Alternative titles; symbols
HGNC Approved Gene Symbol: ATM
SNOMEDCT: 254843006, 363518003, 443487006, 68504005, 74654000, 763065008; ICD10CM: C83.1; ICD9CM: 200.4;
Cytogenetic location: 11q22.3 Genomic coordinates (GRCh38) : 11:108,223,067-108,369,102 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q22.3 | {Breast cancer, susceptibility to} | 114480 | Autosomal dominant; Somatic mutation | 3 |
| Ataxia-telangiectasia | 208900 | Autosomal recessive | 3 | |
| Lymphoma, B-cell non-Hodgkin, somatic | 3 | |||
| Lymphoma, mantle cell, somatic | 3 | |||
| T-cell prolymphocytic leukemia, somatic | 3 |
The ATM protein is a member of the phosphatidylinositol 3-kinase (see 601232) family of proteins that respond to DNA damage by phosphorylating key substrates involved in DNA repair and/or cell cycle control.
Using a positional cloning strategy, Savitsky et al. (1995) identified a gene that they designated ATM. A partial ATM cDNA clone of 5.9 kb identified a 12-kb band on Northern blot. To clone ATM, Savitsky et al. (1995) constructed a YAC contig and cosmid contigs spanning the interval between D11S384 and D11S1818. Two complementary methods were used for identification of transcribed sequences: hybrid selection based on direct hybridization of genomic DNA with cDNAs, and exon amplification to identify putative exons in genomic DNA by their splicing capacity. One cDNA clone had an open reading frame that predicted a protein of 1,708 amino acids corresponding to the C-terminal half of the ATM protein.
Savitsky et al. (1995) reported the sequence of a cDNA contig spanning the entire open reading frame of the ATM gene. The predicted 3,056-amino acid protein has a molecular mass of 350.6 kD and shows significant sequence similarities to several yeast, Drosophila, and mammalian phosphatidylinositol 3-prime (PI-3) kinases (e.g., 171833, 171834) that are involved in mitogenic signal transduction, meiotic recombination, detection of DNA damage, and cell cycle control. Mutations in these genes confer a variety of phenotypes with features similar to those observed in human ataxia-telangiectasia (AT; 208900) cells. Savitsky et al. (1995) speculated that the discovery of ATM may allow the identification of AT heterozygotes who are at increased risk of cancer.
Byrd et al. (1996) reported the 1,348-amino acid sequence of the N-terminal half of the ATM gene product. No homology with other genes was found within the N-terminal half of the AT protein.
Kastan (1995) reviewed the implications of the cloning of the ATM gene.
Pecker et al. (1996) showed that the mouse Atm gene encodes a deduced 3,066-amino acid protein with 84% identity to the human sequence. Northern blot analysis detected expression of a 13-kb transcript in brain, skeletal muscle, and testis, with lower expression in other tissues. A 10.5-kb band was also seen in testis mRNA.
Uziel et al. (1996) determined the genomic organization of the ATM gene, using long distance PCR between exons. The gene contains 66 exons spanning approximately 150 kb of genomic DNA. The first 2 exons, 1a and 1b, are used differentially in alternative transcripts; the initiation codon lies within exon 4; and the final, 3.8-kb exon has about 3.6 kb of 3-prime untranslated sequence.
Linkage analysis of ataxia-telangiectasia led to mapping of the ATM gene to chromosome 11q22.3 (Gatti et al. (1988, 1993)).
Matsuda et al. (1996) determined the chromosomal locations of the Atm and Acat1 (607809) genes in mouse, rat, and Syrian hamster by direct R-banding fluorescence in situ hybridization. The 2 genes colocalized to mouse 9C-D, the proximal end of rat 8q24.1, and 12qa4-qa5 of Syrian hamster. The regions in the mouse and rat are homologous to human chromosome 11q. In the study of interspecific backcross mice, no recombinants were found among Atm, Npat (601448), and Acat1.
By interspecific backcross analysis, Xia et al. (1996) also mapped the mouse Atm gene to chromosome 9. By FISH, Pecker et al. (1996) refined the location of the mouse Atm gene to band 9C.
For early functional studies in yeast and Drosophila, see below.
Using an antiserum developed to a peptide corresponding to the deduced amino acid sequence of ATM, Brown et al. (1997) showed that the ATM protein is a single, high molecular weight protein predominantly confined to the nucleus of human fibroblasts, although it is present in both nuclear and microsomal fractions from human lymphoblast cells and peripheral blood lymphocytes. ATM protein levels and localization remain constant throughout all stages of the cell cycle. Truncated ATM protein was not detected in lymphoblasts from AT patients homozygous for mutations leading to premature protein termination. Exposure of normal human cells to gamma-irradiation and the radiomimetic drug neocarzinostatin had no effect on ATM protein levels, in contrast to a noted rise in p53 (TP53; 191170) levels over the same time interval. The findings of constitutive expression and nuclear localization of the ATM protein were consistent with its potential role in choreographing appropriate cellular responses to genomic damage.
Hawley and Friend (1996) commented on the state of ATM research and concluded that ATM must play a crucial role in normally developing or undamaged cells, as well as the studied role in irradiated cells, in order to explain the neurologic, immune, and reproductive problems observed in AT patients. They also proposed that ATM may be intimately associated with both p53 and the molecular machinery required for chromosomal exchange, perhaps as components of the recombination nodules.
Zhang et al. (1997) discussed the cloning of a full-length cDNA encoding ATM and correction of multiple aspects of the radiosensitive phenotype of AT cells by transfection with this cDNA. Overexpression of ATM cDNA in AT cells enhanced their survival after radiation exposure, decreased radiation-induced chromosome aberrations, reduced radioresistant DNA synthesis, and partially corrected defective cell cycle checkpoints and induction of stress-activated protein kinase. This correction of the defects of AT cells provided further evidence of the multiplicity of effector functions of the ATM protein and suggested possible approaches to gene therapy.
Banin et al. (1998) and Canman et al. (1998) observed enhanced phosphorylation of p53 by ATM in response to DNA damage. Both found that ATM had intrinsic protein kinase activity and phosphorylated p53 on serine-15 in a manganese-dependent manner. Ionizing radiation, but not ultraviolet radiation, rapidly enhanced the p53-directed kinase activity of endogenous ATM. Phosphorylation of p53 on serine-15 in response to ionizing radiation was reduced in ataxia-telangiectasia cells.
Khanna et al. (1998) reported direct interaction between ATM and p53 involving 2 regions in ATM, one at the N terminus and the other at the C terminus, corresponding to the PI-3 kinase domain. Recombinant ATM protein phosphorylated p53 on serine 15 near the N terminus. Ectopic expression of ATM in AT cells restored normal ionizing radiation-induced phosphorylation of p53, whereas expression of ATM antisense RNA in control cells abrogated the rapid IR-induced phosphorylation of p53 on serine 15. The results demonstrated that ATM can bind p53 directly and is responsible for its serine 15 phosphorylation, thereby contributing to the activation and stabilization of p53 during the IR-induced DNA damage response.
Using the yeast 2-hybrid system, Lim et al. (1998) demonstrated that the ATM protein binds to beta-adaptin (600157), one of the components of the AP-2 adaptor complex, which is involved in clathrin-mediated endocytosis of receptors. The interaction between ATM and beta-adaptin was confirmed in vitro, and coimmunoprecipitation and colocalization studies showed that the proteins also associate in vivo. The ATM protein also interacted in vitro with beta-NAP (602166), a neuronal beta-adaptin homolog that had been identified as an autoantigen in a patient with cerebellar degeneration. The finding of an association of ATM with beta-adaptin in vesicles indicated that ATM may play a role in intracellular vesicle and/or protein transport mechanisms. The interaction may help explain how mutations in the ATM gene cause the pleiotropic nature of the ataxia-telangiectasia phenotype. The large size of the ATM protein and its multiple subcellular localization suggest that ATM may have more than one function.
Cortez et al. (1999) demonstrated that the checkpoint protein kinase ATM is required for phosphorylation of Brca1 (113705) in response to ionizing radiation. ATM resides in a complex with Brca1 and phosphorylated Brca1 in vivo and in vitro, in a region that contains clusters of serine-glutamine residues. Cortez et al. (1999) used tandem mass spectrometry to demonstrate the 4 serines (S1189, S1457, S1524, S1542) in this region of Brca1 that are phosphorylated in vivo. A mutated Brca1 protein lacking 2 phosphorylation sites (serines 1423 and 1524) failed to rescue the radiation hypersensitivity of a Brca1-deficient cell line. Cortez et al. (1999) concluded that phosphorylation of Brca1 by ATM may be critical for proper response to DNA double-strand breaks and may provide a molecular explanation for the role of ATM in breast cancer.
Wang et al. (2000) used immunoprecipitation and mass spectrometry analyses to identify BRCA1-associated proteins. They found that BRCA1 is part of a large multisubunit protein complex of tumor suppressors, DNA damage sensors, and signal transducers. They named this complex BASC, for 'BRCA1-associated genome surveillance complex.' Among the DNA repair proteins identified in the complex were ATM, BLM (604610), MSH2 (609309), MSH6 (600678), MLH1 (120436), the RAD50-MRE11-NBS1 complex, and the RFC1 (102579)-RFC2 (600404)-RFC4 (102577) complex. Wang et al. (2000) suggested that BASC may serve as a sensor of abnormal DNA structures and/or as a regulator of the postreplication repair process.
By coimmunoprecipitation and in vitro pull-down assays, Beamish et al. (2002) verified direct interaction between ATM and BLM. By mutation analysis, they mapped the BLM-binding domain of ATM to residues 82 through 89, amino acids that are also involved in ATM binding of p53 and BRCA1. The ATM-binding region of BLM mapped to residues 636 to 1,074. Beamish et al. (2002) determined that the mitosis-associated hyperphosphorylation of BLM was partially dependent upon ATM phosphorylating thr99 and thr122 in the N-terminal region of BLM. Radiation-induced phosphorylation of BLM at thr99 was dose-dependent in normal cells and was defective in AT cells.
Because of the similarities between ataxia-telangiectasia and Nijmegen breakage syndrome (251260), Lim et al. (2000) evaluated the functional interactions between the ATM and nibrin (NBS1; 602667) genes. Activation of the ATM kinase by ionizing radiation and induction of ATM-dependent responses in NBS cells indicated that NBS1 may not be required for signaling to ATM after ionizing radiation. However, NBS1 was phosphorylated on serine-343 in an ATM-dependent manner in vitro and in vivo after ionizing radiation. An NBS1 construct mutated at the ATM phosphorylation site abrogated an S-phase checkpoint induced by ionizing radiation in normal cells and failed to compensate for this functional deficiency in NBS cells. These observations linked ATM and NBS1 in a common signaling pathway and provided an explanation for the phenotypic similarities between the 2 disorders.
Gatei et al. (2000) demonstrated that NBS1 is phosphorylated within 1 hour of treatment of cells with ionizing radiation. This response was abrogated in AT cells that either do not express ATM protein or express near full-length mutant protein. Gatei et al. (2000) also showed that ATM physically interacts with and phosphorylates NBS1 on serine-343 both in vivo and in vitro. Phosphorylation of this site appears to be functionally important because mutated nibrin (S343A) does not completely complement radiosensitivity in NBS cells. ATM phosphorylation of NBS1 does not affect NBS1-MRE11-RAD50 (604040) association, as revealed by radiation-induced foci formation. Gatei et al. (2000) concluded that their data provide a biochemical explanation for the similarity in phenotype between AT and NBS.
Zhao et al. (2000) demonstrated that catalytically active ATM is required for phosphorylation of NBS1, induced by ionizing radiation. Complexes containing ATM and NBS1 exist in vivo in both untreated cells and cells treated with ionizing radiation. Zhao et al. (2000) identified 2 residues of NBS1, serine-278 and serine-343, that are phosphorylated in vitro by ATM and whose modification in vivo is essential for the cellular response to DNA damage. This response includes S-phase checkpoint activation, formation of the NBS1/Mre11/Rad50 nuclear foci, and rescue of hypersensitivity to ionizing radiation. Zhao et al. (2000) concluded that together these results demonstrated a biochemical link between cell cycle checkpoints activated by DNA damage and DNA repair in 2 genetic diseases with overlapping phenotypes.
Wu et al. (2000) reported that phosphorylation of NBS1 mediated by gamma-radiation, but not that induced by hydroxyurea or ultraviolet light, was markedly reduced in ATM cells. In vivo, NBS1 was phosphorylated on many serine residues, of which serine-343, serine-397, and serine-615 were phosphorylated by ATM in vitro. At least 2 of these sites were underphosphorylated in ATM cells. Inactivation of these serines by mutation partially abrogated ATM-dependent phosphorylation. Reconstituting NBS1 cells with a mutant form of NBS1 that cannot be phosphorylated at selected ATM-dependent serine residues led to a specific reduction in clonogenic survival after gamma-radiation. Wu et al. (2000) concluded that phosphorylation of NBS1 by ATM is critical for certain responses of human cells to DNA damage.
When exposed to ionizing radiation, eukaryotic cells activate checkpoint pathways to delay the progression of the cell cycle. Defects in the ionizing radiation-induced S-phase checkpoint cause 'radioresistant DNA synthesis,' a phenomenon that has been identified in cancer-prone patients suffering from ataxia-telangiectasia. The CDC25A phosphatase (116947) activates the cyclin-dependent kinase 2 (CDK2; 116953) needed for DNA synthesis, but becomes degraded in response to DNA damage or stalled replication. Falck et al. (2001) reported a functional link between ATM, checkpoint signaling kinase CHK2 (604373), and CDC25A, and implicated this mechanism in controlling the S-phase checkpoint. Falck et al. (2001) showed that ionizing radiation-induced destruction of CDC25A requires both ATM and the CHK2-mediated phosphorylation of CDC25A on serine-123. An ionizing radiation-induced loss of CDC25A protein prevents dephosphorylation of CDK2 and leads to a transient blockade of DNA replication. Falck et al. (2001) also showed that tumor-associated CHK2 alleles cannot bind or phosphorylate CDC25A, and that cells expressing these CHK2 alleles, elevated CDC25A, or a CDK2 mutant unable to undergo inhibitory phosphorylation (CDK2AF) fail to inhibit DNA synthesis when irradiated. Falck et al. (2001) concluded that their results support CHK2 as a candidate tumor suppressor, and identify the ATM--CHK2--CDC25A--CDK2 pathway as a genomic integrity checkpoint that prevents radioresistant DNA synthesis.
Falck et al. (2002) demonstrated that experimental blockade of either the NBS1-MRE11 function or the CHK2-triggered events leads to a partial radioresistant DNA synthesis phenotype in human cells. In contrast, concomitant interference with NBS1-MRE11 and the CHK2-CDC25A-CDK2 pathways entirely abolishes inhibition of DNA synthesis induced by ionizing radiation, resulting in complete radioresistant DNA synthesis analogous to that caused by defective ATM. In addition, CDK2-dependent loading of CDC45 (603465) onto replication origins, a prerequisite for recruitment of DNA polymerase, was prevented upon irradiation of normal or NBS1/MRE11-defective cells but not cells with defective ATM. Falck et al. (2002) concluded that in response to ionizing radiation, phosphorylation of NBS1 and CHK2 by ATM triggers 2 parallel branches of the DNA damage-dependent S-phase checkpoint that cooperate by inhibiting distinct steps of DNA replication.
Lee and Paull (2005) showed that the MRE11-RAD50-NBS1 (MRN) complex acts as a double-strand break sensor for ATM and recruits ATM to broken DNA molecules. Inactive ATM dimers were activated in vitro with DNA in the presence of MRN, leading to phosphorylation of the downstream cellular targets p53 and CHK2. ATM autophosphorylation was not required for monomerization of ATM by MRN. The unwinding of DNA ends by MRN was essential for ATM stimulation, which is consistent with the central role of single-stranded DNA as an evolutionarily conserved signal for DNA damage.
Bao et al. (2001) demonstrated a direct regulatory linkage between RAD17 and the checkpoint kinases ATM and ATR (601215). Treatment of human cells with genotoxic agents induced ATM/ATR-dependent phosphorylation of RAD17 at serine-635 and serine-645. Overexpression of a RAD17 mutant bearing alanine substitutions at both phosphorylation sites abrogated the DNA damage-induced G2 checkpoint and sensitized human fibroblasts to genotoxic stress. In contrast to wildtype RAD17, the RAD17 mutant showed no ionizing radiation-inducible association with RAD1 (603153), a component of the RAD1-RAD9 (603761)-HUS1 (603760) checkpoint complex. These findings demonstrated that ATR/ATM-dependent phosphorylation of RAD17 is a critical early event during checkpoint signaling in DNA-damaged cells.
Taniguchi et al. (2002) identified FANCD2 (227646) as a link between the FA (607139) and ATM damage response pathways. ATM phosphorylated FANCD2 on ser222 in vitro. This site was also phosphorylated in vivo in an ATM-dependent manner following ionizing radiation. Phosphorylation of FANCD2 was required for activation of an S-phase checkpoint. The authors determined that the ATM-dependent phosphorylation of FANCD2 on ser222 and the FA pathway-dependent monoubiquitination of FANCD2 on lys561 are independent posttranslational modifications regulating discrete cellular signaling pathways. Biallelic disruption of FANCD2 resulted in both mitomycin C and ionizing radiation hypersensitivity.
Bakkenist and Kastan (2003) demonstrated that ATM is dormant in unirradiated cells as a dimer or higher-order multimer, with the kinase domain bound to a region surrounding serine-1981 that is contained within the previously described FAT domain. Cellular irradiation induced intermolecular autophosphorylation of serine-1981 that caused dimer dissociation and initiated cellular ATM kinase activity. Most ATM molecules in the cell were rapidly phosphorylated on this site after doses of radiation as low as 0.5 Gy, and binding of a phosphospecific antibody was detectable after the introduction of only a few DNA double-strand breaks in the cell. Activation of the ATM kinase seems to be an initiating event in cellular responses to irradiation. Bakkenist and Kastan (2003) concluded that ATM activation is not dependent on direct binding to DNA strand breaks, but may result from changes in the structure of chromatin.
Ito et al. (2004) showed that ATM has an essential role in the reconstitutive capacity of hematopoietic stem cells but is not as important for the proliferation or differentiation of progenitors, in a telomere-independent manner. Atm-null mice older than 24 weeks showed progressive bone marrow failure resulting from a defect in the hematopoietic stem cell function that was associated with elevated reactive oxygen species. Treatment with antioxidative agents restored the reconstitutive capacity of Atm-null hematopoietic stem cells, resulting in the prevention of bone marrow failure. Activation of the p16(INK4a) (600160)-retinoblastoma (RB1; 614041) gene product pathway in response to elevated reactive oxygen species led to the failure of Atm-null hematopoietic stem cells. Ito et al. (2004) concluded that the self-renewal capacity of hematopoietic stem cells depends on ATM-mediated inhibition of oxidative stress.
Bolderson et al. (2004) showed that thymidine, which slows the progression of replication forks by depleting cellular pools of dCTP, induced a novel DNA damage response that depended on both ATM and ATR (601215). Thymidine induced ATM-mediated phosphorylation of CHK2 and NBS1 (602667) and an ATM-independent phosphorylation of CHK1 (603078) and SMC1 (300040). AT cells exposed to thymidine showed decreased viability and failed to induce homologous recombination repair.
Falck et al. (2005) identified related, conserved C-terminal motifs in human NBS1, ATRIP (606605), and Ku80 (194364) proteins that are required for their interaction with members of the phosphoinositide 3 kinase-related protein kinase (PIKK; see 607032) family, ATM, ATR, and DNA-PKcs (600899), respectively. These EEXXXDDL motifs are essential not only for efficient recruitment of ATM, ATR, and DNA-PKcs to sites of damage, but are also critical for ATM-, ATR-, and DNA-PKcs-mediated signaling events that trigger cell cycle checkpoints and DNA repair. Falck et al. (2005) concluded that recruitment of these PIKKs to DNA lesions occurs by common mechanisms through an evolutionarily conserved motif, and provide direct evidence that PIKK recruitment is required for PIKK-dependent DNA-damage signaling.
Wu et al. (2006) demonstrated that NEMO (300248), the regulatory subunit of the IKK complex (see 600664), which phosphorylates the NF-kappa-B (see 164011) inhibitor I-kappa-B (see 164008), associates with activated ATM after the induction of DNA double-strand breaks. ATM phosphorylates serine-85 of NEMO to promote its ubiquitin-dependent nuclear export. ATM is also exported in a NEMO-dependent manner to the cytoplasm, where it associates with and causes the activation of IKK in a manner dependent on another IKK regulator, a protein rich in glutamate, leucine, lysine, and serine (ELKS; 607127). Thus, Wu et al. (2006) concluded that regulated nuclear shuttling of NEMO links 2 signaling kinases, ATM and IKK, to activate NF-kappa-B by genotoxic signals. An Expression of Concern regarding 'data integrity' has been published for the article by Wu et al. (2006).
Giuliano et al. (2003) developed stable cell lines expressing green fluorescent protein fusion proteins containing polyglutamine repeats of various lengths. The expression of the expanded (43Q) repeat protein resulted in aggregate formation in a time-dependent fashion, but did not induce apoptosis. However, the expression of 43Q-expanded protein strongly activated the ATM and Rad3-related kinase (ATR; 601215) (ATM/ATR)-dependent DNA damage response, as shown by selective phosphorylation of ATM substrates. Similarly, Giuliano et al. (2003) found phosphorylated ATM substrates in fibroblasts from Huntington disease (143100) and SCA2 (183090) patients. Oxidative stress increased accumulation of these phosphorylated ATM substrates. The authors concluded that polyglutamine induces ATM/ATR-dependent DNA damage response through accumulation of reactive oxygen species.
Using yeast mutants, Saiardi et al. (2005) showed that inositol pyrophosphates physiologically antagonized the actions of Tel1 and Mec1. Mutants with reduced or elevated levels of inositol pyrophosphates displayed longer and shorter telomeres, respectively.
Lau et al. (2005) hypothesized that the poorly defined DNA damage response to HIV-1 infection may involve a pathway susceptible to inhibition of a crucial part of the retroviral life cycle. Using genetic and pharmacologic approaches, they found that KU-55933, a compound that specifically and potently inhibits ATM, suppressed the replication of wildtype and drug-resistant HIV-1 isolates by targeting the postintegration DNA repair phase of the retroviral life cycle. Lau et al. (2005) demonstrated that efficient viral replication requires ATM and that infection activates the ATM-dependent DNA damage response pathway. In the absence of ATM, host cells had reduced survival in response to HIV-1 integrase-induced DNA damage. Lau et al. (2005) suggested that inhibition of ATM, a nonessential cellular target, may represent a novel approach to treatment of HIV-1 infection.
Bartkova et al. (2005) showed that in clinical specimens from different stages of human tumors of the urinary bladder, breast, lung, and colon, the early precursor lesions, but not normal tissues, commonly express markers of an activated DNA damage response. These include phosphorylated kinases ATM and CHK2 (604373) and phosphorylated histone H2AX (601772) and p53 (191170). Similar checkpoint responses were induced in cultured cells upon expression of different oncogenes that deregulate DNA replication. Together with genetic analyses, including a genomewide assessment of allelic imbalances, Bartkova et al. (2005) concluded that early in tumorigenesis (before genomic instability and malignant conversion), human cells activate an ATR/ATM-regulated DNA damage response network that delays or prevents cancer. Mutations compromising this checkpoint, including defects in the ATM-CHK2-p53 pathway, might allow cell proliferation, survival, increased genomic instability, and tumor progression.
Sun et al. (2005) determined that DNA damage in HeLa cells induced rapid acetylation of ATM that was dependent on TIP60 (HTATIP; 601409). Suppression of TIP60 blocked activation of ATM kinase activity and prevented ATM-dependent phosphorylation of p53 and CHK2. Furthermore, inactivation of TIP60 sensitized cells to ionizing radiation. ATM formed a stable complex with TIP60, and DNA damage activated the histone acetyltransferase activity of the ATM-TIP60 complex. Activation of TIP60 by DNA damage and recruitment of the ATM-TIP60 complex to sites of DNA damage were independent of ATM kinase activity.
Bredemeyer et al. (2006) demonstrated that ATM functions directly in the repair of chromosomal DNA double-stranded breaks by maintaining DNA ends in repair complexes generated during lymphocyte gene assembly. They concluded that when coupled with cell-cycle checkpoint and proapoptotic activities of ATM, their findings provide a molecular explanation for the increase in lymphoid tumors with translocations involving antigen receptor loci associated with ataxia-telangiectasia.
Dornan et al. (2006) reported that in response to DNA damage, ATM phosphorylated COP1 (608067) on ser387 and stimulated a rapid autodegradation mechanism. Ionizing radiation triggered an ATM-dependent movement of COP1 from the nucleus to the cytoplasm, and ATM-dependent phosphorylation of COP1 on ser387 was both necessary and sufficient to disrupt the COP1-p53 complex and subsequently to abrogate the ubiquitination and degradation of p53. Furthermore, phosphorylation of COP1 on ser387 was required to permit p53 to become stabilized and to exert its tumor suppressor properties in response to DNA damage.
Bartkova et al. (2006) showed that oncogene-induced senescence is associated with signs of DNA replication stress, including prematurely terminated DNA replication forks and DNA double-strand breaks. Inhibiting the DNA double-strand break response kinase ATM suppressed the induction of senescence and in a mouse model led to increased tumor size and invasiveness. Analysis of human precancerous lesions further indicated that DNA damage and senescence markers cosegregate closely. Thus, Bartkova et al. (2006) concluded that senescence in human preneoplastic lesions is a manifestation of oncogene-induced DNA replication stress and, together with apoptosis, provides a barrier to malignant progression.
Kruhlak et al. (2007) monitored RNA Pol I (see 602000) activity in mouse cells exposed to genotoxic stress and showed that induction of DNA breaks leads to a transient repression in Pol I transcription. Surprisingly, Kruhlak et al. (2007) found that Pol I inhibition is not itself the direct result of DNA damage but is mediated by ATM kinase activity and the repair factor proteins NBS1 (602667) and MDC1 (607593). Using live cell imaging, laser microirradiation, and photobleaching technology, Kruhlak et al. (2007) demonstrated that DNA lesions interfere with Pol I initiation complex assembly and lead to a premature displacement of elongating holoenzymes from ribosomal DNA. Kruhlak et al. (2007) concluded that their data revealed a novel ATM/NBS1/MDC1-dependent pathway that shuts down ribosomal gene transcription in response to chromosome breaks.
Matsuoka et al. (2007) performed a large-scale proteomic analysis of proteins phosphorylated in response to DNA damage on consensus sites recognized by ATM and ATR (601215) and identified more than 900 regulated phosphorylation sites encompassing over 700 proteins. Functional analysis of a subset of this dataset indicated that this list was highly enriched for proteins involved in the DNA damage response. This set of proteins was highly interconnected, and Matsuoka et al. (2007) identified a large number of protein modules and networks not previously linked to the DNA damage response. Matsuoka et al. (2007) concluded that their database painted a much broader landscape for the DNA damage response than had been appreciated and opened new avenues of investigation into the responses to DNA damage in mammals.
Soutoglou and Misteli (2008) demonstrated that prolonged binding of DNA repair factors to chromatin can elicit the DNA damage response in an ATM- and DNAPK (600899)-dependent manner in the absence of DNA damage. Targeting of single repair factors to chromatin revealed a hierarchy of protein interactions within the repair complex and suggested amplification of the damage signal. Soutoglou and Misteli (2008) concluded that activation of the DNA damage response does not require DNA damage, and stable association of repair factors with chromatin is likely a critical step in triggering, amplifying, and maintaining the DNA damage repair signal.
Lee et al. (2008) developed a yeast-based system that induces a reciprocal chromosome translocation by formation and ligation of breaks on 2 different chromosomes. They showed that interchromosomal end joining is efficiently suppressed by the Tel1- and Mre11-Rad50-Xrs2-dependent pathway; this is distinct from the role of Tel1 in telomeric integrity and from Mec1- and Tel1-dependent checkpoint controls. Suppression of double-strand break (DSB)-induced chromosome translocations depends on the kinase activity of Tel1 and Dun1, and the damage-induced phosphorylation of Sae2 (see 604124) and histone H2AX (601772) proteins. Tel1- and Sae2-dependent tethering and promotion of 5-prime to 3-prime degradation of broken chromosome ends discourage error-prone nonhomologous end-joining (NHEJ) and interchromosomal NHEJ, preserving chromosome integrity on DNA damage. Lee et al. (2008) concluded that, like human ATM, Tel1 serves as a key regulator for chromosome integrity in the pathway that reduces the risk for DSB-induced chromosome translocations, and are probably pertinent to the oncogenic chromosome translocations in ATM-deficient cells.
In an analysis of expression phenotypes among AT carriers, AT patients, and noncarrier controls, Smirnov and Cheung (2008) uncovered a regulatory pathway in which ATM regulates expression of TNFSF4 (603594) through MIRN125B (see 610104). In AT carriers and AT patients, this pathway is disrupted. As a result, the level of MIRN125B is lower and the level of its target gene, TNFSF4, is higher than in noncarriers. A decreased level of MIRN125B is associated with breast cancer, and an elevated level of TNFSF4 is associated with atherosclerosis. Thus, Smirnov and Cheung (2008) concluded that their findings provided a mechanistic suggestion for the increased risk of breast cancer and heart disease in AT carriers.
Tian et al. (2009) found that APAK (ZNF420; 617216) interacted with p53 and KAP1 (TRIM28; 601742) via its zinc fingers and KRAB domain, respectively, in unstressed human cells. KAP1 recruited ATM and HDAC1 (601241) to attenuate acetylation of p53, thereby repressing p53 activity and expression of proapoptotic genes. APAK, KAP1, and ATM did not regulate p53 targets that induce cell cycle arrest. In response to DNA damage, ATM phosphorylated APAK on ser68, causing dissociation of APAK and HDAC1 from p53, allowing expression of proapoptotic p53 target genes and apoptosis.
Guo et al. (2010) demonstrated that oxidation of ATM directly induces ATM activation in the absence of DNA double-strand breaks and the Mre11-Rad50-Nbs1 (MRN) complex. The oxidized form of ATM is a disulfide-crosslinked dimer, and mutation of a critical cysteine residue involved in disulfide bond formation specifically blocked activation through the oxidation pathway. Guo et al. (2010) concluded that identification of this pathway explains observations of ATM activation under conditions of oxidative stress and shows that ATM is an important sensor of reactive oxygen species in human cells.
Zha et al. (2011) showed that XLF (611290), ATM, and H2AX (601772) all have fundamental roles in processing and joining DNA ends during V(D)J recombination, but that these roles have been masked by unanticipated functional redundancies. Thus, combined deficiency of ATM and XLF nearly blocks mouse lymphocyte development due to an inability to process and join chromosomal V(D)J recombination DSB intermediates. Combined XLF and ATM deficiency also severely impairs classical NHEJ, but not alternative end-joining, during IgH class switch recombination. Redundant ATM and XLF functions in classical NHEJ are mediated by ATM kinase activity and are not required for extrachromosomal V(D)J recombination, indicating a role for chromatin-associated ATM substrates. Correspondingly, conditional H2AX inactivation in XLF-deficient pro-B lines leads to V(D)J recombination defects associated with marked degradation of unjoined V(D)J ends, revealing that H2AX has a role in this process.
Janssen et al. (2011) demonstrated that chromosome segregation errors can also result in structural chromosome aberrations. Chromosomes that missegregate are frequently damaged during cytokinesis, triggering a DNA double-strand break response in the respective daughter cells involving ATM, CHK2 (604373), and p53 (191170). Janssen et al. (2011) showed that these double-strand breaks can lead to unbalanced translocations in the daughter cells. Janssen et al. (2011) concluded that their data showed that segregation errors can cause translocations and provided insights into the role of whole-chromosome instability in tumorigenesis.
Lange et al. (2011) reported that the number of meiotic double-strand breaks in mouse is controlled by Atm. Levels of Spo11 (605114)-oligonucleotide complexes, byproducts of meiotic double-strand break formation, are elevated at least 10-fold in spermatocytes lacking Atm. Moreover, Atm mutation renders Spo11-oligonucleotide levels sensitive to genetic manipulations that modulate Spo11 protein levels. Lange et al. (2011) proposed that ATM restrains SPO11 via a negative feedback loop in which kinase activation by double-strand breaks suppresses further double-strand break formation. Lange et al. (2011) concluded that their findings explained previously puzzling phenotypes of Atm-null mice and provided a molecular basis for the gonadal dysgenesis observed in ataxia telangiectasia.
Erttmann et al. (2016) found that, similar to their findings in Atm -/- mice (see ANIMAL MODEL), cells from patients with AT had diminished Il1b (147720) production in response to bacteria. They concluded that ATM is essential for optimal inflammasome-dependent antibacterial innate immunity.
Early Functional Studies in Yeast and Drosophila
Mutants of the mei-41 gene in Drosophila melanogaster, which is homologous to the human ATM gene, were first identified on the basis of a defect in meiotic recombination and subsequently by their mutagen sensitivity to a wide range of mutagens, including ionizing radiation, ultraviolet radiation, methyl methanesulfonate, and hydroxyurea (Banga et al., 1986; Baker et al., 1976). Indeed, there is no overlap between the x-ray dose-kill curves for wildtype and for mei-41 mutants, and females heterozygous for mei-41 mutations display an intermediate level of mutagen sensitivity (Boyd et al., 1976; Nguyen et al., 1979). Hari et al. (1995) noted that mutations in the mei-41 gene also cause high levels of chromosome breakage and instability in mitotic cells and in the male germline. A number of gaps and breaks are enhanced following treatment with x-rays to the extent that after 220 R of irradiation, virtually all of the subsequent metaphases possess at least 1 break or rearrangement. They commented that the observation of chromatid breaks and gaps in the metaphase chromosomes of both mutagenized and unmutagenized mei-41 cells is surprising, because many organisms possess cell cycle checkpoint controls that prevent cells with damaged DNA from exiting G2 and entering the M phase. Hari et al. (1995) demonstrated that mei-41 has a similar if not identical effect on G2/M progression of x-irradiated neuroblasts in Drosophila as is observed in ataxia-telangiectasia: cells irradiated in G2 fail to display an initial block in cell cycle progression that is characteristic of normal cells. Hari et al. (1995) also showed that the Drosophila mei-41 and the human ATM gene are homologous at the level of predicted amino acid sequence. Like the ATM protein, the mei-41 protein belongs to a family of phosphatidylinositol 3-kinase (PI3K)-like proteins that include the yeast rad3 and Mec1p proteins. Hari et al. (1995) concluded that the mei-41 gene of Drosophila is a functional homolog of the human ATM gene.
Greenwell et al. (1995) showed that the ATM gene has strong homology to 2 known yeast genes, ESR1/MEC1 of Saccharomyces cerevisiae and rad3 of Schizosaccharomyces pombe, and to a yeast open reading frame, YBLO88. Greenwell et al. (1995) showed that YBLO88 encodes TEL1, a gene required for maintaining wildtype telomere length. Yeast chromosomes terminate in tracts of simple repetitive DNA, poly-G1-3-T. Mutations in the TEL1 gene result in shortened telomeres. Sequence analysis of TEL1 indicated that it encodes a very large protein (322 kD) with amino acid motifs found in phosphatidylinositol/protein kinases. The authors found that the closest homolog to TEL1 is the human ATM gene. Morrow et al. (1995) presented data indicating that TEL1 and the checkpoint gene MEC1 in S. cerevisiae are functionally related and that functions of the human ATM gene are apparently divided between at least 2 S. cerevisiae homologs. Paulovich and Hartwell (1995) likewise identified MEC1 as a yeast homolog of ATM.
Zakian (1995) provided a dendrogram indicating the relationship between ATM and the various ATM-like genes. She pointed out that 'whether or not these ATM-like genes are ATM homologs, continued inquiry in genetically tractable model organisms like yeast and Drosophila will surely provide valuable insight into the functions of this family of proteins.'
Telomeres are essential for stable maintenance of linear chromosomes in eukaryotes. As indicated earlier, the ATM family of genes, including TEL1 of budding yeast, rad3+ of fission yeast, and human ATM itself, appear to be involved in telomere length regulation. Naito et al. (1998) cloned another fission yeast ATM homolog, tel1+, and found that a tel1rad3 double mutant lost all telomeric DNA sequences. Thus, the ATM homologs are essential in telomere maintenance. The mutant grew poorly and formed irregular-shaped colonies, probably due to chromosome instability; however, during prolonged culture of double mutants, cells forming normal round-shaped colonies arose at a relatively high frequency. All 3 chromosomes in these derivative cells were circular and lacked telomeric sequences. This appeared to be the first report of eukaryotic cells whose chromosomes were all circular. Upon meiosis, these derivative cells produced few viable spores. Therefore, the exclusively circular genome lacking telomeric sequences is proficient for mitotic growth, but does not permit meiosis.
Ataxia-Telangiectasia
Savitsky et al. (1995) found that ATM was mutated in ataxia-telangiectasia (AT; 208900) patients from all complementation groups, indicating that it is probably the sole gene responsible for this disorder. In affected members of an extended Palestinian-Arab AT family that had not been assigned to a complementation group (Ziv et al., 1992), Savitsky et al. (1995) identified a homozygous deletion in the ATM gene that included almost the entire genomic region spanned by the original cDNA clone. This finding led to a systematic search for mutations in additional AT patients. The restriction endonuclease fingerprinting (REF) method was applied to DNA products of RT-PCR-amplified RNA derived from AT cell lines. When an abnormal REF pattern was found, the relevant portion of the transcript was directly sequenced. Most of the mutations identified in 14 patients, including 3 sib pairs, were predicted to lead to premature termination of the protein product. Three mutations were predicted to create in-frame deletions of 1, 2, or 3 amino acid residues; see 607585.0001, 607585.0002, and 607585.0003.
Byrd et al. (1996) identified 6 mutations affecting the N-terminal half of the ATM protein. One of these mutations was found to be associated with a haplotype that is common to 4 apparently unrelated families of Irish descent. All the patients so far examined for both AT alleles had been shown to be compound heterozygotes. None of these mutations affected the putative promoter region which made direct divergent transcription of both the ATM gene and a novel gene, E14 (601448). All of the mutations identified by Byrd et al. (1996) were deletions except for 1 insertion.
Gilad et al. (1996) performed mutation analysis in 55 families with AT, using RT-PCR of total RNA from cultured fibroblasts or lymphoblasts, followed by restriction endonuclease fingerprinting of PCR products. Of the 44 AT mutations identified, 39 (89%) were expected to inactivate the ATM protein by truncating it, abolishing correct initiation or termination of translation, or deleting large segments. Additional mutations included 4 smaller in-frame deletions and insertions, and 1 substitution of a highly conserved amino acid at the PI-3 kinase domain.
Wright et al. (1996) assayed 38 cell lines, including 36 from unrelated AT patients and 2 control cell lines, for ATM gene mutations. They detected 30 mutations. Twenty-five of these were distinct, and most of the patients were compound heterozygotes. The mutations included nucleotide substitutions (2 cases), insertions (1 case), and deletions of 2 to 298 nucleotides (27 cases). The most frequent variant (detected in 3 unrelated patients) was a 9-bp deletion at codon 2546 in exon 54 (607585.0007). This mutation had previously been reported in 5 different patients and constituted 8% of the reported mutations at that time. Twenty-two of the observed alterations would be predicted to lead to protein alterations. Wright et al. (1996) discussed the practicality of population screening in light of their results.
Concannon and Gatti (1997) pointed out that although in vitro cell fusion studies had suggested that AT is genetically heterogeneous, all AT patients studied to that time had been found to harbor mutations in the ATM gene. More than 100 ATM mutations had been documented; these were broadly distributed throughout the gene. Except for patients from families with known consanguinity, most AT patients were compound heterozygotes. More than 70% of the mutations were predicted to lead to protein truncation. Many of the reported mutations affected mRNA splicing with at least half of the coding exons (32/62) having been found to undergo exon skipping. The large size of the ATM gene (66 exons spanning approximately 150 kb of genomic DNA), together with the diversity and broad distribution of mutations in AT patients, limited direct mutation screening as a diagnostic tool, or method of carrier identification, except where founder effect mutations are involved.
Teraoka et al. (1999) found that mutations resulting in defective splicing constituted a significant proportion (30 of 62, or 48%) of a new series of mutations in the ATM gene that were detected by the protein-truncation assay followed by sequence analysis of genomic DNA in patients with ataxia-telangiectasia. Fewer than half of the splicing mutations involved the canonical AG splice acceptor site or GT splice donor site. A higher proportion of mutations occurred at less stringently conserved sites, including silent mutations of the last nucleotide of exons, mutations in nucleotides other than the conserved AG and GT in the consensus splice sites, and creation of splice acceptor or splice donor sites in either introns or exons. These splicing mutations led to a variety of consequences, including exon skipping and, to a lesser degree, intron retention, activation of cryptic splice sites, or creation of new splice sites. In addition, 5 of 12 nonsense mutations and 1 missense mutation were associated with deletion in the cDNA of the exons in which the mutations occurred. No ATM protein was detected by Western blotting in any AT cell line in which splicing mutations were identified. Teraoka et al. (1999) also observed several cases of exon skipping in both normal controls and patients for whom no underlying defect could be found in genomic DNA, suggesting caution in the interpretation of exon deletions observed in ATM cDNA when there is no accompanying identification of genomic mutations.
By PCR amplification from genomic DNA and automated sequencing of the entire coding region (66 exons) and splice junctions of the ATM gene, Li and Swift (2000) detected 77 mutations in 90 AT chromosomes (85%). Heteroduplex analysis detected another 42 mutations at the AT locus. Of a total of 71 unique mutations, 50 were found only in a single family, and 51 had not been reported previously. Most (58/71, 82%) mutations were frameshift and nonsense mutations that were predicted to cause truncation of the AT protein; less common mutation types were missense (9/71, 13%), splicing (3/71, 4%), and 1 in-frame deletion of 3 bp beginning at nucleotide 2546. The mean survival and height distribution of 134 AT patients correlated significantly with the specific mutations present in the patients. Patients homozygous for a single truncating mutation, typically near the N-terminal end of the gene, or heterozygous for the in-frame deletion, were shorter and had significantly shorter survival than those heterozygous for a splice site or missense mutation, or heterozygous for 2 truncating mutations. (See also POPULATION GENETICS in 208900 for characterization of mutations in selected ethnic groups.)
Tchirkov and Lansdorp (2003) monitored the changes in telomere length in A-T homozygous, heterozygous, and control fibroblasts cultured in vitro under various conditions of oxidative stress using quantitative fluorescent in situ hybridization. Compared with normal cells, the rate of telomere shortening was 1.5-fold increased under 'normal' levels of oxidative stress in A-T heterozygous cells and 2.4- to 3.2-fold in A-T homozygous cells. Mild chronic oxidative stress induced by hydrogen peroxide increased the rate of telomere shortening in A-T cells but not in normal fibroblasts, and the telomere shortening rate decreased in both normal and A-T fibroblasts if cultures were supplemented with the antioxidant phenyl-butyl-nitrone. Increased telomere shortening upon oxidative stress in A-T cells was associated with a significant increase in the number of extrachromosomal fragments of telomeric DNA and chromosome ends without detectable telomere repeats. The authors proposed that the ATM (A-T mutated) protein may have a role in the prevention or repair of oxidative damage to telomeric DNA, and that enhanced sensitivity of telomeric DNA to oxidative damage in A-T cells may result in accelerated telomere shortening and chromosomal instability.
Eng et al. (2004) described 9 examples of nonclassic splicing mutations in 12 ataxia-telangiectasia patients and compared cDNA changes to estimates of splice junction strengths based on maximum entropy modeling. These mutations fell into 3 categories: pseudoexon insertions (type II), single-nucleotide changes within the exon (type III), and intronic changes that disrupt the conserved 3-prime splice sequence and lead to partial exon deletion (type IV). Four patients with a previously reported type II (pseudoexon) mutation (Pagani et al., 2002) all shared a common founder haplotype. Three patients with apparent missense or silent mutations actually had type III aberrant splicing and partial deletion of an exon. Five patients had type IV mutations that could have been misinterpreted as classic splicing mutations; instead, their mutations disrupted a splice site and used another AG splice site located nearby within the exon and led to partial deletions at the beginning of exons. The nonclassic splicing mutations created frameshifts that resulted in premature termination codons. Without screening of cDNA or using accurate models of splice site strength, the consequences of these genomic mutations cannot be reliably predicted, possibly leading to further misinterpretation of genotype-phenotype correlations and subsequently impacting upon gene-based therapy.
Jacquemin et al. (2012) identified 15 different missense mutations, including 11 novel mutations, in the ATM gene in 17 patients, 16 with a clinical diagnosis of AT and 1 with an 'undefined diagnosis.' Cell lines derived from the patients with AT all showed a significantly decreased H2AX and KAP1 (TRIM28; 601742) phosphorylation response to ionizing radiation compared to wildtype cells. The missense mutations resulted in decreased ATM protein expression (8-67% of normal) in 15 of the 16 AT cases. Twelve of the 16 AT cell lines showed abnormal ATM cytoplasmic localization, which correlated with decreased protein expression. The study indicated that ATM mislocalization is a mechanism of ATM dysfunction in AT.
Malignancy
By analyzing tumor DNA from patients with sporadic T-cell prolymphocytic leukemia (TPLL), a rare clonal malignancy with similarities to a mature T-cell leukemia seen in ataxia-telangiectasia, Vorechovsky et al. (1997) demonstrated a high frequency of ATM mutations in TPLL. In marked contrast to the ATM mutation pattern in AT, the most frequent nucleotide changes in this leukemia were missense mutations (e.g., 607585.0009). These clustered in the region corresponding to the kinase domain, which is highly conserved in ATM-related proteins in mouse, yeast, and Drosophila. The resulting amino acid substitutions were predicted to interfere with ATP binding or substrate recognition. Two of 17 mutated TPLL samples had a previously reported AT allele. One of these, a 9-bp deletion causing loss of a string of 3 amino acids (607585.0007), was the most frequent ATM allele reported in AT patients. The other, val2424 to gly (607585.0005), had been observed in a patient with atypically mild ataxia-telangiectasia. In neither of these 2 cases was any wildtype allele detectable. Vorechovsky et al. (1997) also studied B-cell non-Hodgkin lymphomas (BNHL) for ATM mutations and detected 3 missense mutations (e.g.; 607585.0010).
In mantle cell lymphoma (MCL), the translocation t(11;14) is considered the cytogenetic hallmark of the disease. Stilgenbauer et al. (1999) identified a commonly deleted region of 11q22-q23, smaller than 1 Mb in size, that includes the ATM locus in cases of MCL. Schaffner et al. (2000) performed mutation analysis of ATM in 12 sporadic cases of MCL, 7 of whom had a deletion of 1 ATM gene copy. In all 7 cases containing a deletion of 1 ATM allele, a point mutation in the remaining allele was detected, which resulted in aberrant transcript splicing, truncation, or alteration of the protein. In addition, biallelic ATM mutations were identified in 2 MCLs that did not contain 11q deletions. In 3 cases analyzed, the ATM mutations detected in the tumor cells were not present in nonmalignant cells, demonstrating their somatic rather than germline origin. The inactivation of both alleles of the ATM gene by deletion and deleterious point mutation in the majority of cases analyzed indicated that ATM plays a role in the initiation and/or progression of MCL.
Deletion in chromosome bands 11q22-q23 is one of the most frequent chromosomal aberrations in B-CLL. It is associated with extensive lymph node involvement and poor survival. The ATM gene falls within the minimal consensus deletion segment. To investigate the potential pathogenic role of ATM in B-cell tumorigenesis, Schaffner et al. (1999) performed mutation analysis of ATM in 29 malignant lymphomas of B-cell origin (27 cases of B-CLL and 2 cases of mantle cell lymphoma). Twenty-three of the 29 patients carried an 11q22-q23 deletion. In 5 B-CLLs and 1 mantle cell lymphoma with deletion of 1 ATM allele, a point mutation in the remaining allele was detected, which resulted in aberrant transcript splicing, alteration, or truncation of the protein. In addition, mutation analysis identified point mutations in 3 cases without 11q deletion: 2 B-CLLs with 1 altered allele and 1 mantle cell lymphoma with both alleles mutated. In 4 cases analyzed, the ATM alterations were not present in the germline, indicating a somatic origin of the mutations. The study demonstrated somatic disruption of both alleles at the ATM locus by deletion of point mutation and thus its pathogenic role in sporadic B-cell lineage tumors.
Mutations have been described in the ATM gene in small numbers of cases of lymphoid neoplasia. Surveys of the ATM mutation status in lymphoma have been limited due to the large size (62 exons) and complex mutational spectrum of this gene. Fang et al. (2003) used microarray-based assays with 250,000 oligonucleotides to screen lymphomas from 120 patients for all possible ATM coding and splice junction mutations. The subtypes included 6 varieties. They found the highest percentage of ATM mutations within the mantle cell (MCL) subtype: 12 of 28 cases (43%). In 6 MCL cases examined, 4 ATM variants were due to somatic mutation in the tumor cells, whereas 2 others seemed to be germline in origin. There was no difference in p53 mutation status in the ATM mutant and wildtype groups of MCL. There was no statistically significant difference in the median overall survival of patients with wildtype versus mutated ATM in MCL.
Li et al. (2000) demonstrated that the BRCA1-associated protein CTIP (604124) becomes hyperphosphorylated and dissociated from BRCA1 upon ionizing radiation. This phosphorylation event requires the protein kinase ATM. ATM phosphorylates CTIP at serine residues 664 and 745, and mutation of these sites to alanine abrogates the dissociation of BRCA1 from CTIP, resulting in persistent repression of BRCA1-dependent induction of GADD45 upon ionizing radiation. Li et al. (2000) concluded that ATM, by phosphorylating CTIP upon ionizing radiation, may modulate BRCA1-mediated regulation of the DNA damage-response GADD45 gene, thus providing a potential link between ATM deficiency and breast cancer.
Epidemiologic data support an increased risk for breast and other cancers in AT heterozygotes. However, screening breast cancer cases for truncating mutations in the ATM gene has largely failed to reveal an increased incidence in these patients. Though some evidence supports the implication of ATM missense mutations in breast cancer, the presence of a large variety of rare missense variants in addition to common polymorphisms in ATM has made it difficult to establish such a relationship by association studies. To investigate the functional significance of these changes, Scott et al. (2002) introduced missense substitutions that had been identified in either AT or breast cancer patients into ATM cDNA before establishing stable cell lines to determine their effect on ATM function. Pathogenic missense mutations and neutral missense variants were distinguished initially by their capacity to correct the radiosensitive phenotype in AT cells. Furthermore, missense mutations abolished the radiation-induced kinase activity of ATM in normal control cells, caused chromosome instability, and reduced cell viability in irradiated control cells, whereas neutral variants failed to do so. Mutant ATM was expressed at the same level as endogenous protein, and interference with normal ATM function seemed to be by multimerization. The approach of Scott et al. (2002) represented a means of identifying genuine ATM mutations and addressing the significance of missense changes in the ATM gene in a variety of cancers, including breast cancer. (See also HETEROZYGOTES in 208900).
Stredrick et al. (2006) presented evidence suggesting that missense mutations in ATM, particularly S49C (607585.0032), may be breast cancer susceptibility alleles. Another missense mutation, phe858 to leu, was associated with a significant increased risk in a study in the United States but not in a study in Poland (combined odds ratio = 1.44).
Studies of the families of individuals with ataxia-telangiectasia suggested that female relatives heterozygous for an ATM mutation have a 2- to 5-fold increase in risk of breast cancer (Swift et al., 1987; Thompson et al., 2005). Renwick et al. (2006) screened individuals from 443 familial breast cancer pedigrees and 521 controls for ATM sequence variants and identified 12 mutations in affected individuals and 2 in controls (p = 0.0047). These results demonstrated that ATM mutations that cause ataxia-telangiectasia in biallelic carriers are breast cancer susceptibility alleles in monoallelic carriers, with an estimated relative risk of 2.37 (95% CI = 1.57-3.78, p = 0.0003).
Medulloblastoma occurs with increased frequency in ataxia-telangiectasia (Gatti et al., 1991); however, Liberzon et al. (2003) did not identify mutations in 13 childhood medulloblastomas.
Flanagan et al. (2009) hypothesized that epigenetic misregulation of cancer-related genes could partially account for a predisposition to bilaterality of breast cancer (114480). They performed methylation microarray analysis of peripheral blood DNA from 14 women with bilateral breast cancer and 14 controls at 17 candidate breast cancer susceptibility genes, including ATM. The majority of methylation variability was associated with intragenic repetitive elements. Detailed validation by bisulfite modification and sequencing of the tiled region around ATM was performed in a total of 204 bilateral breast cancer patients and 204 controls. There was significant hypermethylation of 1 intragenic repetitive element in breast cancer cases compared with controls (p = 0.0017), with the highest quartile of methylation associated with a 3-fold increased risk of breast cancer (odds ratio = 3.20; 95% confidence interval = 1.78-5.86; p = 0.000083). Increased methylation of this locus was associated with lower steady-state ATM mRNA level and correlated with age of cancer patients, but not controls, suggesting a combined age-phenotype-related association.
Biankin et al. (2012) performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort of 142 patients with early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumors identified substantial heterogeneity with 2,016 nonsilent mutations and 1,628 copy number variations. Biankin et al. (2012) defined 16 significantly mutated genes, reaffirming known mutations and uncovering novel mutated genes including additional genes involved in chromatin modification (EPC1, 610999 and ARID2, 609539), DNA damage repair (ATM), and other mechanisms (ZIM2 (see 601483); MAP2K4, 601335; NALCN, 611549; SLC16A4, 603878; and MAGEA6, 300176). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signaling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. Biankin et al. (2012) also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO (see 603742) signaling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.
Chessa et al. (2009) identified mutations in the ATM gene in 104 Italian patients from 91 unrelated families with AT. Sixty-seven percent of patients had compound heterozygous mutations in the ATM gene and 33% had homozygous mutations. Twenty-one recurrent mutations were found in 63 families. To evaluate for founder effects, haplotyping by STR analysis was performed in 48 of the families, accounting for 16 of the recurrent mutations. Fifteen recurrent mutations were located on a common haplotype, and most patients with the same recurrent mutation originated from the same area in Italy. One mutation (R805X) was found on 3 different haplotypes, suggesting a mutation hotspot.
Rawat et al. (2022) reported clinical and molecular data on 26 North Indian patients with AT, including 1 sib pair. Mutations in the ATM gene were identified in 16 of 25 unrelated patients; 9 patients did not have molecular testing. Eleven patients had homozygous mutations and 5 patients had compound heterozygous mutations. Among the 16 patients, 14 different mutations were identified. The most frequent mutations were c.67C-T (5/32 alleles), c.6547G-T (4/32 alleles), and c.5631_5635delCTCGCinsA (4/32 alleles). The mutations included 56% stopgain, 22% frameshift, 13% missense, and 9% splicing mutations. Seven of the mutations were located in the FAT domain, 1 was in the PI3K domain, 6 affected the N-terminal domain, and 1 was located between the FAT and PI3K domains.
Schon et al. (2019) reported on 57 patients with variant ataxia-telangiectasia (patients with retained ATM kinase activity). Using Sanger sequencing of PCR-amplified ATM exon sequences, mutations were identified in 111 of 114 alleles. When compared to leaky splice site mutations, missense mutations were associated with milder neurologic disease severity, but with a higher risk of malignancy.
Barlow et al. (1996) created a murine model of ataxia-telangiectasia by disrupting the Atm locus via gene targeting. Mice homozygous for the disrupted Atm allele displayed growth retardation, neurologic dysfunction, male and female infertility secondary to the absence of mature gametes, defects in T lymphocyte maturation, and extreme sensitivity to gamma-irradiation. Most of the animals developed malignant thymic lymphomas between 2 and 4 months of age. Several chromosomal anomalies were detected in one of these tumors. Fibroblasts from these mice grew slowly and exhibited abnormal radiation-induced G1 checkpoint function. Atm-disrupted mice recapitulated the ataxia-telangiectasia phenotype in humans. The authors noted that humans also show incomplete sexual maturation in ATM (Boder, 1975).
Elson et al. (1996) generated a mouse model for ataxia-telangiectasia using gene targeting to generate mice that did not express the Atm protein. Atm-deficient mice were retarded in growth, did not produce mature sperm, and exhibited severe defects in T-cell maturation while going on to develop thymomas. Atm-deficient fibroblasts grew poorly in culture and displayed a high level of double-stranded chromosome breaks. Atm-deficient thymocytes underwent spontaneous apoptosis in vitro significantly more often than controls. Atm-deficient mice then exhibited many of the same symptoms found in ataxia-telangiectasia patients and in cells derived from them. Furthermore, Elson et al. (1996) demonstrated that the Atm protein exists as 2 discrete molecular species, and that loss of 1 or both of these can lead to the development of the disease.
Xu and Baltimore (1996) disrupted the mouse ATM gene by homologous recombination. Xu et al. (1996) reported that Atm -/- mice are viable, growth-retarded, and infertile. The infertility results from meiotic failure, as meiosis is arrested at the zygotene/pachytene stage of prophase I as a result of abnormal chromosomal synapsis and subsequent chromosome fragmentation. The cerebella of Atm -/- mice appear normal by histologic examination, and the mice have no gross behavioral abnormalities. Atm -/- mice exhibit multiple immune defects similar to those of AT patients, and most develop thymic lymphomas at 3 to 4 months of age and die of the tumors by 4 months. Xu and Baltimore (1996) showed that mouse Atm -/- cells are hypersensitive to gamma irradiation and defective in cell cycle arrest following radiation, and Atm -/- thymocytes are more resistant to apoptosis induced by gamma radiation than normal thymocytes. They also provided direct evidence that ATM acts as an upregulator of p53.
Atm-null mice, as well as those null for p53, develop mainly T-cell lymphomas, supporting the view that these genes have similar roles in thymocyte development. To study the interactions of these 2 genes on an organismal level, Westphal et al. (1997) bred mice heterozygous for null alleles of both atm and p53 to produce all genotypic combinations. Mice doubly null for atm and p53 exhibited a dramatic acceleration of tumor formation relative to singly null mice, suggesting that the 2 genes collaborate to prevent tumorigenesis. With respect to their roles in apoptosis, loss of atm rendered thymocytes only partly resistant to irradiation-induced apoptosis, whereas additional loss of p53 engendered complete resistance. This implied that the irradiation-induced atm and p53 apoptotic pathways are not completely congruent. Furthermore, Westphal et al. (1997) found that atm and p53 do not appear to interact in acute radiation toxicity, suggesting a separate atm effector pathway for this DNA damage response and having implications for the prognosis and treatment of human tumors.
To study the role of p21 (116899) in ATM-mediated signal transduction pathways, Wang et al. (1997) examined the combined effects of the genetic loss of ATM and p21 on growth control, radiation sensitivity, and tumorigenesis. They found that p21 modifies the in vitro senescent response seen in AT fibroblasts. Wang et al. (1997) found that p21 is a downstream effector of ATM-mediated growth control. However, loss of p21 in the context of an Atm-deficient mouse leads to delay in thymic lymphomagenesis and an increase in acute radiation sensitivity in vivo (the latter principally because of effects on the gut epithelium). Modification of these 2 crucial aspects of the ATM phenotype can be related to an apparent increase in spontaneous apoptosis seen in tumor cells and in the irradiated intestinal epithelium of mice doubly null for Atm and p21. Thus, loss of p21 seems to contribute to tumor suppression by a mechanism that operates via a sensitized apoptotic response.
Ataxia-telangiectasia is characterized by markedly increased sensitivity to ionizing radiation. Ionizing radiation oxidizes macromolecules and causes tissue damage through the generation of reactive oxygen species (ROS). Barlow et al. (1999) therefore hypothesized that AT is due to oxidative damage resulting from loss of function of the ATM gene product. To assess this hypothesis, they employed an animal model of AT, i.e., the mouse with a disrupted Atm gene. They showed that organs that develop pathologic changes in the Atm-deficient mice are targets of oxidative damage, and that cerebellar Purkinje cells are particularly affected. They suggested that these observations provide a mechanistic basis for the AT phenotype and lay a rational foundation for therapeutic intervention.
Barlow et al. (1999) exposed Atm +/+ and Atm +/- littermates to a sublethal dose, 4 Gy (400 Rad) of ionizing radiation. The Atm +/- mice had premature graying and decreased life expectancy (median survival 99 weeks vs 71 weeks in wildtype and heterozygous mice, respectively, P = 0.0042). Tumors and infections of similar type were found in all autopsied animals, regardless of genotype.
The central nervous system (CNS) of Atm null mice shows a pronounced defect in apoptosis induced by genotoxic stress, suggesting that ATM functions to eliminate neurons with excessive genomic damage. Chong et al. (2000) reported that the death effector Bax (600040) is required for a large proportion of Atm-dependent apoptosis in the developing CNS after IR. Although many of the same regions of the CNS in both Bax -/- and Atm -/- mice were radioresistant, mice nullizygous for both Bax and Atm showed additional reduction in IR-induced apoptosis in the CNS. Therefore, although the major IR-induced apoptotic pathway in the CNS requires Atm and Bax, a p53-dependent collateral pathway exists that has both Atm- and Bax-independent branches. Furthermore, Atm- and Bax-dependent apoptosis in the CNS also required caspase-3 (600636) activation. These data implicated Bax and caspase-3 as death effectors in neurodegenerative pathways.
Through gene targeting, Borghesani et al. (2000) generated a line of Atm mutant mice. In contrast to other Atm mutant mice, their Atm y/y mice showed a lower incidence of thymic lymphoma and survived beyond a few months of age. They exhibited deficits in motor learning indicative of cerebellar dysfunction. Even though they found no gross cerebellar degeneration in older Atm y/y animals, ectopic and abnormally differentiated Purkinje cells were apparent in mutant mice of all ages. These findings established that some neuropathologic abnormalities seen in ataxia-telangiectasia patients also are present in Atm mutant mice. In addition, they found a previously unrecognized effect of Atm deficiency on development or maintenance of CD4+8+ thymocytes.
Hande et al. (2001) examined the length of individual telomeres in cells from Atm -/- mice by fluorescence in situ hybridization. Telomeres were extensively shortened in multiple tissues of Atm -/- mice. More than the expected number of telomere signals was observed in interphase nuclei of Atm -/- mouse fibroblasts. Signals corresponding to 5 to 25 kb of telomeric DNA that were not associated with chromosomes were also noticed in Atm -/- metaphase spreads. Extrachromosomal telomeric DNA was also detected in fibroblasts from AT patients. The authors proposed a role for ATM in telomere maintenance and replication, which may explain in part the poor growth of Atm -/- cells and increased tumor incidence in both AT patients and Atm -/- mice.
Spring et al. (2002) provided evidence in mice that human AT carriers have a cancer predisposition. Although no tumors had been observed in heterozygous Atm-knockout mice (Atm +/-), the authors demonstrated that Atm 'knock-in' heterozygous mice harboring an in-frame deletion corresponding to the human 7636del9 mutation (607585.0007) showed an increased susceptibility to developing tumors. In parallel, Spring et al. (2002) reported the appearance of tumors in 6 humans, from 12 families, who were heterozygous for the 7636del9 mutation. Expression of ATM cDNA containing the 7636del9 mutation had a dominant-negative effect in control cells, inhibiting radiation-induced ATM kinase activity in vivo and in vitro. The inhibited ATM kinase activity reduced the survival of control cells after radiation exposure and enhanced the level of radiation-induced chromosomal aberrations. Spring et al. (2002) concluded that their results showed for the first time that mouse carriers of the mutated Atm that are capable of expressing Atm have a higher risk of cancer.
Stern et al. (2002) found that Atm null mice accumulated DNA breaks in neuronal tissue. These animals showed depleted pyridine nucleotide levels, including NAD(+) required for DNA repair, and increased mitochondrial respiration rate. The cerebellum was prominent among the neural tissues affected.
Allen et al. (2001) studied proliferation and differentiation of neural cells of the dentate gyrus in wildtype and Atm -/- mice. They found that Atm is abundant in wildtype dividing neural progenitor cells and is downregulated in differentiated cells. Atm -/- neural progenitor cells showed abnormally high rates of proliferation and genomic instability. Atm -/- cells in vivo and in cell culture showed blunted responses to environmental stimuli that normally promote neuronal progenitor cell proliferation, survival, and differentiation.
Wong et al. (2003) examined the impact of Atm deficiency as a function of progressive telomere attrition at both the cellular and whole-organism level in mice doubly null for Atm and Terc. These compound mutants showed increased telomere erosion and genomic instability, yet they experienced a substantial elimination of T-cell lymphomas associated with Atm deficiency. A generalized proliferation defect was evident in all cell types and tissues examined, and this defect extended to tissue stem/progenitor cell compartments, thereby providing a basis for progressive multiorgan system compromise, accelerated aging, and premature death. Wong et al. (2003) showed that Atm deficiency and telomere dysfunction act together to impair cellular and whole-organism viability, thus supporting the view that aspects of ataxia-telangiectasia pathophysiology are linked to the functional state of telomeres and its adverse effects on stem/progenitor cell reserves.
A widely used biologic marker to identify the active form of ATM is the autophosphorylation of ATM at a single, conserved serine residue (ser1981 in humans; ser1987 in mouse). Pellegrini et al. (2006) showed that Atm-dependent responses are functional at the organismal and cellular level in mice that express a mutant form of Atm (mutation of ser to ala at position 1987) as their sole Atm species. Moreover, the mutant protein did not exhibit dominant-negative interfering activity when expressed physiologically or overexpressed in the context of Atm heterozygous mice. Pellegrini et al. (2006) concluded that their results suggest an alternative mode for stimulation of Atm by double-stranded breaks in which Atm autophosphorylation at ser1987, like transphosphorylation of downstream substrates, is a consequence rather than a cause of Atm activation.
Schubert et al. (2004) showed that the nitroxide antioxidant, tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), acts as a chemopreventative agent in Atm mutant mice. Tempol administered continuously via the diet after weaning resulted in an increased life span by prolonging the latency to thymic lymphomas. Tempol treatment reduced ROS, restored mitochondrial membrane potential, reduced tissue oxidative damage and oxidative stress, consistent with antioxidant effects. In addition, tempol lowered weight gain of tumor-prone mice without changes in food intake, metabolism, or activity level and exhibited an antiproliferative effect in vitro.
Ziv et al. (2005) augmented specific features of AT by generating mouse strains that combined Atm deficiency with dysfunction of other proteins. Increasing oxidative stress by combining deficiencies in Atm and superoxide dismutase-1 (SOD1; 147450) exacerbated growth retardation and markedly reduced the mean survival time following ionizing radiation. In contrast, increasing genomic instability by combining deficiencies of Atm and the mismatch repair protein Mlh1 (120436) caused a moderate increase in radiation sensitivity and dramatic increase in aggressive lymphomas, compared with the Atm-knockout mice. Atm, Mlh1, or Mlh1/Atm single or double heterozygosity did not significantly affect the life span of the various genotypes. The genomic region on mouse chromosome 15 containing c-Myc (190080) was commonly amplified in tumors, and elevated levels of the c-Myc protein were subsequently observed in the tumors. Ziv et al. (2005) suggested that impaired genomic instability may be an important contributing factor to cancer predisposition in AT, whereas oxidative stress may be more important in the radiation sensitivity and growth retardation facets of this disease.
Lu et al. (2005) showed that the expression level of Atm protein was gradually increased during liver regeneration, which correlated with the onset of DNA replication. The induction of Stat3 (102582) and JNK (MAPK8; 601158) signaling, which are essential processes in normal regeneration response, was attenuated during the early phases of liver regeneration in Atm-deficient mice. TP53 (191170) was transiently phosphorylated at serine-23 during liver regeneration in an Atm-dependent manner. Cyclin A (CCNA1; 604036) induction was delayed and p21 (CDKN1A; 116899) was overexpressed, which correlated with reduced and delayed DNA replication in Atm -/- mice during liver regeneration. Increased apoptosis was observed in Atm -/- mice in response to partial hepatectomy, indicating that Atm may be required for the survival of hepatocytes. Lu et al. (2005) concluded that liver regeneration is impaired in Atm-deficient mice.
Erttmann et al. (2016) showed that Atm -/- mice had impaired Nlrp3 (606416) and Nlrc4 (606831) inflammasome-dependent antibacterial immunity. Cells from Atm -/- mice had diminished Il1b production in response to bacteria. Atm -/- mice were more susceptible to pulmonary Streptococcus pneumoniae infection in a manner consistent with inflammasome defects. These defects appeared to be due to oxidative inhibition of inflammasome complex assembly. Erttmann et al. (2016) concluded that reactive oxygen species function in negative regulation of inflammasomes and that ATM is essential for optimal inflammasome-dependent antibacterial immunity.
The article by Kaidi and Jackson (2013) was retracted because the authors could not confirm the results in some of the figures.
In a Dutch family (AT3NG) in which ataxia-telangiectasia of complementation group A was observed (ATA; 208900), Savitsky et al. (1995) found compound heterozygosity for mutations in the ATM gene. One allele showed deletion of 3 bp, resulting in loss of serine-1512.
In an Australian family of Irish/British ethnic extraction, Savitsky et al. (1995) found that 2 sibs with ataxia-telangiectasia of complementation group E (ATE; 208900) were homozygous for deletion of 9 bp, resulting in a loss of amino acids 1198-1200 in the gene product. The typing of these patients (AT1ABR and AT2ABR) was performed by Chen et al. (1984).
In 2 sibs of Indian/English ancestry, Savitsky et al. (1995) found that their ataxia-telangiectasia complementation group D (ATD; 208900) was a result of compound heterozygosity for mutations in the ATM gene. One allele showed deletion of 6 bp, resulting in deletion of 2 amino acids (1079 and 1080) in the gene product.
McConville et al. (1996) identified 14 families with ataxia-telangiectasia (AT; 208900) in which the ATM gene mutation was associated with a less severe clinical and cellular phenotype ('variant' AT). This form of AT constituted 10 to 15% of AT families in the UK and was characterized by a later mean age of onset and a slower rate of neurological deterioration. In 10 of these families all homozygotes have a 137-bp insertion in their cDNA caused by a point mutation in a sequence resembling a splice donor site. The second allele of ATM had a different mutation in each patient.
In 2 brothers with exceptionally mild adult-onset AT, Sutton et al. (2004) identified homozygosity for a 5762A-G transition in the ATM gene, resulting in the 5762ins137 mutation. Protein expression studies showed that the ATM protein was expressed from both the wildtype and mutant alleles, yielding approximately 11% of normal levels. In vitro functional analysis of the 5762ins137 mutant protein showed that it retains inducible residual kinase activity. Age at onset was 17 years in one brother and 22 years in the other, with mild ataxia, ocular movement abnormalities, and identification of ocular telangiectasia.
McConville et al. (1996) reported a 7271T-G point mutation in the ATM gene in patients from 2 families with a mild form of ataxia-telangiectasia ('variant') (AT; 208900). The transversion results in a val2424-to-gly (V2424G) substitution. They also reported another point mutation (F2827C; 607585.0006). The authors noted that point mutations are uncommon in AT.
In a sporadic case of T-cell prolymphocytic leukemia (TPLL), Vorechovsky et al. (1997) observed this same mutation in tumor tissue. No wildtype allele was demonstrable in tumor DNA. Material was not available to permit determination of whether the mutation was present in the germline.
Stankovic et al. (1998) observed 2 families in which members affected with a milder clinical and cellular phenotype of AT shared a 7271T-G transversion in the ATM gene and a common haplotype. The 7271T-G mutation was predicted to produce a V2424G substitution. One family, in which the mutation was present in homozygous state, contained the oldest patients in the British Isles with demonstrable AT, including 1 patient in his seventh decade, possibly the oldest AT patient reported. Furthermore, 1 affected female, 50 years old at the time of report, had an unaffected son. Three members of a sibship of 4 had long-standing ataxia. Their parents were first cousins and originated from Orkney, in the north of Scotland. The proband, her older sister with AT, and her mother had breast cancer. The affected individuals had minimal telangiectasia and no obvious increased tendency toward infections, except for recurrent urinary tract infections in the brother of the proband. The second family had the 7271T-G transversion in compound heterozygous state with a 3910del7nt mutation. The mutation was predicted to cause premature termination of the ATM protein, but no truncated ATM protein was detected. There were 2 affected brothers, aged 16 and 28 years, whose age at onset of ataxia was 8 and 4 years, respectively. Two of 3 paternal aunts had breast cancer, one at age 50 years and the other at age 55 years.
In a population-based study, Bernstein et al. (2006) identified a heterozygous 7271T-G transversion in 7 (0.2%) of 3,743 patients with breast cancer (114480) and none of 1,268 controls. Among the patients, the mutant allele was more prevalent in women with an affected mother (odds ratio of 5.5) and delayed child-bearing (odds ratio of 5.1). The estimated cumulative risk for breast cancer in carriers to age 70 years (penetrance) was 52%.
McConville et al. (1996) reported this 8480T-G point mutation in patients from 2 families with a mild form of ataxia-telangiectasia ('variant') (AT; 208900). The transversion results in a phe2827-to-cys (F2827C) substitution in ATM. They also reported another point mutation (V2424G; 607585.0005). The authors noted that point mutations are uncommon in AT.
The most frequent variant of the ATM gene detected out of 30 ataxia-telangiectasia (AT; 208900) mutant lines studied by Wright et al. (1996) was a 9-bp deletion at codon 2546 in exon 54. The deletion was detected by them in 3 unrelated patients and had been previously reported in 5 different patients, corresponding to 8% of the mutations reported at that time.
This same mutation was identified by Vorechovsky et al. (1997) in tumor tissue from a sporadic case of T-cell prolymphocytic leukemia (TPLL), a rare clonal malignancy with similarities to a mature T-cell leukemia seen in ataxia-telangiectasia.
This mutation was identified in heterozygous form in a female breast cancer patient with a family history of multiple malignancies (Vorechovsky et al., 1996). The deleted sequence is 5-prime-TCTAGAATT-3-prime.
Spring et al. (2002) demonstrated the appearance of tumors in 6 humans, from 12 families, who were heterozygous for the 7636del9 mutation. In parallel, they showed that 'knock-in' heterozygous mice harboring an in-frame deletion corresponding to the human 7636del9 mutation showed increased susceptibility to tumors. The 7636del9 mutation had a dominant-negative effect in control cells, inhibiting radiation-induced ATM kinase activity in vivo and in vitro.
Gilad et al. (1996) reported that a single ataxia-telangiectasia (AT; 208900) mutation was observed in 32 of 33 defective ATM alleles in Jewish AT families of North African origin, coming from various regions of Morocco and Tunisia. This mutation, a 103C-T transition, results in a stop codon at position 35 of the ATM protein (R35X). No ATM protein could be detected in cells from patients with this mutation. Gilad et al. (1996) developed a rapid carrier detection assay for this mutation suitable for population-based screening.
One of the TPLL mutations identified by Vorechovsky et al. (1997) was a G-to-C transversion at nucleotide 5044, predicted to produce an asp1682-to-his (D1682H) amino acid change. The wildtype allele was absent from tumor tissue. Because of the way in which the study was done it was impossible to determine whether any of these mutations were in the germline.
Vorechovsky et al. (1997) found ATM mutations in sporadic T-cell prolymphocytic leukemia, a rare clonal malignancy with similarities to a mature T-cell leukemia seen in AT (607585.0009). In addition to the increased risk of neoplasia of T-cell origin, AT homozygotes also show elevated risk of developing B-cell malignancies, especially B-cell non-Hodgkin lymphomas (BNHL). In a study of tumor DNAs from 32 patients with BNHL and 5 BNHL cell lines, analyzed by SSCP, 3 missense mutations of the ATM gene were found. One was an A-to-G transition of nucleotide 3118 predicted to lead to a met1040-to-val (M1040V) amino acid substitution in the ATM protein. The wildtype allele could not be demonstrated in tumor DNA. The tumor in this case was a high-grade diffuse large cell BNHL.
Toyoshima et al. (1998) reported the case of a 24-year-old Japanese male with ataxia-telangiectasia (AT; 208900) without immunodeficiency. He had developed ataxic gait at 6 years of age and telangiectases at 9 years. There was no susceptibility to infections. His height and weight were 165 cm and 35.2 kg, respectively. Truncal ataxia, intention tremor, nystagmus, oculomotor apraxia, dysarthria, and ocular telangiectasia were observed. Deep tendon reflexes were decreased. He also had dystonic movements of the trunk and limbs, and mild mental retardation. Laboratory findings included elevated alpha-fetoprotein and increased sensitivity to DNA-damaging chemicals. Mutation analysis demonstrated compound heterozygosity for a missense mutation leading to a leu2656-to-pro amino acid substitution and a nonsense mutation leading to truncation at codon 3047 (R3047X; 607585.0012). The latter mutation was within the phosphatidylinositol 3-kinase-like domain and the former was outside but close to that domain.
For discussion of the arg3047-to-ter (R3047X) mutation in the ATM gene that was found in compound heterozygous state in a patient with ataxia-telangiectasia (AT; 208900) by Toyoshima et al. (1998), see 607585.0011.
In a Dutch family, van Belzen et al. (1998) demonstrated that affected members with ataxia-telangiectasia (AT; 208900) were homozygous for 2 consecutive base substitutions in exon 55 of the ATM gene: a T-to-G transversion at position 7875 of the ATM cDNA and a G-to-C transversion at position 7876. The double base substitution resulted in an amino acid change of an aspartic acid to a glutamic acid at codon 2625 (D2625E) and of an alanine to a proline at codon 2626 (A2626P) of the ATM protein. Both amino acids are conserved between the ATM protein and its functional homolog, the Atm gene product in the mouse. The change in secondary structure of the ATM protein carrying the D2625E/A2626P mutation, as predicted by the method of Chou and Fasman (1978) and of Garnier et al. (1978), suggested that the double base substitution is a disease-causing mutation.
Dork et al. (2004) described a patient with an attenuated form of AT in whom the disorder was diagnosed at the age of 52 years and who died at the age of 60 years. He was found to be a compound heterozygote for a double missense mutation (D2625E and A2626P) and a novel splicing mutation (496+5G-A; 607585.0031) of the ATM gene. Cytogenetic studies of the patient's lymphoblastoid cells revealed modest levels of bleomycin-induced chromosomal instability. Residual ATM protein was 10 to 20% of wildtype. Low residual ATM kinase activity could be demonstrated towards p53 (191170), whereas it was poorly detectable towards nibrin (602667). The results corroborated the view that the clinical variability of AT is partly determined by the mutation type and indicated that AT can present as a late adulthood disease. Although ataxia-telangiectasia was diagnosed at the age of 52 years, the patient had developed the first symptoms of ataxia at the age of 7 years. Ataxia had become prominent by the age of 14 years, and he had lost the ability to walk alone by the age of 22 years. He became permanently wheelchair-bound by the age of 45 years. Clinical diagnosis was made at the age of 52 years and confirmed by cytogenetic analysis 3 years later. His clinical phenotype thereafter was progressively dominated by chronic obstipation associated with megacolon and gastroenteritis.
In identical twin girls, Curry et al. (1989) identified a classic ataxia-telangiectasia phenotype (AT; 208900) combined with features of the Nijmegen breakage syndrome (251260). Gilad et al. (1998) derived a fibroblast cell line from 1 of the sisters originally described by Curry et al. (1989) and found that it was as radiosensitive as a typical AT cell line. Using an anti-ATM antibody, Gilad et al. (1998) identified no immunoreactive material in this cell line. Screening the ATM transcript in this cell line revealed homozygosity for a typical AT mutation, which abolished a splice site at intron 33 of the ATM gene and led to skipping of exon 32. A deletion of 165 nucleotides beginning with nucleotide 4612 led to in-frame deletion of 55 amino acids beginning at codon 1538. The large deletion in the protein probably severely destabilized the ATM molecule.
Ejima and Sasaki (1998) found deletion of 5 nucleotides following nucleotide 7883 to be 1 of 2 common mutations in the population of 8 unrelated Japanese families with ataxia-telangiectasia (AT; 208900). The other common mutation was a 4612del165 (607585.0014). Forty-four percent of the mutant alleles in these 8 families had 1 of these 2 mutations.
In 11 Norwegian families with ataxia-telangiectasia (AT; 208900), Laake et al. (1998) found that 12 of 22 ATM alleles carried a mutation affecting nucleotides 3245-3247 and codon 1082 of the ATM gene, changing the sequence from ATC to TGAT (3245delATCinsTGAT). The result was the introduction of a stop codon downstream at codon 1095, leading to truncation of the ATM protein. Haplotype analyses using 8 microsatellite markers, within and flanking the ATM gene, demonstrated that all carriers of this mutation had the same haplotype of the 5 closest CA-repeat microsatellite markers. Genealogic investigations identified a common ancestor for 3 of the families: a women born in 1684 in the area from which these families originated. The prevalence of this mutation in Norwegian patients allowed 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.
In the study of ATM mutations in Nordic families, Laake et al. (2000) included 15 Norwegian families; 17 of the 30 mutant alleles (57%) carried the indel mutation, indicating a founder effect.
In a 7-year-old girl with ataxia-telangiectasia (AT; 208900) who developed ataxia by the age of 3 years, Sandoval et al. (1999) observed homozygosity for a 3-bp deletion in exon 56 of the ATM gene, leading to deletion of val2662, 1 of 3 consecutive valines in exon 56. The patient remained free of recurrent infections despite laboratory evidence of absent IgA and lowered IgG3 levels. Chromosome instability was shown by increased bleomycin-induced chromosome breakage rates. Cell lines from this patient with the val2662del mutation exhibited detectable ATM levels, which varied from culture to culture and ranged between apparently normal and 20% of the normal level. The protein was thought to be unstable, possibly in certain tissues, and therefore to fluctuate according to physiologic conditions.
In 3 unrelated patients with ataxia-telangiectasia (AT; 208900), 1 Italian, 1 Turkish, and 1 Georgian, Sandoval et al. (1999) found a G-to-A transition at nucleotide 3576 in exon 26, which caused aberrant splicing of the ATM message. The mutation was present in homozygous form in 2 of the patients and heterozygous in 1 patient. Because of the origin of the patients, Sandoval et al. (1999) suggested that this splicing mutation may be more common in southeast Europe than in Germany, where the study was performed. The mutation resulted in skipping of exon 26.
Telatar et al. (1998) found an arg2443-to-ter (R2443X) mutation in the ATM gene as the cause of ataxia-telangiectasia (AT; 208900) in African Americans. Sandoval et al. (1999) found the same mutation in 2 unrelated patients in Germany. The mutations may have arisen by independent mutation events, as the underlying nucleotide substitution affects the CpG dinucleotide, a known hotspot of mutations in general (Cooper and Youssoufian, 1988). The truncating mutation was caused by a C-to-T transition at nucleotide 7327 in exon 52.
In a family with multiple cancers, Bay et al. (1999) found heterozygosity for an insertion of TA at position +2 of intron 61 of the ATM gene, which caused skipping of exon 61 in the mRNA. The mutation was associated with a previously undescribed polymorphism in intron 61, a C-to-T transition abolishing a Taq1 restriction site at position +104. The mutation was inherited by 2 sisters, one of whom developed breast cancer (114480) at age 39 years and the second at age 44 years, from their mother, who developed kidney cancer at age 67 years. Studies of irradiated lymphocytes from both sisters revealed elevated numbers of chromatid breaks, typical of AT heterozygotes. In the breast tumor of the older sister, loss of heterozygosity (LOH) was found in the ATM region of 11q23.1, indicating that the normal ATM allele was lost in the breast tumor. LOH was not seen at the BRCA1 (113705) or BRCA2 (600185) loci. BRCA2 was considered an unlikely cancer-predisposing gene in this family because each sister inherited different chromosomes 13 from each parent. The findings suggested that haploinsufficiency at ATM may promote tumorigenesis, even though LOH at the ATM locus supported a more classic 2-hit tumor suppressor gene model.
This variant, formerly titled ATAXIA-TELANGIECTASIA and BREAST CANCER, SUSCEPTIBILITY TO, has been reclassified because its contribution to either phenotype has not been confirmed.
In a series of 82 Dutch patients who had developed breast cancer (114480) under the age of 45 years and had survived 5 years or more, Broeks et al. (2000) identified 3 who carried a splice site mutation of the ATM gene, a T-to-G transversion at position -6 of the 3-prime splice acceptor site of intron 10. They stated that this mutation had not been detected in a small series of Dutch patients with ataxia-telangiectasia (AT; 208900) (Broeks et al., 1998). However, they pointed to a German patient with AT who was homozygous for this mutation.
Broeks et al. (2003) genotyped a number of polymorphic markers in and around the ATM locus in 18 samples from different populations carrying the IVS10-6T-G mutation: 17 unrelated breast cancer patients who were heterozygous for the mutation and a single AT patient who was homozygous. The same markers were also genotyped among 39 unrelated healthy individuals without this mutation. Haplotype analyses revealed one common ancestor in all mutation carriers. By means of a maximum likelihood method, they estimated the age of this mutation to be approximately 2,000 generations. They concluded that the mutation occurred only once during human evolution, at least 50,000 years ago. They predicted that this mutation could be widely distributed across Europe and probably the Middle East and Western Asia.
In a population-based study, Bernstein et al. (2006) found no association between the IVS10-6T-G allele and increased risk of breast cancer. The allele was identified in 13 (0.3%) of 3,757 patients and 10 (0.8%) of 1,268 controls.
Schaffner et al. (2000) found biallelic ATM mutations in 2 mantle cell lymphomas that contained no 11q deletions. One of these cases had a 7268A-G transition in exon 51 resulting in a glu2423-to-gly (G2423G) amino acid substitution in the gene product; and, in the other allele, an insertion of 3 bp, GAA, in exon 51 resulting in insertion of a lysine residue between codons 2418 and 2419 (607585.0023).
For discussion of the 3-bp insertion (7253insGAA) in the ATM gene that was found in compound heterozygous state in 2 mantle cell lymphomas by Schaffner et al. (2000), see 607585.0022.
In a patient with mantle cell lymphoma and deletion of 11q22-q23 on 1 chromosome, Schaffner et al. (2000) found a 4081C-T transition in exon 29 of the ATM gene, resulting in a gln1361-to-ter (Q1361X) truncating mutation. This mutation was not found in leukopheresis cells obtained from the patient in remission, demonstrating the somatic rather than germline origin.
Given the marked predisposition of patients with ataxia-telangiectasia (AT; 208900) to develop neoplasms of the T-cell lineage, Stilgenbauer et al. (1997) analyzed a series of T-cell leukemias (T-cell prolymphocytic leukemia, or TPLL) in non-AT patients in a search for genomic changes associated with development of this disease. Deletion of 11q was very frequent. A small commonly deleted segment at 11q22.3-q23.1 was defined in 15 of 24 TPLLs studied. Since this critical region contained ATM, they further analyzed the remaining copy of the gene in 6 cases showing deletions affecting 1 ATM allele. In all 6 cases, mutations of the second ATM allele were identified, leading to the absence, premature termination, or alteration of the ATM gene product. Thus, the study demonstrated disruption of both ATM alleles by deletion or point mutation in TPLL, suggesting that ATM functions as a tumor suppressor gene in tumors of non-AT individuals. One of the mutations was a ser1770-to-ter (S1770X) substitution caused by a 5309C-G transversion in exon 37 of the ATM gene.
Pagani et al. (2002) found an unusual type of mutation in the ATM gene causing ataxia-telangiectasia (AT; 208900). The patient was a 20-year-old male of German-Polish descent who suffered from cerebellar ataxia, immunodeficiency, and cellular radiosensitivity. He was a compound heterozygote with respect to both a 2250G-A splicing mutation that caused complete skipping of exon 16 and an intron deletion that caused a cryptic exon inclusion between exons 20 and 21. No other mutation had been identified in a previous sequencing analysis of all exons of ATM in his genomic DNA (Sandoval et al., 1999). The deletion involved 4 nucleotides (GTAA) in intron 20 and resulted in the aberrant inclusion of a cryptic exon of 65 bp. The deletion was located 12 bp downstream and 53 bp upstream from the 5-prime and 3-prime ends of the cryptic exon, respectively. Through analysis of the splicing defect using a hybrid minigene system, Pagani et al. (2002) identified a new intron-splicing processing element (ISPE) complementary to U1 snRNA (180680), the RNA component of the U1 small nuclear ribonucleoprotein (snRNP). They found that the element mediates accurate intron processing and interacts specifically with U1 snRNP particles. The 4-nucleotide deletion completely abolished this interaction, causing activation of the cryptic exon. On the basis of the analysis in this instructive case, Pagani et al. (2002) described a new type of U1 snRNP binding site in an intron that is essential for accurate intron removal. Deletion of this sequence is directly involved in the splicing processing defect.
Eng et al. (2004) referred to this type of mutation as a pseudoexon insertion and in a discussion of nonclassic splicing mutations in ataxia-telangiectasia patients referred to this as type II. They described 4 patients of diverse ethnicity with the mutation IVS20-579delAAGT and found that they all shared a common founder haplotype.
For discussion of the 2250G-A splicing mutation in the ATM gene that was found in compound heterozygous state in a patient with ataxia-telangiectasia (AT; 208900) by Pagani et al. (2002), see 607585.0026.
In 2 sisters with variant ataxia-telangiectasia (AT; 208900) with onset of ataxia at age 27 years, polyneuropathy, choreoathetosis, and absence of telangiectasia, immunodeficiency, and cancer, Saviozzi et al. (2002) identified compound heterozygosity for mutations in the ATM gene: an 8030A-G change in exon 57, resulting in a tyr2677-to-cys (Y2677C) substitution, and a 1-bp insertion at nucleotide 7481 (7481insA; 607585.0029) in exon 52, resulting in a frameshift. Western blot analysis showed a low level of ATM protein with residual phosphorylation activity, which the authors suggested contributed to the milder phenotype.
For discussion of the 1-bp insertion in the ATM gene (7481insA) that was found in compound heterozygous state in 2 sisters with variant ataxia-telangiectasia (AT; 208900) by Saviozzi et al. (2002), see 607585.0028.
In a patient with an attenuated form of ataxia-telangiectasia (AT; 208900), Dork et al. (2004) identified compound heterozygosity for a double missense mutation in the ATM gene (607585.0013), and a novel splicing mutation (496+5G-A) in the splice donor site of intron 7.
Stredrick et al. (2006) presented analyses which, they suggested, provided the most convincing evidence to that time that missense mutations in ATM, particularly ser49 to cys (S49C, 146C-G), may be breast cancer (114480) susceptibility alleles. Among subjects in the United States, 3.9% of breast cancer cases and 2.6% of controls were heterozygous for S49C, while in Polish subjects 2.3% of cases and 1.2% of controls carried this mutation, with a combined odds ratio of 1.69 (95% CI, 1.19-2.40; P = 0.004). Previous studies had identified this variant more commonly in breast cancer patients (e.g., Maillet et al., 2002; Buchholz et al., 2004).
In 13 individuals from 3 Canadian Mennonite families with variant ataxia-telangiectasia (AT; 208900) ascertained for early-onset dystonia, Saunders-Pullman et al. (2012) identified a homozygous 6200C-A transversion in exon 43 of the ATM gene, resulting in an ala2067-to-asp (A2067D) substitution. Cells from 2 mutation carriers showed increased radiosensitivity and only trace amounts of ATM protein. The patients had onset of dystonia in the first 2 decades (range, 1-20 years). Dystonia mostly affected the neck, face, tongue, and limbs, and became generalized in 60% of patients. Dysarthria was very common. Additional features in some patients included myoclonus, facial choreiform movements, and irregular tremor. Some patients had clumsy gait, and although none had overt ataxia, 2 patients had ataxia in childhood that spontaneously resolved. None had prominent telangiectases. Postmortem examination showed mild loss of cerebellar Purkinje cells in 1 patient, but cerebellar atrophy was not a prominent finding in any of the patients. Heterozygous mutation carriers did not have dystonia. Family history revealed that 2 homozygous mutation carriers in 1 family had died of malignancy in adulthood.
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