|Coordinate||53,479,673 bp (GRCm38)|
|Base Change||A ⇒ T (forward strand)|
|Gene Name||ataxia telangiectasia mutated|
|Chromosomal Location||53,439,149-53,536,740 bp (-)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]
PHENOTYPE: Homozygotes for null mutations may exhibit locomotor abnormalities, motor learning deficits, growth retardation, sterility due to meiotic arrest, and susceptibility to thymic lymphomas. Mice homozygous for a kinase dead allele exhibit early embryonic lethality associated with genetic instability. [provided by MGI curators]
|Amino Acid Change||Leucine changed to Glutamine|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000113388] [ENSMUSP00000156344]|
AA Change: L1867Q
|Predicted Effect||probably damaging
PolyPhen 2 Score 0.994 (Sensitivity: 0.69; Specificity: 0.97)
|Predicted Effect||probably damaging
PolyPhen 2 Score 0.994 (Sensitivity: 0.69; Specificity: 0.97)
|Meta Mutation Damage Score||0.082|
|Is this an essential gene?||Possibly essential (E-score: 0.721)|
|Candidate Explorer Status||CE: excellent candidate; human score: 2; ML prob: 0.618|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Unknown|
|Last Updated||2019-09-04 9:31 PM by Diantha La Vine|
|Record Created||2019-01-15 8:13 PM by Bruce Beutler|
The osphere phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R1630, some of which showed increased B to T cell ratios (Figure 1), increased frequencies of peripheral blood B1 cells (Figure 2), reduced secretion of the proinflammatory cytokine interleukin (IL)-1β in response to priming with lipopolysaccharide (LPS) followed by nigericin treatment (i.e., NLRP3 inflammasome signaling defect; Figure 3), and defective phagocytosis of peritoneal exudate cells (Figure 4). Phagocytosis was detected by measuring the fluorescence intensity of pHrodo® Green E. coliconjugates two hours after treatment of PECs with an experimental phagocytosis effector (e.g., Cytochalasin D). The pHrodo® Green E. coli conjugates fluoresce at acidic pH, such as in phagosomes.
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 61 mutations. All of the above anomalies were linked by continuous variable mapping to mutations in two genes on chromosome 9: Atm and Dennd4a. The mutation in Atm was presumed causative as the immune phenotypes observed in tropo mice mimics that of other mice expressing mutant Atm alleles (see MGI). The mutation in Atm is a T to A transversion at base pair 53,479,673 (v38) on chromosome 9, or base pair 57,144 in the GenBank genomic region NC_000075. The strongest association was found with a recessive model of inheritance to the B1 cell phenotype, wherein two variant homozygotes departed phenotypically from five homozygous reference mice and seven heterozygous mice with a P value of 3.837 x 10-6 (Figure 5).
The mutation corresponds to residue 5,739 in the mRNA sequence NM_007499 within exon 36 of 64 total exons.
The mutated nucleotide is indicated in red. The mutation results in a leucine to glutamine substitution at amino acid 1,867 (L1867Q) in the ATM protein, and is strongly predicted by PolyPhen-2 to be damaging (score = 0.994).
ATM (ataxia telangiectasia mutated) is a member of the PI3/PI4-kinase (PIKK) family. The PIKK family members DNA-PKCS (DNA-dependent protein kinase; see clover), ATR (ATM and Rad3-related), and ATM are involved in DNA repair [(1); reviewed in (2)]. A 250-amino acid region at the C-terminus of ATM constitutes the catalytic PIKK domain (Figure 6). The PIKK domain is flanked by the FAT domain (named for its homology to FRAP, ATM and TRRAP) and a FATC domain (FAT at the extreme C-terminus). The FAT and FATC domains occur in combination in all PIKK family members, suggesting a possible role in maintaining a structural conformation essential for the activation of the catalytic site (3;4). The FAT domain mediates ATM dimerization and has three tetratriocpeptide repeat domains (TRDs). The N-terminal portion of the protein up to the FAT domain consists of HEAT (Huntingtin, Elongation factor 3, A subunit of protein phosphatase 2A and TOR1) repeats (5). HEAT repeats are helical structural repeats that mediate protein-protein interactions (6).
The osphere mutation results in a leucine to glutamine substitution at amino acid 1,867 (L1867Q); amino acid 1,867 is within the HEAT repeat region.
For more information about Atm, please see the record for mockingbird.
ATM is a cell cycle checkpoint kinase that phosphorylates proteins in several cell processes, including DNA repair, apoptosis, cell cycle checkpoints, telomere dysfunction, translation initiation, gene regulation, mitosis, and hypoxia. In all, there are 900 putative ATM/ATR phosphorylation sites on over 700 proteins in the DNA damage response (DDR) pathway alone (7).
Mutations in human ATM are linked to ataxia-telangiectasia [OMIM: #208900; (8;9)] and susceptibility to breast cancer (OMIM: #114480) as well as somatic B-cell non-Hodgkin lymphoma, somatic mantle cell lymphoma, and somatic T-cell prolymphocytic leukemia. Ataxia-telangiectasia is characterized by progressive cerebellar ataxia due to premature degeneration of Purkinje and granule cells, telangiectasia (dilated blood vessels), growth retardation, gonadal atrophy, immune defects, and a predisposition to malignancy (lymphoma, leukemia, and breast cancer). Fibroblasts from ataxia-telangiectasia patients exhibit aberrant gross morphology and cytoskeletal organization, poor cell growth, defective cell-cycle checkpoints, telomere loss, and chromosome end-to-end associations.
Atm-deficient (Atm-/-) mice exhibited reduced body weights, increased incidence of T-cell-derived lymphoma, premature death (median survival is 113 days), reduced numbers of CD4+ and CD8+ T cells, reduced numbers of CD3/CD4 and CD3/CD8 T cells, reduced numbers of active T cells, reduced numbers of pre-B cells, reduced levels of IgG, male and female infertility, hypoactivity, impaired coordination, impaired glucose tolerance, and insulin resistance (10-18). B cells from the Atm-/- mice exhibited reduced class switch recombination with increased genomic instability after tamoxifen treatment compared to cells from wild-type mice (19). Homozygous mice expressing a kinase dead mutant Atm allele exhibited embryonic lethality from embryonic day (E) 9.5 to E10.5 (19). Homozygous mice expressing a mutant Atm allele (a 9 base pair in-frame deletion in exon 54 resulting in deletion of Ser2556-Arg2557-Iso2558 in the protein) exhibited premature death by 40 weeks of age (50%), reduced body size, increased tumor incidence, increased numbers of double-negative and single-positive T cells, reduced thymocyte numbers, and male infertility (16). The phenotype of the osphere mice indicates loss of ATM-associated function.
osphere(F):5'- ACAATGCCTGGTGTAAGGAGTGTG -3'
osphere(R):5'- AGGTCGGAAACCCTTTGCTTGG -3'
osphere_seq(F):5'- GTGTGCAGAAAGTTGCCC -3'
osphere_seq(R):5'- GAAACCCTTTGCTTGGTATTGC -3'
1) 94°C 2:00
The following sequence of 474 nucleotides is amplified (chromosome 9, - strand):
1 aggtcggaaa ccctttgctt ggtattgctg ggttgttttt gttctgttct gtttttcttt
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red.
1. Falck, J., Coates, J., and Jackson, S. P. (2005) Conserved Modes of Recruitment of ATM, ATR and DNA-PKcs to Sites of DNA Damage. Nature. 434, 605-611.
2. Abraham, R. T. (2001) Cell Cycle Checkpoint Signaling through the ATM and ATR Kinases. Genes Dev. 15, 2177-2196.
3. Dip, R., and Naegeli, H. (2005) More than just Strand Breaks: The Recognition of Structural DNA Discontinuities by DNA-Dependent Protein Kinase Catalytic Subunit. FASEB J. 19, 704-715.
4. Hill, R., and Lee, P. W. (2010) The DNA-Dependent Protein Kinase (DNA-PK): More than just a Case of Making Ends Meet? Cell Cycle. 9, 3460-3469.
5. Perry, J., and Kleckner, N. (2003) The ATRs, ATMs, and TORs are Giant HEAT Repeat Proteins. Cell. 112, 151-155.
6. Andrade, M. A., Perez-Iratxeta, C., and Ponting, C. P. (2001) Protein Repeats: Structures, Functions, and Evolution. J Struct Biol. 134, 117-131.
7. Matsuoka, S., Ballif, B. A., Smogorzewska, A., McDonald, E. R.,3rd, Hurov, K. E., Luo, J., Bakalarski, C. E., Zhao, Z., Solimini, N., Lerenthal, Y., Shiloh, Y., Gygi, S. P., and Elledge, S. J. (2007) ATM and ATR Substrate Analysis Reveals Extensive Protein Networks Responsive to DNA Damage. Science. 316, 1160-1166.
8. Buzin, C. H., Gatti, R. A., Nguyen, V. Q., Wen, C. Y., Mitui, M., Sanal, O., Chen, J. S., Nozari, G., Mengos, A., Li, X., Fujimura, F., and Sommer, S. S. (2003) Comprehensive Scanning of the ATM Gene with DOVAM-S. Hum Mutat. 21, 123-131.
9. Savitsky, K., Bar-Shira, A., Gilad, S., Rotman, G., Ziv, Y., Vanagaite, L., Tagle, D. A., Smith, S., Uziel, T., Sfez, S., Ashkenazi, M., Pecker, I., Frydman, M., Harnik, R., Patanjali, S. R., Simmons, A., Clines, G. A., Sartiel, A., Gatti, R. A., Chessa, L., Sanal, O., Lavin, M. F., Jaspers, N. G., Taylor, A. M., Arlett, C. F., Miki, T., Weissman, S. M., Lovett, M., Collins, F. S., and Shiloh, Y. (1995) A Single Ataxia Telangiectasia Gene with a Product Similar to PI-3 Kinase. Science. 268, 1749-1753.
10. Barlow, C., Hirotsune, S., Paylor, R., Liyanage, M., Eckhaus, M., Collins, F., Shiloh, Y., Crawley, J. N., Ried, T., Tagle, D., and Wynshaw-Boris, A. (1996) Atm-Deficient Mice: A Paradigm of Ataxia Telangiectasia. Cell. 86, 159-171.
11. Genik, P. C., Bielefeldt-Ohmann, H., Liu, X., Story, M. D., Ding, L., Bush, J. M., Fallgren, C. M., and Weil, M. M. (2014) Strain Background Determines Lymphoma Incidence in Atm Knockout Mice. Neoplasia. 16, 129-136.
12. Treuner, K., Helton, R., and Barlow, C. (2004) Loss of Rad52 Partially Rescues Tumorigenesis and T-Cell Maturation in Atm-Deficient Mice. Oncogene. 23, 4655-4661.
13. Morales, M., Theunissen, J. W., Kim, C. F., Kitagawa, R., Kastan, M. B., and Petrini, J. H. (2005) The Rad50S Allele Promotes ATM-Dependent DNA Damage Responses and Suppresses ATM Deficiency: Implications for the Mre11 Complex as a DNA Damage Sensor. Genes Dev. 19, 3043-3054.
14. Xu, Y., Ashley, T., Brainerd, E. E., Bronson, R. T., Meyn, M. S., and Baltimore, D. (1996) Targeted Disruption of ATM Leads to Growth Retardation, Chromosomal Fragmentation during Meiosis, Immune Defects, and Thymic Lymphoma. Genes Dev. 10, 2411-2422.
15. Borghesani, P. R., Alt, F. W., Bottaro, A., Davidson, L., Aksoy, S., Rathbun, G. A., Roberts, T. M., Swat, W., Segal, R. A., and Gu, Y. (2000) Abnormal Development of Purkinje Cells and Lymphocytes in Atm Mutant Mice. Proc Natl Acad Sci U S A. 97, 3336-3341.
16. Spring, K., Cross, S., Li, C., Watters, D., Ben-Senior, L., Waring, P., Ahangari, F., Lu, S. L., Chen, P., Misko, I., Paterson, C., Kay, G., Smorodinsky, N. I., Shiloh, Y., and Lavin, M. F. (2001) Atm Knock-in Mice Harboring an in-Frame Deletion Corresponding to the Human ATM 7636del9 Common Mutation Exhibit a Variant Phenotype. Cancer Res. 61, 4561-4568.
17. Elson, A., Wang, Y., Daugherty, C. J., Morton, C. C., Zhou, F., Campos-Torres, J., and Leder, P. (1996) Pleiotropic Defects in Ataxia-Telangiectasia Protein-Deficient Mice. Proc Natl Acad Sci U S A. 93, 13084-13089.
18. Takagi, M., Uno, H., Nishi, R., Sugimoto, M., Hasegawa, S., Piao, J., Ihara, N., Kanai, S., Kakei, S., Tamura, Y., Suganami, T., Kamei, Y., Shimizu, T., Yasuda, A., Ogawa, Y., and Mizutani, S. (2015) ATM Regulates Adipocyte Differentiation and Contributes to Glucose Homeostasis. Cell Rep. .
|Science Writers||Anne Murray|
|Illustrators||Diantha La Vine|
|Authors||Xue Zhong, Jin Huk Choi, and Bruce Beutler|