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Home / Equine Research Bank / J Immunol / A kinase-negative mutation of DNA-PK(CS) in equine SCID resu...
Journal of immunology (Baltimore, Md. : 1950)1997; 158(8); 3565-3569;

A kinase-negative mutation of DNA-PK(CS) in equine SCID results in defective coding and signal joint formation.

Abstract: The equine SCID defect is more severe than its murine counterpart in that SCID foals are incapable of forming either coding or signal joints, whereas SCID mice manifest normal signal joint formation. To determine the basis of this difference and whether DNA-dependent kinase, catalytic subunit (DNA-PK(CS)), is involved in signal joint formation, equine DNA-PK(CS) transcripts were cloned and sequenced from normal and SCID cell lines. In the mutant allele, a frame-shift mutation truncates the protein N terminal of the domain with homology to the phosphatidylinositol 3-kinase family resulting in complete absence of full length DNA-PK(CS) and accounting for the kinase-negative phenotype of these cells; the mutation in SCID mice allows for some DNA-PK(CS) expression. The difference in DNA-PK(CS) expression in SCID mice and foals explains the more severe phenotype of equine SCID, and definition of DNA-PK(CS) as the defect in equine SCID demonstrates that DNA-PK(CS) is required for both coding and signal joint formation.
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Publication Date: 1997-04-15 PubMed ID: 9103416
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  • Journal Article
  • Research Support
  • Non-U.S. Gov't
  • Research Support
  • U.S. Gov't
  • P.H.S.

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research studied the role of the DNA-PK(CS) mutation in equine Severe Combined Immunodeficiency (SCID) and found it was responsible for the disorder’s severity, as it disrupts coding and signal joint formation – actions essential for immune system development.

Understanding the Context: Equine SCID and DNA-PK(CS)

  • The researchers examined Severe Combined Immunodeficiency (SCID) in horses. SCID is a disorder where the animal’s immune system development is incomplete, leaving them extremely vulnerable to infections.
  • This condition is particularly severe in horses, where foals suffering from SCID are incapable of forming coding and signal joints, key components of the body’s immune response.
  • The research team focused their attention on the DNA-dependent kinase, catalytic subunit (DNA-PK(CS)) – an enzyme previously linked to SCID in mice.

Technical Exploration: Sequencing and Mutation

  • The team cloned and sequenced equine DNA-PK(CS) transcripts from normal and SCID cell lines to understand the differences and potential mutations.
  • They found a frame-shift mutation in the mutant allele that truncates the protein N terminal of the domain with homology to the phosphatidylinositol 3-kinase family.
  • This mutation was found to cause a complete absence of full length DNA-PK(CS), accounting for the kinase-negative phenotype of these cells.
  • In contrast, the frame-shift mutation permits some level of DNA-PK(CS) expression in SCID mice.

The Role of DNA-PK CS in Equine SCID

  • The research identifies the DNA-PK CS mutation as the key factor contributing to the more severe phenotype of equine SCID compared to its murine counterpart.
  • This differential DNA-PK CS expression explains why SCID foals are unable to form coding and signal joints, therefore rendering them more susceptible to infections.
  • By pinpointing the key defect in equine SCID, researchers showed that DNA-PK CS is vital for coding and signal joint formation, thereby highlighting its significance for immune system development.

Implications and Conclusion

  • This research offers deep insights into equine SCID’s genetic underpinnings, potentially paving the way for new treatment methods for this debilitating condition.
  • Moreover, understanding the role of DNA-PK CS in immunodeficiency disorders can potentially help researchers address other similar conditions in different species.

Cite This Article

APA
Shin EK, Perryman LE, Meek K. (1997). A kinase-negative mutation of DNA-PK(CS) in equine SCID results in defective coding and signal joint formation. J Immunol, 158(8), 3565-3569.

Publication

Journal of immunology (Baltimore, Md. : 1950)
ISSN: 0022-1767
NlmUniqueID: 2985117R
Country: United States
Language: English
Volume: 158
Issue: 8
Pages: 3565-3569

Researcher Affiliations

Shin, E K
  • Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235, USA.
Perryman, L E
    Meek, K

      MeSH Terms

      • Amino Acid Sequence
      • Animals
      • Base Sequence
      • Cell Line
      • DNA-Activated Protein Kinase
      • DNA-Binding Proteins
      • Gene Rearrangement
      • Horses
      • Immunoglobulin Variable Region / genetics
      • Mice
      • Mice, SCID
      • Molecular Sequence Data
      • Mutation
      • Protein Serine-Threonine Kinases / genetics
      • Severe Combined Immunodeficiency / genetics
      • Signal Transduction / genetics

      Grant Funding

      • AI32600 / NIAID NIH HHS
      • SR01HL46651 / NHLBI NIH HHS

      Citations

      This article has been cited 51 times.
      1. Reich P, Falker-Gieske C, Pook T, Tetens J. Development and validation of a horse reference panel for genotype imputation. Genet Sel Evol 2022 Jul 4;54(1):49.
        doi: 10.1186/s12711-022-00740-8pubmed: 35787788google scholar: lookup
      2. Ayad A, Almarzook S, Besseboua O, Aissanou S, Piórkowska K, Musiał AD, Stefaniuk-Szmukier M, Ropka-Molik K. Investigation of Cerebellar Abiotrophy (CA), Lavender Foal Syndrome (LFS), and Severe Combined Immunodeficiency (SCID) Variants in a Cohort of Three MENA Region Horse Breeds. Genes (Basel) 2021 Nov 26;12(12).
        doi: 10.3390/genes12121893pubmed: 34946842google scholar: lookup
      3. Matsumoto Y, Asa ADDC, Modak C, Shimada M. DNA-Dependent Protein Kinase Catalytic Subunit: The Sensor for DNA Double-Strand Breaks Structurally and Functionally Related to Ataxia Telangiectasia Mutated. Genes (Basel) 2021 Jul 27;12(8).
        doi: 10.3390/genes12081143pubmed: 34440313google scholar: lookup
      4. Neal JA, Meek K. Deciphering phenotypic variance in different models of DNA-PKcs deficiency. DNA Repair (Amst) 2019 Jan;73:7-16.
        doi: 10.1016/j.dnarep.2018.10.004pubmed: 30409670google scholar: lookup
      5. Chung JH. The role of DNA-PK in aging and energy metabolism. FEBS J 2018 Jun;285(11):1959-1972.
        doi: 10.1111/febs.14410pubmed: 29453899google scholar: lookup
      6. Meek K, Xu Y, Bailie C, Yu K, Neal JA. The ATM Kinase Restrains Joining of Both VDJ Signal and Coding Ends. J Immunol 2016 Oct 15;197(8):3165-3174.
        doi: 10.4049/jimmunol.1600597pubmed: 27574300google scholar: lookup
      7. Neal JA, Xu Y, Abe M, Hendrickson E, Meek K. Restoration of ATM Expression in DNA-PKcs-Deficient Cells Inhibits Signal End Joining. J Immunol 2016 Apr 1;196(7):3032-42.
        doi: 10.4049/jimmunol.1501654pubmed: 26921311google scholar: lookup
      8. Schwartz EJ, Nanda S, Mealey RH. Antibody escape kinetics of equine infectious anemia virus infection of horses. J Virol 2015 Jul;89(13):6945-51.
        doi: 10.1128/JVI.00137-15pubmed: 25878104google scholar: lookup
      9. Jun J, Cho YS, Hu H, Kim HM, Jho S, Gadhvi P, Park KM, Lim J, Paek WK, Han K, Manica A, Edwards JS, Bhak J. Whole genome sequence and analysis of the Marwari horse breed and its genetic origin. BMC Genomics 2014;15 Suppl 9(Suppl 9):S4.
        doi: 10.1186/1471-2164-15-S9-S4pubmed: 25521865google scholar: lookup
      10. Metzger J, Tonda R, Beltran S, Agueda L, Gut M, Distl O. Next generation sequencing gives an insight into the characteristics of highly selected breeds versus non-breed horses in the course of domestication. BMC Genomics 2014 Jul 4;15(1):562.
        doi: 10.1186/1471-2164-15-562pubmed: 24996778google scholar: lookup
      11. Finno CJ, Bannasch DL. Applied equine genetics. Equine Vet J 2014 Sep;46(5):538-44.
        doi: 10.1111/evj.12294pubmed: 24802051google scholar: lookup
      12. Ramsay JD, Ueti MW, Johnson WC, Scoles GA, Knowles DP, Mealey RH. Lymphocytes and macrophages are infected by Theileria equi, but T cells and B cells are not required to establish infection in vivo. PLoS One 2013;8(10):e76996.
        doi: 10.1371/journal.pone.0076996pubmed: 24116194google scholar: lookup
      13. Lee BS, Gapud EJ, Zhang S, Dorsett Y, Bredemeyer A, George R, Callen E, Daniel JA, Osipovich O, Oltz EM, Bassing CH, Nussenzweig A, Lees-Miller S, Hammel M, Chen BP, Sleckman BP. Functional intersection of ATM and DNA-dependent protein kinase catalytic subunit in coding end joining during V(D)J recombination. Mol Cell Biol 2013 Sep;33(18):3568-79.
        doi: 10.1128/MCB.00308-13pubmed: 23836881google scholar: lookup
      14. Runkle EA, Zhang H, Cai Z, Zhu Z, Karger BL, Wu SL, O'Rourke DM, Zhou Z, Wang Q, Greene MI. Reversion of the ErbB malignant phenotype and the DNA damage response. Exp Mol Pathol 2012 Dec;93(3):324-33.
        doi: 10.1016/j.yexmp.2012.09.007pubmed: 23022358google scholar: lookup
      15. Masuda Y, Kamiya K. Molecular nature of radiation injury and DNA repair disorders associated with radiosensitivity. Int J Hematol 2012 Mar;95(3):239-45.
        doi: 10.1007/s12185-012-1008-ypubmed: 22351161google scholar: lookup
      16. Doan R, Cohen ND, Sawyer J, Ghaffari N, Johnson CD, Dindot SV. Whole-genome sequencing and genetic variant analysis of a Quarter Horse mare. BMC Genomics 2012 Feb 17;13:78.
        doi: 10.1186/1471-2164-13-78pubmed: 22340285google scholar: lookup
      17. Mealey RH, Kappmeyer LS, Ueti MW, Wagner B, Knowles DP. Protective effects of passively transferred merozoite-specific antibodies against Theileria equi in horses with severe combined immunodeficiency. Clin Vaccine Immunol 2012 Jan;19(1):100-4.
        doi: 10.1128/CVI.05301-11pubmed: 22038847google scholar: lookup
      18. Fox-Clipsham LY, Carter SD, Goodhead I, Hall N, Knottenbelt DC, May PD, Ollier WE, Swinburne JE. Identification of a mutation associated with fatal Foal Immunodeficiency Syndrome in the Fell and Dales pony. PLoS Genet 2011 Jul;7(7):e1002133.
        doi: 10.1371/journal.pgen.1002133pubmed: 21750681google scholar: lookup
      19. Gapud EJ, Sleckman BP. Unique and redundant functions of ATM and DNA-PKcs during V(D)J recombination. Cell Cycle 2011 Jun 15;10(12):1928-35.
        doi: 10.4161/cc.10.12.16011pubmed: 21673501google scholar: lookup
      20. Andersson LS, Lyberg K, Cothran G, Ramsey DT, Juras R, Mikko S, Ekesten B, Ewart S, Lindgren G. Targeted analysis of four breeds narrows equine Multiple Congenital Ocular Anomalies locus to 208 kilobases. Mamm Genome 2011 Jun;22(5-6):353-60.
        doi: 10.1007/s00335-011-9325-7pubmed: 21465164google scholar: lookup
      21. Zha S, Jiang W, Fujiwara Y, Patel H, Goff PH, Brush JW, Dubois RL, Alt FW. Ataxia telangiectasia-mutated protein and DNA-dependent protein kinase have complementary V(D)J recombination functions. Proc Natl Acad Sci U S A 2011 Feb 1;108(5):2028-33.
        doi: 10.1073/pnas.1019293108pubmed: 21245310google scholar: lookup
      22. Brosnahan MM, Brooks SA, Antczak DF. Equine clinical genomics: A clinician's primer. Equine Vet J 2010 Oct;42(7):658-70.
        doi: 10.1111/j.2042-3306.2010.00166.xpubmed: 20840582google scholar: lookup
      23. Taylor SD, Leib SR, Carpenter S, Mealey RH. Selection of a rare neutralization-resistant variant following passive transfer of convalescent immune plasma in equine infectious anemia virus-challenged SCID horses. J Virol 2010 Jul;84(13):6536-48.
        doi: 10.1128/JVI.00218-10pubmed: 20392850google scholar: lookup
      24. Meek K, Jutkowitz A, Allen L, Glover J, Convery E, Massa A, Mullaney T, Stanley B, Rosenstein D, Bailey SM, Johnson C, Georges G. SCID dogs: similar transplant potential but distinct intra-uterine growth defects and premature replicative senescence compared with SCID mice. J Immunol 2009 Aug 15;183(4):2529-36.
        doi: 10.4049/jimmunol.0801406pubmed: 19635917google scholar: lookup
      25. Bauer TR Jr, Adler RL, Hickstein DD. Potential large animal models for gene therapy of human genetic diseases of immune and blood cell systems. ILAR J 2009;50(2):168-86.
        doi: 10.1093/ilar.50.2.168pubmed: 19293460google scholar: lookup
      26. Andersson LS, Juras R, Ramsey DT, Eason-Butler J, Ewart S, Cothran G, Lindgren G. Equine Multiple Congenital Ocular Anomalies maps to a 4.9 megabase interval on horse chromosome 6. BMC Genet 2008 Dec 19;9:88.
        doi: 10.1186/1471-2156-9-88pubmed: 19099555google scholar: lookup
      27. van der Burg M, Ijspeert H, Verkaik NS, Turul T, Wiegant WW, Morotomi-Yano K, Mari PO, Tezcan I, Chen DJ, Zdzienicka MZ, van Dongen JJ, van Gent DC. A DNA-PKcs mutation in a radiosensitive T-B- SCID patient inhibits Artemis activation and nonhomologous end-joining. J Clin Invest 2009 Jan;119(1):91-8.
        doi: 10.1172/JCI37141pubmed: 19075392google scholar: lookup
      28. Ruis BL, Fattah KR, Hendrickson EA. The catalytic subunit of DNA-dependent protein kinase regulates proliferation, telomere length, and genomic stability in human somatic cells. Mol Cell Biol 2008 Oct;28(20):6182-95.
        doi: 10.1128/MCB.00355-08pubmed: 18710952google scholar: lookup
      29. Chowdhary BP, Raudsepp T. The horse genome derby: racing from map to whole genome sequence. Chromosome Res 2008;16(1):109-27.
        doi: 10.1007/s10577-008-1204-zpubmed: 18274866google scholar: lookup
      30. Mealey RH, Littke MH, Leib SR, Davis WC, McGuire TC. Failure of low-dose recombinant human IL-2 to support the survival of virus-specific CTL clones infused into severe combined immunodeficient foals: lack of correlation between in vitro activity and in vivo efficacy. Vet Immunol Immunopathol 2008 Jan 15;121(1-2):8-22.
        doi: 10.1016/j.vetimm.2007.07.011pubmed: 17727961google scholar: lookup
      31. Beskow C, Kanter L, Holgersson A, Nilsson B, Frankendal B, Avall-Lundqvist E, Lewensohn R. Expression of DNA damage response proteins and complete remission after radiotherapy of stage IB-IIA of cervical cancer. Br J Cancer 2006 Jun 5;94(11):1683-9.
        doi: 10.1038/sj.bjc.6603153pubmed: 16685270google scholar: lookup
      32. Convery E, Shin EK, Ding Q, Wang W, Douglas P, Davis LS, Nickoloff JA, Lees-Miller SP, Meek K. Inhibition of homologous recombination by variants of the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs). Proc Natl Acad Sci U S A 2005 Feb 1;102(5):1345-50.
        doi: 10.1073/pnas.0406466102pubmed: 15668400google scholar: lookup
      33. Sellon DC, Knowles DP, Greiner EC, Long MT, Hines MT, Hochstatter T, Tibary A, Dame JB. Infection of immunodeficient horses with Sarcocystis neurona does not result in neurologic disease. Clin Diagn Lab Immunol 2004 Nov;11(6):1134-9.
        doi: 10.1128/CDLI.11.6.1134-1139.2004pubmed: 15539518google scholar: lookup
      34. Ward TL, Valberg SJ, Adelson DL, Abbey CA, Binns MM, Mickelson JR. Glycogen branching enzyme (GBE1) mutation causing equine glycogen storage disease IV. Mamm Genome 2004 Jul;15(7):570-7.
        doi: 10.1007/s00335-004-2369-1pubmed: 15366377google scholar: lookup
      35. Mealey RH, Leib SR, Pownder SL, McGuire TC. Adaptive immunity is the primary force driving selection of equine infectious anemia virus envelope SU variants during acute infection. J Virol 2004 Sep;78(17):9295-305.
        doi: 10.1128/JVI.78.17.9295-9305.2004pubmed: 15308724google scholar: lookup
      36. Moshous D, Pannetier C, Chasseval Rd Rd, Deist Fl Fl, Cavazzana-Calvo M, Romana S, Macintyre E, Canioni D, Brousse N, Fischer A, Casanova JL, Villartay JP. Partial T and B lymphocyte immunodeficiency and predisposition to lymphoma in patients with hypomorphic mutations in Artemis. J Clin Invest 2003 Feb;111(3):381-7.
        doi: 10.1172/JCI16774pubmed: 12569164google scholar: lookup
      37. Woods T, Wang W, Convery E, Errami A, Zdzienicka MZ, Meek K. A single amino acid substitution in DNA-PKcs explains the novel phenotype of the CHO mutant, XR-C2. Nucleic Acids Res 2002 Dec 1;30(23):5120-8.
        doi: 10.1093/nar/gkf625pubmed: 12466535google scholar: lookup
      38. Douglas P, Sapkota GP, Morrice N, Yu Y, Goodarzi AA, Merkle D, Meek K, Alessi DR, Lees-Miller SP. Identification of in vitro and in vivo phosphorylation sites in the catalytic subunit of the DNA-dependent protein kinase. Biochem J 2002 Nov 15;368(Pt 1):243-51.
        doi: 10.1042/BJ20020973pubmed: 12186630google scholar: lookup
      39. Mealey RH, Fraser DG, Oaks JL, Cantor GH, McGuire TC. Immune reconstitution prevents continuous equine infectious anemia virus replication in an Arabian foal with severe combined immunodeficiency: lessons for control of lentiviruses. Clin Immunol 2001 Nov;101(2):237-47.
        doi: 10.1006/clim.2001.5109pubmed: 11683583google scholar: lookup
      40. Kurimasa A, Kumano S, Boubnov NV, Story MD, Tung CS, Peterson SR, Chen DJ. Requirement for the kinase activity of human DNA-dependent protein kinase catalytic subunit in DNA strand break rejoining. Mol Cell Biol 1999 May;19(5):3877-84.
        doi: 10.1128/MCB.19.5.3877pubmed: 10207111google scholar: lookup
      41. Bogue MA, Jhappan C, Roth DB. Analysis of variable (diversity) joining recombination in DNAdependent protein kinase (DNA-PK)-deficient mice reveals DNA-PK-independent pathways for both signal and coding joint formation. Proc Natl Acad Sci U S A 1998 Dec 22;95(26):15559-64.
        doi: 10.1073/pnas.95.26.15559pubmed: 9861008google scholar: lookup
      42. Lindgren G, Sandberg K, Persson H, Marklund S, Breen M, Sandgren B, Carlstén J, Ellegren H. A primary male autosomal linkage map of the horse genome. Genome Res 1998 Sep;8(9):951-66.
        doi: 10.1101/gr.8.9.951pubmed: 9750194google scholar: lookup
      43. Nicolas N, Moshous D, Cavazzana-Calvo M, Papadopoulo D, de Chasseval R, Le Deist F, Fischer A, de Villartay JP. A human severe combined immunodeficiency (SCID) condition with increased sensitivity to ionizing radiations and impaired V(D)J rearrangements defines a new DNA recombination/repair deficiency. J Exp Med 1998 Aug 17;188(4):627-34.
        doi: 10.1084/jem.188.4.627pubmed: 9705945google scholar: lookup
      44. Kulesza P, Lieber MR. DNA-PK is essential only for coding joint formation in V(D)J recombination. Nucleic Acids Res 1998 Sep 1;26(17):3944-8.
        doi: 10.1093/nar/26.17.3944pubmed: 9705502google scholar: lookup
      45. Errami A, He DM, Friedl AA, Overkamp WJ, Morolli B, Hendrickson EA, Eckardt-Schupp F, Oshimura M, Lohman PH, Jackson SP, Zdzienicka MZ. XR-C1, a new CHO cell mutant which is defective in DNA-PKcs, is impaired in both V(D)J coding and signal joint formation. Nucleic Acids Res 1998 Jul 1;26(13):3146-53.
        doi: 10.1093/nar/26.13.3146pubmed: 9628911google scholar: lookup
      46. Priestley A, Beamish HJ, Gell D, Amatucci AG, Muhlmann-Diaz MC, Singleton BK, Smith GC, Blunt T, Schalkwyk LC, Bedford JS, Jackson SP, Jeggo PA, Taccioli GE. Molecular and biochemical characterisation of DNA-dependent protein kinase-defective rodent mutant irs-20. Nucleic Acids Res 1998 Apr 15;26(8):1965-73.
        doi: 10.1093/nar/26.8.1965pubmed: 9518490google scholar: lookup
      47. Dynan WS, Yoo S. Interaction of Ku protein and DNA-dependent protein kinase catalytic subunit with nucleic acids. Nucleic Acids Res 1998 Apr 1;26(7):1551-9.
        doi: 10.1093/nar/26.7.1551pubmed: 9512523google scholar: lookup
      48. Sharif MB, Mohaseb AF, Orlando L, Saliari K, Kunst GK, Czeika S, Mashkour M, Cucchi T, Peters J, Trixl S, Mohandesan E. Late Iron Age and Roman equine breeding north of the Alps: Genetic insights and cultural implications. iScience 2025 Sep 19;28(9):113224.
        doi: 10.1016/j.isci.2025.113224pubmed: 40837235google scholar: lookup
      49. Julia M, Felippe B. Equine common variable immunodeficiency: lessons from 100 clinical cases. Equine Vet Educ 2024 Oct;36(10):543-554.
        doi: 10.1111/eve.13948pubmed: 39555145google scholar: lookup
      50. Pascarella G, Conner KN, Goff NJ, Carninci P, Olive AJ, Meek K. Compared to other NHEJ factors, DNA-PK protein and RNA levels are markedly increased in all higher primates, but not in prosimians or other mammals. DNA Repair (Amst) 2024 Oct;142:103737.
        doi: 10.1016/j.dnarep.2024.103737pubmed: 39128395google scholar: lookup
      51. Durward-Akhurst SA, Marlowe JL, Schaefer RJ, Springer K, Grantham B, Carey WK, Bellone RR, Mickelson JR, McCue ME. Predicted genetic burden and frequency of phenotype-associated variants in the horse. Sci Rep 2024 Apr 10;14(1):8396.
        doi: 10.1038/s41598-024-57872-8pubmed: 38600096google scholar: lookup
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