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At least 1,009 records · Page 56Linked to original sources
PubMed2005

Ataxia-telangiectasia-mutated dependent phosphorylation of Artemis in response to DNA damage.

Artemis plays a crucial role in the hairpin-opening step of antigen receptor VDJ gene recombination in the presence of catalytic subunit of deoxyribonucleic acid (DNA)-dependent protein kinase (DNA-PKcs). A defect in Artemis causes human radiosensitive-severe combined immunodeficiency. Cells from Artemis-deficient patients and mice display increased chromosomal instability, but the precise function of this factor in the response to DNA damage remains to be elucidate. In this study, we show that Artemis is hyperphosphorylated in an Ataxia-telangiectasia-mutated (ATM)- and Nijmegen breakage syndrome 1 (Nbs1)-dependent manner in response to ionizing radiation (IR), and that S645 is an SQ/TQ site that contributes to retarded mobility of Artemis upon IR. The hyperphosphorylation of Artemis is markedly reduced in ATM- and Nbs1-null cells. Reintroduction of wild-type ATM or Nbs1 reconstituted Artemis hyperphosphorylation in ATM- or Nbs1-deficient cells, respectively. In support of this functional link, hyperphosphorylated Artemis was found to physically associate with the Mre11/Rad50/Nbs1 complex in an ATM-dependent manner in response to IR-induced DNA double strand breaks (DSB). Since deficiency of either DNA-Pkcs or ATM leads to defective repair of IR-induced DSB, our finding places Artemis at the signaling crossroads downstream of DNA-PKcs and ATM in IR-induced DSB repair.

Ataxia Telangiectasia↗
PubMed1977

Energetics of streptococcal growth inhibition by hydrostatic pressure.

Growth of Streptococcus faecalis in complex media with various fuel sources appeared to be limited by the rate of supply of adenosine-5' -triphosphate (ATP) at 1 atm and also under 408 atm of hydrostatic pressure. Growth under pressure was energetically inefficient, as indicated by an average cell yield for exponentially growing cultures of only 10.7 g (dry weight) per mol of ATP produced compared with a 1-atm value of 15.6. Use of ATP for pressure-volume work or for turnover of protein, peptidoglycan, or stable ribonucleic acid (RNA) did not appear to be significant causes of growth inefficiency under pressure. In addition, there did not seem to be an increased ATP requirement for ion uptake because cells growing at 408 atm had significantly lower internal K(+) levels than did those growing at 1 atm. Pressure did stimulate the membrane adenosine triphosphatase (ATPase) or S. faecalis at ATP concentrations greater than 0.5 mM. Intracellular ATP levels were found to vary during the culture cycle from about 2.5 mumol/ml of cytoplasmic water for lag-phase or stationary-phase cells to maxima for exponentially growing cells of about 7.5 mumol/ml at 1 atm and 5.5 mumol/ml at 408 atm. N,N'-dicyclohexylcarbodiimide at a 10 muM concentration improved growth efficiency under pressure, as did Mg(2+) or Ca(2+) ions at 50 mM concentration. These agents also enhanced ATP pooling, and it seemed that at least part of the growth inefficiency under pressure was due to increased ATPase activity. In all, it appeared that S. faecalis growing under pressure has somewhat reduced ATP supply but significantly increased demand and that the inhibitory effects of pressure can be interpreted largely in terms of ATP supply and demand.

Adenosine Triphosphate↗
PubMed1988

Pressure and Temperature Effects on Growth and Methane Production of the Extreme Thermophile Methanococcus jannaschii.

The marine archaebacterium Methanococcus jannaschii was studied at high temperatures and hyperbaric pressures of helium to investigate the effect of pressure on the behavior of a deep-sea thermophile. Methanogenesis and growth (as measured by protein production) at both 86 and 90 degrees C were accelerated by pressure up to 750 atm (1 atm = 101.29kPa), but growth was not observed above 90 degrees C at either 7.8 or 250 atm. However, growth and methanogenesis were uncoupled above 90 degrees C, and the high-temperature limit for methanogenesis was increased by pressure. Substantial methane formation was evident at 98 degrees C and 250 atm, whereas no methane formation was observed at 94 degrees C and 7.8 atm. In contrast, when argon was substituted for helium as the pressurizing gas at 250 atm, no methane was produced at 86 degrees C. Methanogenesis was also suppressed at 86 degrees C and 250 atm when the culture was pressurized with a 4:1 mix of H(2) and CO(2), although limited methanogenesis did occur when the culture was pressurized with H(2).

Journal Article↗
PubMed1977

Binding of sodium [195Au]aurothiomalate to Mycoplasma arthritidis.

The binding of sodium [195Au]aurothiomalate (ATM) to whole cells of Mycoplasma arthritidis has been measured within the temperature range of 4 to 53 degrees C. The time course (kinetics) and the effect of varying the total concentration of free ATM in the suspension at 37 degrees C were also measured. The extent of binding at 37 degrees C leveled off after 30 min at approximately 65 nCi of [195Au]ATM per mg of membrane protein. The amount of ATM bound per cell appeared to be directly proportional to the concentration of free ATM in the range of 0.25 to 0.60 muCi of [195Au]ATM per ml. An Arrhenius plot showed two distinct regions with slopes of -0.56 degrees K/mg of protein (5 to 22 degrees C) and -2.78 degrees K/mg of protein (22 to 53 degrees C). The break in the Arrhenius plot corresponds to a temperature known to be related to a sudden change in mycoplasma membrane fluidity. Estimations of Scatchard binding constants and number of binding sites per membrane protein molecule resulted in 0.8 to 1.4 sites per molecule in the intact organisms compared to 1.4 to 1.8 sites in membrane fragments. The latter were purified by repeated washings in phosphate-buffered saline after alkaline lysis of the cells. It is suggested that ATM reacts with available protein sulfhydryl groups in the mycoplasmal membrane.

Bacterial Proteins↗
PubMed1974

Effect of helium gas at elevated pressure on iron transport and growth of Escherichia coli.

Helium at an ambient pressure of 68 at m with 0.2 atm of O(2) shortened by 1 to 1.5 h the lag phase for growth of Escherichia coli in minimal medium supplemented with 2 muliters of cell-free culture filtrate (CFF) per ml or with 1 muM 2,3-dihydroxybenzoylserine (DHBS), an iron chelator. The lag phase of cultures not exposed to helium could be shortened by use of supplements, but higher concentrations were required-10 to 30 muliters of CFF per ml or 10 to 50 muM DHBS. Strain AN 193 of E. coli, which requires the DHBS precursor 2,3-dihydroxybenzoic acid (DHBA), grew well in media with 10 muM DHBA when exposed to helium at 68 atm, whereas 100 muM DHBA was required for growth in unexposed cultures. In the presence of 100 muM DHBA plus 1.0 muM ethylenediaminetetraactic acid, growth was inhibited at 1 and 68 atm. Growth was restored, however, by the addition of 0.1 muM FeSO(4) at 68 atm and 1.0 muM FeSO(4) at 1 atm, but lag times were invariably shorter in the pressurized cultures. Hydrostatic pressures of 68 atm did not reduce the lag phase in the presence of CFF, DHBS, or DHBA. Our results suggest that 68 atm of helium pressure, but not hydrostatic pressure, elicited a more rapid transport of iron into the cells.

Benzoates↗
PubMed1977

Initiation of Bacillus spore germination by hydrostatic pressure: effect of temperature.

Suspensions of Bacillus cereus T, B. subtilis, and B. pumilus spores in water or potassium phosphate buffer were germinated by hydrostatic pressures of between 325 and 975 atm. Kinetics of germination at temperatures within the range of 25 to 44 degrees C were determined, and thermodynamic parameters were calculated. The optimum temperature for germination was dependent on pressure, species, suspending medium, and storage time after heat activation. Germination rates increased significantly with small increments of pressure, as indicated by high negative deltaV values of -230 +/- 5 cm3/mol for buffered B. subtilis (500 to 700 atm) and B. pumilus (500 atm) spores and -254 +/- 18 cm3/mol for aqueous B. subtilis (400 to 550 atm) spores at 40 degrees C and -612 +/- 41 cm3/mol for B. cereus (500 to 700 atm) spores at 25 degrees C. The ranges of thermodynamic constants calculated at 40 degrees C for buffered B. pumilus and B. subtilis spores at 500 and 600 atm and for aqueous B. subtilis spores at 500 atm were: Ea = 181,000 to 267,000 J/mol; deltaH = 178,000 to 264,000 J/mol; deltaG = 94,000 to 98,300 J/mol; deltaS = 264 to 544 J/mol per degree K. These values are consistent with the concept that the transformation of a dormant to a germinating spore induced by hydrostatic pressure involves either hydration or a reduction in the visocosity of the spore core and a conformational change of an enzyme.

Bacillus↗
PubMed1999

Altered telomere nuclear matrix interactions and nucleosomal periodicity in ataxia telangiectasia cells before and after ionizing radiation treatment.

Cells derived from ataxia telangiectasia (A-T) patients show a prominent defect at chromosome ends in the form of chromosome end-to-end associations, also known as telomeric associations, seen at G(1), G(2), and metaphase. Recently, we have shown that the ATM gene product, which is defective in the cancer-prone disorder A-T, influences chromosome end associations and telomere length. A possible hypothesis explaining these results is that the defective telomere metabolism in A-T cells are due to altered interactions between the telomeres and the nuclear matrix. We examined these interactions in nuclear matrix halos before and after radiation treatment. A difference was observed in the ratio of soluble versus matrix-associated telomeric DNA between cells derived from A-T and normal individuals. Ionizing radiation treatment affected the ratio of soluble versus matrix-associated telomeric DNA only in the A-T cells. To test the hypothesis that the ATM gene product is involved in interactions between telomeres and the nuclear matrix, we examined such interactions in human cells expressing either a dominant-negative effect or complementation of the ATM gene. The phenotype of RKO colorectal tumor cells expressing ATM fragments containing a leucine zipper motif mimics the altered interactions of telomere and nuclear matrix similar to that of A-T cells. A-T fibroblasts transfected with wild-type ATM gene had corrected telomere-nuclear matrix interactions. Further, we found that A-T cells had different micrococcal nuclease digestion patterns compared to normal cells before and after irradiation, indicating differences in nucleosomal periodicity in telomeres. These results suggest that the ATM gene influences the interactions between telomeres and the nuclear matrix, and alterations in telomere chromatin could be at least partly responsible for the pleiotropic phenotypes of the ATM gene.

Adolescent↗
PubMed2005

Ataxia telangiectasia-mutated, a DNA damage-inducible kinase, contributes to high NaCl-induced nuclear localization of transcription factor TonEBP/OREBP.

High NaCl activates the transcription factor tonicity-responsive enhancer/osmotic response element binding protein (TonEBP/OREBP) by increasing its abundance and transactivation, the latter signaled by a variety of protein kinases. In addition, high NaCl causes TonEBP/OREBP to translocate into the nucleus, but little is known about the signals directing this translocation. The result is increased transcription of protective genes, including those involved in accumulation of organic osmolytes. High NaCl also damages DNA, and DNA damage activates ataxia telangiectasia-mutated (ATM) kinase through autophosphorylation on serine 1981. We previously found that ATM is involved in the high NaCl-induced increase in TonEBP/OREBP transactivation. The purpose of the present studies was to test whether ATM is also involved in high NaCl-induced TonEBP/OREBP nuclear translocation. We quantified TonEBP/OREBP in nuclear and cytoplasmic extracts from cultured cells by Western blot analysis. In COS-7 cells, wortmannin, an inhibitor of ATM, reduces high NaCl-induced nuclear translocation of TonEBP/OREBP. We used AT cells (in which ATM is inactive) to test the specificity of this effect. Nuclear translocation of native TonEBP/OREBP and of its recombinant NH2-terminal rel homology domain, which contains the nuclear localization signal, is reduced in AT cells and is restored when the cells are reconstituted with functional ATM. In conclusion, activation of ATM contributes to high NaCl-induced nuclear translocation of TonEBP/OREBP.

Androstadienes↗
PubMed2006

Ataxia telangiectasia mutated down-regulates phospho-extracellular signal-regulated kinase 1/2 via activation of MKP-1 in response to radiation.

Ataxia telangiectasia mutated (ATM) kinase plays a crucial role in the cellular response to DNA damage and in radiation resistance. Although much effort has focused on the relationship between ATM and other nuclear signal transducers, little is known about interactions between ATM and mitogenic signaling pathways. In this study, we show a novel relationship between ATM kinase and extracellular signal-regulated kinase 1/2 (ERK1/2), a key mitogenic stimulator. Activation of ATM by radiation down-regulates phospho-ERK1/2 and its downstream signaling via increased expression of mitogen-activated protein kinase phosphatase MKP-1 in both cell culture and tumor models. This dephosphorylation of ERK1/2 is independent of epidermal growth factor receptor (EGFR) activity and is associated with radioresistance. These findings show a new function for ATM in the control of mitogenic pathways affecting cell signaling and emphasize the key role of ATM in coordinating the cellular response to DNA damage.

Animals↗
PubMed2007

Obesity induces a phenotypic switch in adipose tissue macrophage polarization.

Adipose tissue macrophages (ATMs) infiltrate adipose tissue during obesity and contribute to insulin resistance. We hypothesized that macrophages migrating to adipose tissue upon high-fat feeding may differ from those that reside there under normal diet conditions. To this end, we found a novel F4/80(+)CD11c(+) population of ATMs in adipose tissue of obese mice that was not seen in lean mice. ATMs from lean mice expressed many genes characteristic of M2 or "alternatively activated" macrophages, including Ym1, arginase 1, and Il10. Diet-induced obesity decreased expression of these genes in ATMs while increasing expression of genes such as those encoding TNF-alpha and iNOS that are characteristic of M1 or "classically activated" macrophages. Interestingly, ATMs from obese C-C motif chemokine receptor 2-KO (Ccr2-KO) mice express M2 markers at levels similar to those from lean mice. The antiinflammatory cytokine IL-10, which was overexpressed in ATMs from lean mice, protected adipocytes from TNF-alpha-induced insulin resistance. Thus, diet-induced obesity leads to a shift in the activation state of ATMs from an M2-polarized state in lean animals that may protect adipocytes from inflammation to an M1 proinflammatory state that contributes to insulin resistance.

3T3 Cells↗
PubMed2004

Common ataxia telangiectasia mutated haplotypes and risk of breast cancer: a nested case-control study.

INTRODUCTION: The ataxia telangiectasia mutated (ATM) gene is a tumor suppressor gene with functions in cell cycle arrest, apoptosis, and repair of DNA double-strand breaks. Based on family studies, women heterozygous for mutations in the ATM gene are reported to have a fourfold to fivefold increased risk of breast cancer compared with noncarriers of the mutations, although not all studies have confirmed this association. Haplotype analysis has been suggested as an efficient method for investigating the role of common variation in the ATM gene and breast cancer. Five biallelic haplotype tagging single nucleotide polymorphisms are estimated to capture 99% of the haplotype diversity in Caucasian populations. METHODS: We conducted a nested case-control study of breast cancer within the Nurses' Health Study cohort to address the role of common ATM haplotypes and breast cancer. Cases and controls were genotyped for five haplotype tagging single nucleotide polymorphisms. Haplotypes were predicted for 1309 cases and 1761 controls for which genotype information was available. RESULTS: Six unique haplotypes were predicted in this study, five of which occur at a frequency of 5% or greater. The overall distribution of haplotypes was not significantly different between cases and controls (chi2 = 3.43, five degrees of freedom, P = 0.63). CONCLUSION: There was no evidence that common haplotypes of ATM are associated with breast cancer risk. Extensive single nucleotide polymorphism detection using the entire genomic sequence of ATM will be necessary to rule out less common variation in ATM and sporadic breast cancer risk.

Adult↗
PubMed1994

A cutoff in potency exists in the perfluoroalkanes.

Anesthetic potencies (minimum alveolar anesthetic concentration [MAC]) of perfluoroalkanes from perfluoromethane to perfluorooctane were assessed in male rats to determine whether a cutoff in anesthetic effect (i.e., an absence of any anesthetic effect) exists for the larger compounds in this series. Although hyperbaric measurements suggested a MAC of 38.9 +/- 6 atm (mean +/- SD) for CF4, this pressure was nearly identical to the lethal pressure of 41.1 +/- 5.8 atm. Hyperbaric studies of C2F6 caused death without causing anesthesia, the lethal pressure being 23.8 +/- 2.6 atm. Results from studies of additivity with desflurane suggested that the MAC of CF4 was 66.5 +/- 13.4 atm at an average CF4 test partial pressure of 17.7 +/- 4.0 atm (i.e., 17.7 atm of CF4 decreased the MAC of desflurane by 26.6%). Studies of additivity with desflurane, isoflurane, or halothane did not reveal an anesthetic effect of C2F6 at a pressure of 7.2 +/- 0.4 atm, or of larger perfluoroalkanes near to or at their saturated vapor pressures. We conclude that a cutoff in anesthetic potency for perfluoroalkanes exists between perfluoromethane and perfluoroethane.

Alkanes↗
PubMed1998

Diameter of large balloons used in endoluminal graft deployment varies with inflation pressure.

PURPOSE: To evaluate the characteristics of large-diameter balloon catheters used during endoluminal repair of aortic aneurysms. METHODS: Thirty-three large balloon dilatation catheters in the diameter range of 15 to 30 mm were measured at controlled pressures from 1 to 4 atm. The balloons were inflated with water using an inflation syringe connected to a pressure transducer. Diameters at stable pressure and pressure changes against time were recorded for each balloon. RESULTS: Dilation catheters in the range of 15 to 20 mm in diameter were significantly smaller (p < 0.005) than their nominal diameter at 1 and 2 atm; they reached nominal diameter only at the relatively high pressure of 4 atm. Most larger diameter balloons (25 and 30 mm) did not attain their nominal diameter even with pressures up to 4 atm. All sizes of balloon catheters tested became relatively compliant at pressures > 3 atm. CONCLUSIONS: The large balloon catheters tested in this study were designed for arterial angioplasty or valvuloplasty. They attained a significantly smaller size than their nominal diameter at pressures < 3 atm and became compliant at pressures exceeding 3 atm. Interventionists should be aware of these characteristics when using balloon catheters such as these during endoluminal graft deployment. Large balloons that reach predictable diameter at lower pressures should be designed specifically for use in endoluminal graft procedures.

Aortic Aneurysm↗
PubMed2000

The psychometric and cardiac effects of pseudoephedrine in the hyperbaric environment.

STUDY OBJECTIVES: To examine the psychometric and cardiac effects of pseudoephedrine at 1 and 3 atmospheres (atm) of pressure (0 and 66 feet of sea water, respectively), and to make recommendations about the agent's safety in the diving environment. DESIGN: Double-blind, placebo-controlled, crossover study. SETTING: Monoplace hyperbaric chamber of a university hospital. SUBJECTS: Thirty active divers (mean age 38 yrs). INTERVENTION: A bank of seven tests was used to assess cognitive function during four different simulated dive combinations: placebo-1 atm, placebo3 atm, pseudoephedrine-1 atm, and pseudoephedrine-3 atm. MEASUREMENTS AND MAIN RESULTS: Heart rate and cardiac rhythm were recorded during all dives. Repeated-measures analysis of variance was used to analyze the effects of pseudoephedrine, depth, and drug-depth interaction. No significant, independent effects of pseudoephedrine were seen on any of the seven psychometric test scores (p>0.05), although the drug tended to increase anxiety scores (p=0.092). Depth resulted in a significant increase in anxiety scores (p=0.021) and a significant decrease in verbal fluency test scores (p=0.041); it had no significant effects on the other five psychometric tests (p>0.05). Pseudoephedrine caused a significant increase (p=0.036) in mean heart rate, and depth caused a significant decrease (p=0.013). Neither pseudoephedrine nor depth affected cardiac rhythm. CONCLUSION: Pseudoephedrine does not cause significant alterations in psychometric performance at 3 atm of pressure that might increase the risk of diving. Depth causes significant adverse effects on anxiety levels and semantic memory at 3 atm. Pseudoephedrine and depth have significant but opposite effects on heart rate; although, these effects are unlikely to be clinically significant during diving. It is unlikely that pseudoephedrine adds significant risk to the diver.

Adult↗
PubMed1999

Non-compressive myelopathy: clinical and radiological study.

Fifty seven patients (42 males and 15 females) with non-compressive myelopathy were studied from 1997 to 1999. Acute transverse myelitis (ATM) was the commonest (31) followed by Vit B12 deficiency myelopathy (8), primary progressive multiple sclerosis (5), hereditary spastic paraplegia (3), tropical spastic paraplegia (2), subacute necrotising myelitis (1), radiation myelitis (1), syphilitic myelitis (1) and herpes zoster myelitis (1). 4 cases remained unclassified. In the ATM group, mean age was 30.35 years, antecedent event was observed in 41.9% case, 25 cases had symmetrical involvement and most of the cases had severe deficit at onset. CSF study carried out in 23 patients of ATM revealed rise in proteins (mean 147.95mg%, range 20-1200 mg/dL) and pleocytosis (mean 20.78/cumm, range 0-200 mm3). Oligoclonal band (OCB) was present in 28% of cases of ATM. The most common abnormality detected was a multisegment hyperintense lesion on T2W images, that occupied the central area on cross section. In 6 patients hyperintense signal was eccentric in location. MRI was normal in 4 cases of ATM. Thus ATM is the leading cause of non-compressive myelopathy. Clinical features combined with MRI findings are helpful in defining the cause of ATM.

Adolescent↗
PubMed1992

Effects of an increased PO2 during recompression therapy for the treatment of experimental cerebral arterial gas embolism.

In this study we investigated the efficacy of an initial compression to 6 atm abs on a 53% nitrogen:47% oxygen mixture (PO2 = 2.8 atm abs) before breathing oxygen at 2.8 and 1.9 atm abs for the treatment of feline cerebral arterial gas embolism. Neurophysiologic function was determined by measuring the cortical somatosensory evoked potential (SEP) amplitude in anesthetized ventilated cats. Air was infused into the carotid artery until the SEP amplitude was reduced to less than 10% of baseline values. The animals were randomly separated into 3 groups. The first group (CONTROL) (n = 7) served as control and remained at the surface, breathing air. The second group (NITROX) (n = 10) was compressed to 6 atm abs breathing a 53:47% nitrox mixture for 30 min followed by breathing 100% oxygen at 2.8 and 1.9 atm abs. The third group (HBO) (n = 10) was compressed to 2.8 and 1.9 atm abs breathing 100% oxygen. Air infusion suppressed the SEP amplitude to the same level in all groups. The CONTROL group recovered 27.6 +/- 31.2% (mean +/- standard deviation) of the baseline SEP amplitude, whereas the NITROX group recovered 63.2 +/- 28.2%, and the HBO group recovered 66.0 +/- 19.3%. An analysis of variance with repeated measures revealed that both treatment profiles promote significant (P = 0.03) recovery of the SEP amplitude compared to no treatment. We find no additional benefit, however, by initiating treatment at 6 atm abs, even when additional oxygen is provided.

Analysis of Variance↗
PubMed2004

Polo-like kinase 1 inactivation following mitotic DNA damaging treatments is independent of ataxia telangiectasia mutated kinase.

Polo-like kinase 1 (Plk1) is an important regulator of several events during mitosis. Recent reports show that Plk1 is involved in both G2 and mitotic DNA damage checkpoints. Ataxia telangiectasia mutated kinase (ATM) is an important enzyme involved in G2 phase cell cycle arrest following interphase DNA damage, and inhibition of Plk1 by DNA damage during G2 occurs in an ATM-/ATM-Rad3-related kinase (ATR)-dependent fashion. However, it is unclear how Plk1 is regulated in response to M phase DNA damage. We found that treatment of mitotic cells with DNA damaging agents inhibits Plk1 activity primarily through dephosphorylation of Plk1, which occurred in both p53 wild-type and mutant cells. Inhibition of Plk1 is not prevented by caffeine pretreatment that inhibits ATM activity and also occurs in ATM mutant cell lines. Furthermore, ATM mutant cell lines, unlike wild-type cells, fail to arrest after mitotic DNA damaging treatments. The phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, reduces Plk1 dephosphorylation following mitotic DNA damaging treatments, suggesting that the PI3K pathway may be involved in regulating Plk1 activity. Earlier studies showed that inhibition of Plk1 by G2 DNA damage occurs in an ATM-dependent fashion. Our results extend the previous studies by showing that ATM is not required for dephosphorylation and inhibition of Plk1 activity following mitotic DNA damage, and also suggest that Plk1 is not a principal regulator or mediator of the mitotic DNA damage response.

Ataxia Telangiectasia Mutated Proteins↗
PubMed1998

Ataxia-telangiectasia without immunodeficiency: novel point mutations within and adjacent to the phosphatidylinositol 3-kinase-like domain.

Ataxia-telangiectasia (AT) is an autosomal recessive disorder characterized by progressive ataxia, telangiectasia, sinopulmonary infections, hypersensitivity to ionizing radiation, and combined immunodeficiency. Recently, the AT gene (ATM) was cloned and shown to be mutated in AT patients. In this report, mutation analysis of ATM was performed in a 24-year-old AT patient without immunodeficiency. ATM amplified with reverse transcriptase-polymerase chain reaction (RT-PCR) was screened with a ribonuclease (RNase) cleavage assay and auto-sequenced. This patient, a compound heterozygote, showed two mutations in ATM: one missense mutation leading to a Leu2656Pro substitution and the other to the truncation at codon 3047 (Arg-->ter). The latter mutation is within the phosphatidylinositol 3-kinase (PI 3-kinase)-like domain and the former is outside but close to the domain. The particular phenotype in our patient, no immunodeficiency, suggests incomplete functional loss of ATM protein. The clinical spectrum of AT caused by ATM mutations may be broader than previously thought. Further analysis of patients with similar phenotypes will make the relation between ATM genotype and phenotype clear.

Adult↗