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11.04.2016 | Original Article

Ligase-4 Deficiency Causes Distinctive Immune Abnormalities in Asymptomatic Individuals

verfasst von: Kerstin Felgentreff, Sachin N. Baxi, Yu Nee Lee, Kerry Dobbs, Lauren A. Henderson, Krisztian Csomos, Erdyni N. Tsitsikov, Mary Armanios, Jolan E. Walter, Luigi D. Notarangelo

Erschienen in: Journal of Clinical Immunology | Ausgabe 4/2016

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Abstract

Purpose

DNA Ligase 4 (LIG4) is a key factor in the non-homologous end-joining (NHEJ) DNA double-strand break repair pathway needed for V(D)J recombination and the generation of the T cell receptor and immunoglobulin molecules. Defects in LIG4 result in a variable syndrome of growth retardation, pancytopenia, combined immunodeficiency, cellular radiosensitivity, and developmental delay.

Methods

We diagnosed a patient with LIG4 syndrome by radiosensitivity testing on peripheral blood cells, and established that two of her four healthy siblings carried the same compound heterozygous LIG4 mutations. An extensive analysis of the immune phenotype, cellular radiosensitivity, telomere length, and T and B cell antigen receptor repertoire was performed in all siblings.

Results

In the three genotypically affected individuals, variable severities of radiosensitivity, alterations of T and B cell counts with an increased percentage of memory cells, and hypogammaglobulinemia, were noticed. Analysis of T and B cell antigen receptor repertoires demonstrated increased usage of alternative microhomology-mediated end-joining (MHMEJ) repair, leading to diminished N nucleotide addition and shorter CDR3 length. However, overall repertoire diversity was preserved.

Conclusions

We demonstrate that LIG4 syndrome presents with high clinical variability even within the same family, and that distinctive immunologic abnormalities may be observed also in yet asymptomatic individuals.

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Lieber MR, Ma Y, Pannicke U, Schwarz K. The mechanism of vertebrate nonhomologous DNA end joining and its role in V(D)J recombination. DNA Repair. 2004;3(8–9):817–26.CrossRefPubMed

Rucci F, Notarangelo LD, Fazeli A, Patrizi L, Hickernell T, Paganini T, et al. Homozygous DNA ligase IV R278H mutation in mice leads to leaky SCID and represents a model for human LIG4 syndrome. Proc Natl Acad Sci U S A. 2010;107(7):3024–9.CrossRefPubMedPubMedCentral

Ma Y, Pannicke U, Schwarz K, Lieber MR. Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination. Cell. 2002;108(6):781–94.CrossRefPubMed

Janeway CA Jr., Travers P, Walport M, et al. The generation of diverstity in immunoglobulins. New York: Garland Science; 2001.

Grawunder U, Wilm M, Wu X, Kulesza P, Wilson TE, Mann M, et al. Activity of DNA ligase IV stimulated by complex formation with XRCC4 protein in mammalian cells. Nature. 1997;388(6641):492–5.CrossRefPubMed

Buck D, Malivert L, de Chasseval R, Barraud A, Fondaneche MC, Sanal O, et al. Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell. 2006;124(2):287–99.CrossRefPubMed

Shearer WT, Dunn E, Notarangelo LD, Dvorak CC, Puck JM, Logan BR, et al. Establishing diagnostic criteria for severe combined immunodeficiency disease (SCID), leaky SCID, and Omenn syndrome: the Primary Immune Deficiency Treatment Consortium experience. J Allergy Clin Immunol. 2014;133(4):1092–8.CrossRefPubMedPubMedCentral

Frank KM, Sekiguchi JM, Seidl KJ, Swat W, Rathbun GA, Cheng HL, et al. Late embryonic lethality and impaired V(D)J recombination in mice lacking DNA ligase IV. Nature. 1998;396(6707):173–7.CrossRefPubMed

Gatz SA, Ju L, Gruber R, Hoffmann E, Carr AM, Wang ZQ, et al. Requirement for DNA ligase IV during embryonic neuronal development. J Neurosci Off J Soc Neurosci. 2011;31(27):10088–100.CrossRef

10.

O’Driscoll M, Cerosaletti KM, Girard PM, Dai Y, Stumm M, Kysela B, et al. DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol cell. 2001;8(6):1175–85.CrossRefPubMed

11.

Ben-Omran TI, Cerosaletti K, Concannon P, Weitzman S, Nezarati MM. A patient with mutations in DNA Ligase IV: clinical features and overlap with Nijmegen breakage syndrome. Am J Med Genet A. 2005;137A(3):283–7.CrossRefPubMed

12.

Gruhn B, Seidel J, Zintl F, Varon R, Tonnies H, Neitzel H, et al. Successful bone marrow transplantation in a patient with DNA ligase IV deficiency and bone marrow failure. Orphanet J Rare Dis. 2007;2:5.CrossRefPubMedPubMedCentral

13.

Toita N, Hatano N, Ono S, Yamada M, Kobayashi R, Kobayashi I, et al. Epstein-Barr virus-associated B-cell lymphoma in a patient with DNA ligase IV (LIG4) syndrome. Am J Med Genet A. 2007;143A(7):742–5.CrossRefPubMed

14.

Unal S, Cerosaletti K, Uckan-Cetinkaya D, Cetin M, Gumruk F. A novel mutation in a family with DNA ligase IV deficiency syndrome. Pediatr Blood Cancer. 2009;53(3):482–4.CrossRefPubMed

15.

Tamura S, Higuchi K, Tamaki M, Inoue C, Awazawa R, Mitsuki N, et al. Novel compound heterozygous DNA ligase IV mutations in an adolescent with a slowly-progressing radiosensitive-severe combined immunodeficiency. Clin Immunol. 2015;160:255–60.CrossRefPubMed

16.

Felgentreff K, Du L, Weinacht KG, Dobbs K, Bartish M, Giliani S, et al. Differential role of nonhomologous end joining factors in the generation, DNA damage response, and myeloid differentiation of human induced pluripotent stem cells. Proc Natl Acad Sci U S A. 2014;111(24):8889–94.CrossRefPubMedPubMedCentral

17.

Buck D, Moshous D, de Chasseval R, Ma Y, le Deist F, Cavazzana-Calvo M, et al. Severe combined immunodeficiency and microcephaly in siblings with hypomorphic mutations in DNA ligase IV. Eur J Immunol. 2006;36(1):224–35.CrossRefPubMed

18.

Enders A, Fisch P, Schwarz K, Duffner U, Pannicke U, Nikolopoulos E, et al. A severe form of human combined immunodeficiency due to mutations in DNA ligase IV. J Immunol. 2006;176(8):5060–8.CrossRefPubMed

19.

Riballo E, Critchlow SE, Teo SH, Doherty AJ, Priestley A, Broughton B, et al. Identification of a defect in DNA ligase IV in a radiosensitive leukaemia patient. Curr Biol: CB. 1999;9(13):699–702.CrossRefPubMed

20.

van der Burg M, van Veelen LR, Verkaik NS, Wiegant WW, Hartwig NG, Barendregt BH, et al. A new type of radiosensitive T-B-NK+ severe combined immunodeficiency caused by a LIG4 mutation. J Clin Invest. 2006;116(1):137–45.CrossRefPubMedPubMedCentral

21.

Grunebaum E, Bates A, Roifman CM. Omenn syndrome is associated with mutations in DNA ligase IV. J Allergy Clin Immunol. 2008;122(6):1219–20.CrossRefPubMed

22.

IJspeert H, Warris A, van der Flier M, Reisli I, Keles S, Chishimba S, et al. Clinical spectrum of LIG4 deficiency is broadened with severe dysmaturity, primordial dwarfism, and neurological abnormalities. Hum Mutat. 2013;34(12):1611–4.CrossRefPubMedPubMedCentral

23.

Riballo E, Doherty AJ, Dai Y, Stiff T, Oettinger MA, Jeggo PA, et al. Cellular and biochemical impact of a mutation in DNA ligase IV conferring clinical radiosensitivity. J Biol Chem. 2001;276(33):31124–32.CrossRefPubMed

24.

Yue J, Lu H, Lan S, Liu J, Stein MN, Haffty BG, et al. Identification of the DNA repair defects in a case of Dubowitz syndrome. PLoS ONE. 2013;8(1):e54389.CrossRefPubMedPubMedCentral

25.

Murray JE, van der Burg M, IJspeert H, Carroll P, Wu Q, Ochi T, et al. Mutations in the NHEJ component XRCC4 cause primordial dwarfism. Am J Hum Genet. 2015;96(3):412–24.CrossRefPubMedPubMedCentral

26.

Murray JE, Bicknell LS, Yigit G, Duker AL, van Kogelenberg M, Haghayegh S, et al. Extreme growth failure is a common presentation of ligase IV deficiency. Hum Mutat. 2014;35(1):76–85.CrossRefPubMedPubMedCentral

27.

Guo C, Nakazawa Y, Woodbine L, Bjorkman A, Shimada M, Fawcett H, et al. XRCC4 deficiency in human subjects causes a marked neurological phenotype but no overt immunodeficiency. J Allergy Clin Immunol. 2015;136(4):1007–17.CrossRefPubMed

28.

Baerlocher GM, Vulto I, de Jong G, Lansdorp PM. Flow cytometry and FISH to measure the average length of telomeres (flow FISH). Nat Protoc. 2006;1(5):2365–76.CrossRefPubMed

29.

Danska JS, Livingstone AM, Paragas V, Ishihara T, Fathman CG. The presumptive CDR3 regions of both T cell receptor alpha and beta chains determine T cell specificity for myoglobin peptides. J Exp Med. 1990;172(1):27–33.CrossRefPubMed

30.

O’Connell AE, Volpi S, Dobbs K, Fiorini C, Tsitsikov E, de Boer H, et al. Next generation sequencing reveals skewing of the T and B cell receptor repertoires in patients with wiskott-Aldrich syndrome. Front Immunol. 2014;5:340.PubMedPubMedCentral

31.

Alamyar E, Duroux P, Lefranc MP, Giudicelli V. IMGT((R)) tools for the nucleotide analysis of immunoglobulin (IG) and T cell receptor (TR) V-(D)-J repertoires, polymorphisms, and IG mutations: IMGT/V-QUEST and IMGT/HighV-QUEST for NGS. Methods Mol Biol. 2012;882:569–604.CrossRefPubMed

32.

Rogosch T, Kerzel S, Hoi KH, Zhang Z, Maier RF, Ippolito GC, et al. Immunoglobulin analysis tool: a novel tool for the analysis of human and mouse heavy and light chain transcripts. Front Immunol. 2012;3:176.CrossRefPubMedPubMedCentral

33.

Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7(4):248–9.CrossRefPubMedPubMedCentral

34.

Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009;4(7):1073–81.CrossRefPubMed

35.

Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46(3):310–5.CrossRefPubMedPubMedCentral

36.

Saadoun D, Terrier B, Bannock J, Vazquez T, Massad C, Kang I, et al. Expansion of autoreactive unresponsive CD21−/low B cells in Sjogren’s syndrome-associated lymphoproliferation. Arthritis Rheum. 2013;65(4):1085–96.CrossRefPubMedPubMedCentral

37.

Frankl JA, Thearle MS, Desmarais C, Bogardus C, Krakoff J. T-cell receptor repertoire variation may be associated with type 2 diabetes mellitus in humans. Diabetes Metab Res Rev. 2016;32(3):297–307.

38.

James LC, Tawfik DS. The specificity of cross-reactivity: promiscuous antibody binding involves specific hydrogen bonds rather than nonspecific hydrophobic stickiness. Protein Science: a publication of the Protein Society 2003;12(10):2183–93.

39.

Simsek D, Brunet E, Wong SY, Katyal S, Gao Y, McKinnon PJ, et al. DNA ligase III promotes alternative nonhomologous end-joining during chromosomal translocation formation. PLoS Genet. 2011;7(6):e1002080.CrossRefPubMedPubMedCentral

40.

Volk T, Pannicke U, Reisli I, Bulashevska A, Ritter J, Bjorkman A, et al. DCLRE1C (ARTEMIS) mutations causing phenotypes ranging from atypical severe combined immunodeficiency to mere antibody deficiency. Hum Mol Genet. 2015;24:7361–72.CrossRefPubMed

41.

Nijnik A, Woodbine L, Marchetti C, Dawson S, Lambe T, Liu C, et al. DNA repair is limiting for haematopoietic stem cells during ageing. Nature. 2007;447(7145):686–90.CrossRefPubMed

42.

Stanley SE, Armanios M. The short and long telomere syndromes: paired paradigms for molecular medicine. Curr Opin Genet Dev. 2015;33:1–9.CrossRefPubMed

43.

Stanley SE, Rao AD, Gable DL, McGrath-Morrow S, Armanios M. Radiation Sensitivity and Radiation Necrosis in the Short Telomere Syndromes. Int J Radiat Oncol Biol Phys. 2015;93(5):1115–7.CrossRefPubMedPubMedCentral

44.

Woodbine L, Gennery AR, Jeggo PA. The clinical impact of deficiency in DNA non-homologous end-joining. DNA Repair. 2014;16:84–96.CrossRefPubMed

45.

Yu X, Almeida JR, Darko S, van der Burg M, DeRavin SS, Malech H, et al. Human syndromes of immunodeficiency and dysregulation are characterized by distinct defects in T-cell receptor repertoire development. J Allergy Clin Immunol. 2014;133(4):1109–15.CrossRefPubMedPubMedCentral

46.

IJspeert H, Driessen GJ, Moorhouse MJ, Hartwig NG, Wolska-Kusnierz B, Kalwak K, et al. Similar recombination-activating gene (RAG) mutations result in similar immunobiological effects but in different clinical phenotypes. J Allergy Clin Immunol. 2014;133(4):1124–33.CrossRefPubMed

47.

Yan CT, Boboila C, Souza EK, Franco S, Hickernell TR, Murphy M, et al. IgH class switching and translocations use a robust non-classical end-joining pathway. Nature. 2007;449(7161):478–82.CrossRefPubMed

48.

Pan-Hammarstrom Q, Jones AM, Lahdesmaki A, Zhou W, Gatti RA, Hammarstrom L, et al. Impact of DNA ligase IV on nonhomologous end joining pathways during class switch recombination in human cells. J Exp Med. 2005;201(2):189–94.CrossRefPubMedPubMedCentral

49.

Ferguson DO, Sekiguchi JM, Chang S, Frank KM, Gao Y, DePinho RA, et al. The nonhomologous end-joining pathway of DNA repair is required for genomic stability and the suppression of translocations. Proc Natl Acad Sci U S A. 2000;97(12):6630–3.CrossRefPubMedPubMedCentral

50.

Jones RE, Oh S, Grimstead JW, Zimbric J, Roger L, Heppel NH, et al. Escape from telomere-driven crisis is DNA ligase III dependent. Cell Rep. 2014;8(4):1063–76.CrossRefPubMed

Titel: Ligase-4 Deficiency Causes Distinctive Immune Abnormalities in Asymptomatic Individuals
verfasst von: Kerstin Felgentreff
Sachin N. Baxi
Yu Nee Lee
Kerry Dobbs
Lauren A. Henderson
Krisztian Csomos
Erdyni N. Tsitsikov
Mary Armanios
Jolan E. Walter
Luigi D. Notarangelo
Publikationsdatum: 11.04.2016
Verlag: Springer US
Erschienen in: Journal of Clinical Immunology / Ausgabe 4/2016
Print ISSN: 0271-9142
Elektronische ISSN: 1573-2592
DOI: https://doi.org/10.1007/s10875-016-0266-5

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Ligase-4 Deficiency Causes Distinctive Immune Abnormalities in Asymptomatic Individuals

Abstract

Purpose

Methods

Results

Conclusions

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