Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder involving cerebellar degeneration, immunodeficiency, chromosomal instability, radiosensitivity and cancer predisposition. The responsible gene, ATM, was recently identified by positional cloning and found to encode a putative 350 kDa protein with a Pl 3-kinase-like domain, presumably involved in mediating cell cycle arrest in response to radiation-induced DNA damage. The nature and location of A-T mutations should provide insight into the function of the ATM protein and the molecular basis of this pleiotropic disease. Of 44 A-T mutations identified by us to date, 39 (89%) are expected to inactivate the ATM protein by truncating it, by abolishing correct initiation or termination of translation, or by deleting large segments. Additional mutations are four smaller in-frame deletions and insertions, and one substitution of a highly conserved amino acid at the Pl 3-kinase domain. The emerging profile of mutations causing A-T is thus dominated by those expected to completely inactivate the ATM protein. ATM mutations with milder effects may result in phenotypes related, but not identical, to A-T.
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PMID:Predominance of null mutations in ataxia-telangiectasia. 884 35

Defects in regulation of the cellular life cycle may lead to premature cellular death or malignant transformation. Most of the proteins known to be involved in these processes are mediators of mitogenic signals or components of the cell cycle machinery. It has recently become evident, however, that systems responsible for ensuring genome stability and integrity are no less important in maintaining the normal life cycle of the cell. These systems include DNA repair enzymes and a recently emerging group of proteins that alert growth regulating mechanisms to the presence of DNA damage. These signals slow down the cell cycle while DNA repair ensues. Ataxia telangiectasia (A-T) is a genetic disorder whose clinical and cellular phenotype points to a defect in such a signaling system. A-T is characterized by neurodegeneration, immunodeficiency, radiosensitivity, cancer predisposition, and defective cell cycle checkpoints. The responsible gene, ATM, was recently cloned and sequenced. ATM encodes a large protein with a region highly similar to the catalytic domain of PI 3-kinases. The ATM protein is similar to a group of proteins in various organisms which are directly involved in the cell cycle response to DNA damage. It is expected to be part of a protein complex that responds to a specific type of DNA strand break by conveying a regulatory signal to other proteins. Interestingly, the immune and nervous systems, which differ markedly in their proliferation rates, are particularly sensitive to the absence of ATM function. The identification of the ATM gene highlights the growing importance of signal transduction initiated in the nucleus rather than in the external environment, for normal cellular growth.
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PMID:Ataxia-telangiectasia and the ATM gene: linking neurodegeneration, immunodeficiency, and cancer to cell cycle checkpoints. 888 93

The ATM gene is responsible for the autosomal recessive disorder ataxia-telangiectasia (A-T), characterized by cerebellar degeneration, immunodeficiency and cancer predisposition. A-T carriers were reported to be moderately cancer-prone. A wide variety of A-T mutations, most of which are unique to single families, were identified in various ethnic groups, precluding carrier screening with mutation-specific assays. However, a single mutation was observed in 32/33 defective ATM alleles in Jewish A-T families of North African origin, coming from various regions of Morocco and Tunisia. This mutation, 103C-->T, results in a stop codon at position 35 of the ATM protein. In keeping with the nature of this mutation, various antibodies directed against the ATM protein failed to defect this protein in patient cells. A rapid carrier detection assay detected this mutation in three out of 488 ATM alleles of Jewish Moroccan or Tunisian origin. This founder effect provides a unique opportunity for population-based screening for A-T carriers in a large Jewish community.
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PMID:Ataxia-telangiectasia: founder effect among north African Jews. 896 60

The autosomal recessive human disorder ataxia-telangiectasia (A-T) was first described as a separate disease entity 40 years ago. It is a multisystem disease characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, radiosensitivity, predisposition to lymphoid malignancies and immunodeficiency, with defects in both cellular and humoral immunity. The pleiotropic nature of the clinical and cellular phenotype suggests that the gene product involved is important in maintaining stability of the genome but also plays a more general role in signal transduction. The chromosomal instability and radiosensitivity so characteristic of this disease appear to be related to defective activation of cell cycle checkpoints. Greater insight into the nature of the defect in A-T has been provided by the recent identification, by positional cloning, of the responsible gene, ATM. The ATM gene is related to a family of genes involved in cellular responses to DNA damage and/or cell cycle control. These genes encode large proteins containing a phosphatidylinositol 3-kinase domain, some of which have protein kinase activity. The mutations causing A-T completely inactivate or eliminate the ATM protein. This protein has been detected and localized to different subcellular compartments.
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PMID:The genetic defect in ataxia-telangiectasia. 914 86

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by neurodegeneration, immunodeficiency, cancer predisposition, genome instability and radiation sensitivity. The cellular phenotype of A-T points to defects in signal transduction pathways involved in activation of cell cycle checkpoints by free radical damage, and other pathways that mediate the transmission of specific mitogenic stimuli. The product of the responsible gene, ATM, belongs to a family of large proteins that contribute to maintaining genome stability and cell cycle progression in various organisms. A recombinant vector that stably expresses a full-length ATM protein is a valuable tool for its functional analysis. We constructed and cloned a recombinant, full-length open reading frame of ATM using a combination of vectors and hosts that overcame an inherent instability of this sequence. Recombinant ATM was stably expressed in insect cells using a baculovirus vector, albeit at a low level, and in human A-T cells using an episomal expression vector. An amino-terminal FLAG epitope added to the protein allowed highly specific detection of the recombinant molecule by immunoblotting, immunoprecipitation and immunostaining, and its isolation using immunoaffinity. Similar to endogenous ATM, the recombinant protein is located mainly in the nucleus, with low levels in the cytoplasm. Ectopic expression of ATM in A-T cells restored normal sensitivity to ionizing radiation and the radiomimetic drug neocarzinostatin, and a normal pattern of post-irradiation DNA synthesis, which represents an S-phase checkpoint. These observations indicate that the recombinant, epitope-tagged protein is functional. Introduction into this molecule of a known A-T missense mutation, Glu2904Gly, resulted in apparent instability of the protein and inability to complement the A-T phenotype. These findings indicate that the physiological defects characteristic of A-T cells result from the absence of the ATM protein, and that this deficiency can be corrected by ectopic expression of this protein.
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PMID:Recombinant ATM protein complements the cellular A-T phenotype. 924 51

The autosomal recessive disorder ataxia-telangiectasia (AT) is highly pleiotropic. It is characterized by gradual loss of Purkinje cells in the cerebellum, leading to progressive neuromotor deterioration, immunodeficiency, developmental defects in specific tissues, profound predisposition to malignancy and acute sensitivity to ionizing radiation. AT cells show chromosomal instability, premature senesence, radiosensitivity and defects in cell cycle checkpoints activated by ionizing radiation. Several radiation induced pathways that regulate the cell cycle seem to be defective in AT cells, at least one of which is mediated by TP53. Extensive characterization of the cellular defects of AT cells, together with the recent isolation of the ATM gene, has provided some insight into the possible physiological roles of the ATM protein. Several lines of evidence, including the nature of the agents that elicit the hypersensitivity of AT cells, point to the possibility of a defect in the response to damage induced by oxidative stress, which affects various cellular macromolecules. The ATM protein might have a role in activating defence mechanisms against oxidative stress. This hypothesis broadens the previous concept of the AT defect and explains several aspects of the AT phenotype that cannot be accounted for by defective processing of DNA damage.
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PMID:The ATM gene and protein: possible roles in genome surveillance, checkpoint controls and cellular defence against oxidative stress. 933 5

Gene mutations provide valuable clues to cellular metabolism. In humans such insights come mainly from genetic disorders. Ataxia-telangiectasia (A-T) and Nijmegen breakage syndrome (NBS) are two distinct but closely related, single gene disorders that highlight a complex junction of several signal transduction pathways. These pathways appear to control defense mechanisms against specific types of damage to cellular macromolecules, and probably regulate the processing of certain types of DNA damage or normal intermediates of DNA metabolism. A-T is characterized primarily by cerebellar degeneration, immunodeficiency, genome instability, clinical radiosensitivity, and cancer predisposition. NBS shares all these features except cerebellar deterioration. The cellular phenotypes of A-T and NBS are almost indistinguishable, however, and include chromosomal instability, radiosensitivity, and defects in cell cycle checkpoints normally induced by ionizing radiation. The recent identification of the gene responsible for A-T, ATM, has revealed its product to be a large, constitutively expressed phosphoprotein with a carboxy-terminal region similar to the catalytic domain of phosphatidylinositol 3-kinases (PI 3-kinases). ATM is a member of a family of proteins identified in various organisms, which share the PI 3-kinase domain and are involved in regulation of cell cycle progression and response to genotoxic agents. Some of these proteins, most notably the DNA-dependent protein kinase, have an associated protein kinase activity, and preliminary data indicate this activity in ATM as well. Mutations in A-T patients are null alleles that truncate or destabilize the ATM protein. Atm-deficient mice recapitulate the human phenotype with slower nervous-system degeneration. Two ATM interactors, c-Abl and p53, underscore its role in cellular responses to genotoxic stress. The complexity of ATM's structure and mode of action make it a paradigm of multifaceted signal transduction proteins involved in many physiological pathways via multiple protein-protein interactions. The as yet unknown NBS protein may be a component in an ATM-based complex, with a key role in sensing and processing specific DNA damage or intermediates and signaling their presence to the cell cycle machinery.
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PMID:Ataxia-telangiectasia and the Nijmegen breakage syndrome: related disorders but genes apart. 944 10

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.
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PMID:Ataxia-telangiectasia without immunodeficiency: novel point mutations within and adjacent to the phosphatidylinositol 3-kinase-like domain. 945 Aug 74

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by cerebellar degeneration, immunodeficiency, chromosomal instability, radiosensitivity, and cancer predisposition. A-T cells are sensitive to ionizing radiation and radiomimetic chemicals and fail to activate cell-cycle checkpoints after treatment with these agents. The responsible gene, ATM, encodes a large protein kinase with a phosphatidylinositol 3-kinase-like domain. The typical A-T phenotype is caused, in most cases, by null ATM alleles that truncate or severely destabilize the ATM protein. Rare patients with milder manifestations of the clinical or cellular characteristics of the disease have been reported and have been designated "A-T variants." A special variant form of A-T is A-TFresno, which combines a typical A-T phenotype with microcephaly and mental retardation. The possible association of these syndromes with ATM is both important for understanding their molecular basis and essential for counseling and diagnostic purposes. We quantified ATM-protein levels in six A-T variants, and we searched their ATM genes for mutations. Cell lines from these patients exhibited considerable variability in radiosensitivity while showing the typical radioresistant DNA synthesis of A-T cells. Unlike classical A-T patients, these patients exhibited 1%-17% of the normal level of ATM. The underlying ATM genotypes were either homozygous for mutations expected to produce mild phenotypes or compound heterozygotes for a mild and a severe mutation. An A-TFresno cell line was found devoid of the ATM protein and homozygous for a severe ATM mutation. We conclude that certain "A-T variant" phenotypes represent ATM mutations, including some of those without telangiectasia. Our findings extend the range of phenotypes associated with ATM mutations.
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PMID:Genotype-phenotype relationships in ataxia-telangiectasia and variants. 949 52

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectasia, immunodeficiency, elevated alpha-fetoprotein levels, chromosomal instability, predisposition to cancer, and radiation sensitivity. We report the identification of a new, double missense mutation in the ataxia telangiectasia gene (ATM) of a Dutch family. This homozygous mutation consists of two consecutive base substitutions in exon 55: a T-->G transversion at position 7875 of the ATM cDNA and a G-->C transversion at position 7876. These transversions were confirmed by polymerase chain reaction/primer-induced restriction analysis with CelII. The double base substitution results in an amino acid change of an aspartic acid to a glutamic acid at codon 2625 and of an alanine to a proline at codon 2626 of the ATM protein. Both amino acids are conserved between the ATM protein and its functional homolog, the Atm gene product in the mouse. Furthermore, the Chou-Fasman and Robson predictions both demonstrate a change in the secondary structure of the ATM protein carrying the D2625E/A2626P mutation. These findings suggest that the double base substitution in the ATM gene is a disease-causing mutation.
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PMID:A double missense mutation in the ATM gene of a Dutch family with ataxia telangiectasia. 952 87


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