Group A) with genetic markers on chromosome 11q22-23. This region of the human genome is syntenic with a large region of the mouse genome on chromosome 9 and includes such "candidate" genes as THY1, NCAM, CD3G-D-3, ets-1, and APOA1-C3-A4. In addition, studies of human chromosomes identify fragile sites in this region as well as breakpoints associated with translocation 4: 11 and 9; 11 in acute non- lymphocytic leukemias. The pathogenetic implications of this localization to 11q22-23 are considered.
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PMID:Ataxia-telangiectasia (group A): localization of ATA gene to chromosome 11q22-23 and pathogenetic implications. 168 42

Ataxia-telangiectasia (A-T) is an autosomal recessive disease involving cerebellar degeneration, immunodeficiency, cancer predisposition, chromosomal instability and radiosensitivity. A-T is heterogeneous, and the majority of A-T cases are associated with two complementation groups, A and C. The ATA and ATC loci are closely linked at chromosome 11q22-q23. Recombination mapping and linkage disequilibrium analysis have confined both loci between the markers D11S1817 and D11S927, spaced approximately 3.5 Mb apart. Isolation in yeast artificial chromosomes of the genomic segment defined by these loci is essential to identify the gene or genes containing the ATA and ATC mutations. A YAC contig spanning 4.5 Mb, which includes the D11S1817-D11S927 interval, was constructed using two whole genome libraries (ICRF and St. Louis), and a chromosome 11-specific library. Construction of this contig was expedited by prior generation of a region-specific ICRF sublibrary using Alu-PCR products derived from a radiation hybrid. The contig was expanded further by screening the libraries with Alu-PCR products derived from YAC clones and with STSs from YAC ends. YAC clones were aligned by fingerprinting with moderately repetitive probes.
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PMID:A YAC contig spanning the ataxia-telangiectasia locus (groups A and C) at 11q22-q23. 769 44

Genetic heterogeneity in ataxia-telangiectasia (A-T) points to four different genes responsible for this disease. The two major A-T genes, ATA and ATC, were localized by genetic analysis close to each other on chromosome 11q22-23, prompting efforts of positional cloning. Essential steps in positional cloning are long-range cloning of the genomic region of interest, and derivation of highly polymorphic markers that would allow further reduction of the interval carrying the A-T gene. We constructed genomic contigs across the D11S611-D1S424 region harbouring the ATA and ATC genes in yeast artificial chromosome (YAC) vectors. These contigs were used as a fine mapping tool and enabled us to localize along the A-T region, eight microsatellite markers generated randomly by genome mapping centres. In addition, we used specific YAC clones to generate five new microsatellite markers based on polymorphic CA repeats. Recombination mapping based on Israeli A-T families indicates that the ATC gene is distal to the locus D11S1817. Further linkage analysis using these markers is expected to reduce the major A-T locus considerably to a size appropriate for cosmid cloning and identification of transcribed sequences.
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PMID:Physical and genetic mapping at the ATA/ATC locus on chromosome 11q22-23. 783 54

Cells derived from patients with the cancer-prone inherited disorder ataxia-telangiectasia (A-T) show an abnormal response to ionizing radiation-induced DNA damage, such as an increased cell killing and a diminished inhibition of DNA synthesis. The enhanced killing of A-T (group D) cells by X-rays can be corrected by multiple cDNAs, mapping to different chromosomes (6, 11, 17, and 18). In order to examine whether genes located on these chromosomes complement AT-D cells, normal neo-tagged chromosomes 6, 11, 17, and 18 were introduced into AT-D cells by microcell-mediated chromosome transfer. However, correction of the enhanced killing of AT-D cells by X-rays could only be achieved by chromosome 11 and by none of the other chromosomes tested. The enhanced killing of A-T (complementation group C) cells was also corrected by chromosome 11. Usually, but not in all microcell hybrid clones, chromosome 11 also corrected the radioresistant DNA synthesis (RDS) phenotype of AT-D and AT-C cells. These results (i) confirm findings by others suggesting assignment of the ATD and ATC genes to chromosome 11, (ii) demonstrate that several genes can modify the cellular radiation response when they are taken out of their normal genomic context and/or control, and (iii) indicate that the RDS phenotype and the enhanced cell killing in A-T are independent pleiotropic features resulting from the primary mutations in A-T. Also, our findings underscore that, in establishing cDNAs as candidate genes for A-T, microcell-mediated chromosome transfer studies are needed to exclude nonspecific correcting effects of these candidate cDNA genes.
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PMID:Studies on phenotypic complementation of ataxia-telangiectasia cells by chromosome transfer. 784 80

The autosomal recessive disorder ataxia-telangiectasia (A-T) is genetically heterogeneous, with four complementation groups. The genes for the two major groups (ATA and ATC) have been mapped to 11q22-q23. Genetic analysis of the disease has been conducted to date using biallelic polymorphisms. We have physically mapped to this region eight new microsatellite markers that were generated by three laboratories that construct whole-genome linkage maps. These markers should be valuable for refined localization and positional cloning of the A-T genes and for diagnostic purposes. The results demonstrate the value of integrating genetic and physical maps generated by different laboratories.
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PMID:Physical localization of microsatellite markers at the ataxia-telangiectasia locus at 11q22-q23. 795 77

It has been shown that the X-ray-sensitive Chinese hamster V79 mutants (V-E5, V-C4 and V-G8) are similar to ataxia-telangiectasia (A-T) cells. To determine whether the AT-like rodent cell mutants are defective in the gene homologous to A-T (group A, C or D), human chromosome 11 was introduced to the V-E5 and V-G8 mutant cells by microcell-mediated chromosome transfer. Forty independent hybrid clones were obtained in which the presence of chromosome 11 was determined by in situ hybridization. The presence of the region of chromosome 11q22-23 was shown by molecular analysis using polymorphic DNA markers specific for the ATA, ATC and ATD loci. Seventeen of the obtained monochromosomal Chinese hamster hybrids contained a cytogenetically normal human chromosome 11, but only twelve hybrid cell lines were shown to contain an intact 11q22-23 region. Despite the complementation of the X-ray sensitivity by a normal chromosome 11 introduced to A-T cells (complementation group D), these twelve Chinese hamster hybrid clones showed lack of complementation of X-ray and streptonigrin hypersensitivity. The observed lack of complementation does not seem to be attributable to hypermethylation of the human chromosome 11 in the rodent cell background, since 5-azacytidine treatment had no effect on the streptonigrin hypersensitivity of the hybrid cell lines. These results indicate that the gene defective in the AT-like rodent cell mutants is not homologous to the ATA, ATC or ATD genes and that the human gene complementing the defect in the AT-like mutants seems not to be located on human chromosome 11.
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PMID:Human chromosome 11 complements ataxia-telangiectasia cells but does not complement the defect in AT-like Chinese hamster cell mutants. 840 33

The ATM gene is responsible for the autosomal recessive disorder Ataxia-Telangiectasia (AT). Many different mutations, located all across the gene, have been reported with a predominance of truncating mutations. By using PTT (protein truncation test) a mutation was found in one Norwegian AT family. Sequencing revealed that the mutation affected nucleotides 3245-3247, codon 1082, and changed the sequence from ATC to TGAT, inducing a stop codon downstream at codon 1095 and leading to early truncation of the ATM protein. Perpendicular DGGE (denaturing gradient gel electrophoresis) was used to screen 10 additional families for this mutation. The 3245 delATC insTGAT mutation was found in 12 of 22 proband alleles: five patients were homozygotes and two heterozygotes. Haplotype analyses were performed using eight microsatellite markers, within and flanking the ATM gene. All carriers of the mutation described were found to have a common haplotype of the five closest CA-repeat microsatellite markers. Genealogical investigations of the families identified a common ancestor for three of the families. The common ancestor was a woman born in 1684 in the area from which these families originate. The prevalence of this mutation in Norwegian patients now allows a major subset of AT heterozygotes to be identified, both in the general population and in breast cancer patients, so that their cancer risk can be evaluated.
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PMID:Identical mutation in 55% of the ATM alleles in 11 Norwegian AT families: evidence for a founder effect. 978 Oct 27

This research investigated controller' situation awareness by comparing COOPANS's acoustic alerts with newly designed semantic alerts. The results demonstrate that ATCOs' visual scan patterns had significant differences between acoustic and semantic designs. ATCOs established different eye movement patterns on fixations number, fixation duration and saccade velocity. Effective decision support systems require human-centered design with effective stimuli to direct ATCO's attention to critical events. It is necessary to provide ATCOs with specific alerting information to reflect the nature of the critical situation in order to minimise the side effects of startle and inattentional deafness. Consequently, the design of a semantic alert can significantly reduce ATCOs' response time, therefore providing valuable extra time in a time-limited situation to formulate and execute resolution strategies in critical air safety events. The findings of this research indicate that the context-specified design of semantic alerts could improve ATCO's situational awareness and significantly reduce response time in the event of Short Term Conflict Alert (STCA) activation which alerts to two aircraft having less than the required lateral or vertical separation. Practitioner Summary: Eye movements are closely linked with visual attention and can be analysed to explore shifting attention whilst performing monitoring tasks. This research has found that context-specific designed semantic alerts facilitated improved ATCO cognitive processing by integrating visual and auditory resources. Semantic designs have been demonstrated to be superior to acoustic design by directing the operator's attention more quickly to critical situations.Abbreviations: APW: area proximity warning; ASRS: aviation safety reporting system; ATC: air traffic control; ATCO: air traffic controller; ATM: air traffic management; COOPANS: cooperation between air navigation service providers; HCI: human-computer interaction; IAA: irish aviation authority; MSAW: minimum safe altitude warning; MTCD: medium-term conflict detection; SA: situation awareness; STCA: short term conflict alert; TP: trajectory prediction.
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PMID:The impact of alerting designs on air traffic controller's eye movement patterns and situation awareness. 2994 81


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