Hostname: page-component-797576ffbb-lm8cj Total loading time: 0 Render date: 2023-12-01T21:03:54.879Z Has data issue: false Feature Flags: { "corePageComponentGetUserInfoFromSharedSession": true, "coreDisableEcommerce": false, "useRatesEcommerce": true } hasContentIssue false
  • English
  • Français

Primary immunodeficiencies associated with DNA-repair disorders

Published online by Cambridge University Press:  18 March 2010

Mary A. Slatter  and
Andrew R. Gennery
Mary A. Slatter
Affiliation:
Department of Paediatric Immunology, Newcastle General Hospital, Newcastle upon Tyne, UK.
Andrew R. Gennery*
Affiliation:
Department of Paediatric Immunology, Newcastle General Hospital, Newcastle upon Tyne, UK. Institute of Cellular Medicine, Child Health, University of Newcastle upon Tyne, Newcastle upon Tyne, UK.
*
*Corresponding Author: Andrew R. Gennery, Department of Paediatric Immunology, Newcastle General Hospital, Westgate Road Newcastle upon Tyne, NE4 6BE, UK. E-mail: a.r.gennery@ncl.ac.uk
Get access Rights & Permissions [Opens in a new window]

Abstract

DNA-repair pathways recognise and repair DNA damaged by exogenous and endogenous agents to maintain genomic integrity. Defects in these pathways lead to replication errors, loss or rearrangement of genomic material and eventually cell death or carcinogenesis. The creation of diverse lymphocyte receptors to identify potential pathogens requires breaking and randomly resorting gene segments encoding antigen receptors. Subsequent repair of the gene segments utilises ubiquitous DNA-repair proteins. Individuals with defective repair pathways are found to be immunodeficient and many are radiosensitive. The role of repair proteins in the development of adaptive immunity by VDJ recombination, antibody isotype class switching and affinity maturation by somatic hypermutation has become clearer over the past few years, partly because of identification of the genes involved in human disease. We describe the mechanisms involved in the development of adaptive immunity relating to DNA repair, and the clinical consequences and treatment of the primary immunodeficiency resulting from such defects.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 12 , January 2010 , e9
Copyright
Copyright © Cambridge University Press 2010

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

References

1Riballo, E. et al. (2004) A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to gamma-H2AX foci. Molecular Cell 16, 715-724Google Scholar
2Bredemeyer, A.L. et al. (2006) ATM stabilizes DNA double-strand-break complexes during V(D)J recombination. Nature 442, 466-470Google Scholar
3Huang, C.Y. et al. (2007) Defects in coding joint formation in vivo in developing ATM-deficient B and T lymphocytes. Journal of Experimental Medicine 204, 1371-1381Google Scholar
4Helmink, B.A. et al. (2009) MRN complex function in the repair of chromosomal Rag-mediated DNA double-strand breaks. Journal of Experimental Medicine 206, 669-679Google Scholar
5Perkins, E.J. et al. (2002) Sensing of intermediates in V(D)J recombination by ATM. Genes and Development 16, 159-164Google Scholar
6Chen, H.T. et al. (2000) Response to RAG-mediated VDJ cleavage by NBS1 and γ-H2AX. Science 290, 1962-1965Google Scholar
7Celeste, A. et al. (2003) Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks. Nature Cell Biology 5, 675-679Google Scholar
8Stracker, T.H. et al. (2004) The Mre11 complex and the metabolism of chromosome breaks: the importance of communicating and holding things together. DNA Repair (Amsterdam) 3, 845-854Google Scholar
9Difilippantonio, S. et al. (2005) Role of Nbs1 in the activation of the Atm kinase revealed in humanized mouse models. Nature Cell Biology 7, 675-685Google Scholar
10Kobayashi, Y. et al. (1991) Transrearrangements between antigen receptor genes in normal human lymphoid tissues and in ataxia telangiectasia. Journal of Immunololgy 147, 3201-3209Google Scholar
11Lieber, M.R. et al. (2004) The mechanism of vertebrate nonhomologous DNA end joining and its role in V(D)J recombination. DNA Repair (Amsterdam) 3, 817-826Google Scholar
12Corneo, B. et al. (2007) Rag mutations reveal robust alternative end joining. Nature 449, 483-486Google Scholar
13Babbe, H. et al. (2007) The Bloom's syndrome helicase is critical for development and function of the alphabeta T-cell lineage. Molecular and Cellular Biology 27, 1947-1959Google Scholar
14Babbe, H. et al. (2009) Genomic instability resulting from Blm deficiency compromises development, maintenance, and function of the B cell lineage. Journal of Immunology 182, 347-360Google Scholar
15Iwasato, T. et al. (1990) Circular DNA is excised by immunoglobulin class switch recombination. Cell 62, 143-149Google Scholar
16Muramatsu, M. et al. (2000) Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102, 553-563Google Scholar
17Revy, P. et al. (2000) Activation-Induced cytidine Deaminase (AID) deficiency causes the autosomal recessive form of Hyper-IgM syndrome (HIGM2). Cell 102, 565-575Google Scholar
18Bransteitter, R. et al. (2003) Activation-induced cytidine deaminase deaminates deoxycytidine on single-stranded DNA but requires the action of RNase. Proceedings of the National Acadamy of Sciences of the United States of America 100, 4102-4107Google Scholar
19Rada, C. et al. (2002) Immunoglobulin isotype switching is inhibited and somatic hypermutation perturbed in UNG-deficient mice. Current Biology 12, 1748-1755Google Scholar
20Guikema, J.E. et al. (2007) APE1- and APE2-dependent DNA breaks in immunoglobulin class switch recombination. Journal of Experimental Medicine 204, 3017-3026Google Scholar
21Xue, K., Rada, C. and Neuberger, M.S. (2006) The in vivo pattern of AID targeting to immunoglobulin switch regions deduced from mutation spectra in msh2-/- ung-/- mice. Journal of Experimental Medicine 203, 2085-2094Google Scholar
22Wilson, T.M. et al. (2005) MSH2-MSH6 stimulates DNA polymerase eta, suggesting a role for A:T mutations in antibody genes. Journal of Experimental Medicine 201, 637-645Google Scholar
23Schrader, C.E., Vardo, J. and Stavnezer, J. (2002) Role for mismatch repair proteins Msh2, Mlh1, and Pms2 in immunoglobulin class switching shown by sequence analysis of recombination junctions. Journal of Experimental Medicine 195, 367-373Google Scholar
24Péron, S. et al. (2008) Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination. Journal of Experimental Medicine 205, 2465-2472Google Scholar
25Sekine, H. et al. (2007) Role for Msh5 in the regulation of Ig class switch recombination. Proceedings of the National Acadamy of Sciences of the United States of America 104, 7193-7198Google Scholar
26Babbe, H. et al. (2007) The Bloom's syndrome helicase is critical for development and function of the alphabeta T-cell lineage. Molecular and Cellular Biology 27, 1947-1959Google Scholar
27Pedrazzi, G. et al. (2003) The Bloom's syndrome helicase interacts directly with the human DNA mismatch repair protein hMSH6. Journal of Biological Chemistry 384, 1155-1164Google Scholar
28Pedrazzi, G. et al. (2001) Direct association of Bloom's syndrome gene product with the human mismatch repair protein MLH1. Nucleic Acids Research 29, 4378-4386Google Scholar
29Schrader, C.E. et al. (2007) Activation-induced cytidine deaminase-dependent DNA breaks in class switch recombination occur during G1 phase of the cell cycle and depend upon mismatch repair. Journal of Immunology 179, 6064-6071Google Scholar
30Yan, C.T. et al. (2007) IgH class switching and translocations use a robust non-classical end-joining pathway. Nature 449, 478-482Google Scholar
31Matsuoka, S. et al. (2007) ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316, 1160-1166Google Scholar
32Berkovich, E., Monnat, R.J. Jr and Kastan, M.B. (2007) Roles of ATM and NBS1 in chromatin structure modulation and DNA double-strand break repair. Nature Cell Biology 9, 683-690Google Scholar
33Burma, S. et al. (2001) ATM phosphorylates histone H2AX in response to DNA double-strand breaks. Journal of Biological Chemistry 276, 42462-42467Google Scholar
34Kobayashi, J. et al. (2009) Histone H2AX participates the DNA damage-induced ATM activation through interaction with NBS1. Biochemical and Biophysical Research Communications 380, 752-757Google Scholar
35Ward, I.M. et al. (2004) 53BP1 is required for class switch recombination. Journal of Cell Biology 165, 459-464Google Scholar
36Rooney, S. et al. (2005) Artemis-independent functions of DNA-dependent protein kinase in Ig heavy chain class switch recombination and development. Proceedings of the National Acadamy of Sciences of the United States of America 102, 2471-2475Google Scholar
37Franco, S. et al. (2008) DNA-PKcs and Artemis function in the end-joining phase of immunoglobulin heavy chain class switch recombination. Journal of Experimental Medicine 205, 557-564Google Scholar
38Rivera-Munoz, P. et al. (2009) Reduced immunoglobulin class switch recombination in the absence of Artemis. Blood 114, 3601-3609Google Scholar
39Du, L. et al. (2008) Involvement of Artemis in non-homologous end-joining during immunoglobulin class switch recombination. Journal of Experimental Medicine 205, 3031-3040Google Scholar
40Pan-Hammarstrom, Q. et al. (2005) Impact of DNA ligase IV on nonhomologous end joining pathways during class switch recombination in human cells. Journal of Experimental Medicine 201, 189-194Google Scholar
41Helleday, T., Bryant, H.E. and Schultz, N. (2005) Poly(ADP-ribose) polymerase (PARP-1) in homologous recombination and as a target for cancer therapy. Cell Cycle 4, 1176-1178Google Scholar
42Audebert, M., Salles, B. and Calsou, P. (2004) Involvement of poly(ADP-ribose) polymerase-1 and XRCC1/DNA ligase III in an alternative route for DNA double-strand breaks rejoining. Journal of Biological Chemistry 279, 55117-55126Google Scholar
43Wang, H. et al. (2005) DNA ligase III as a candidate component of backup pathways of nonhomologous end joining. Cancer Research 65, 4020-4030Google Scholar
44Robert, I., Dantzer, F. and Reina-San-Martin, B. (2009) Parp1 facilitates alternative NHEJ, whereas Parp2 suppresses IgH/c-myc translocations during immunoglobulin class switch recombination. Journal of Experimental Medicine 206, 1047-1056Google Scholar
45Liang, L. et al. (2008) Human DNA ligases I and III, but not ligase IV, are required for microhomology-mediated end joining of DNA double-strand breaks. Nucleic Acids Research 36, 3297-3310Google Scholar
46Kaartinen, M. et al. (1983) mRNA sequences define an unusually restricted IgG response to 2-phenyloxazolone and its early diversification. Nature 304, 320-324Google Scholar
47Storb, U. (1998) Progress in understanding the mechanism and consequences of somatic hypermutation. Immunological Reviews 162, 5-11Google Scholar
48Shivarov, V. et al. (2009) Molecular mechanism for generation of antibody memory. Philosophical Transactions of the Royal Society B 364, 569-575Google Scholar
49Schanz, S. et al. (2009) Interference of mismatch and base excision repair during the processing of adjacent U/G mispairs may play a key role in somatic hypermutation. Proceedings of the National Acadamy of Sciences of the United States of America 106, 5593-5598Google Scholar
50Larson, E.D. et al. (2005) MRE11/RAD50 cleaves DNA in the AID/UNG-dependent pathway of immunoglobulin gene diversification. Molecular Cell 20, 367-375Google Scholar
51Sack, S.Z. et al. (1998) Somatic hypermutation of immunoglobulin genes is independent of the Bloom's syndrome DNA helicase. Clinical and Experimental Immunology 112, 248-254Google Scholar
52Schwarz, K. et al. (1996) RAG mutations in human B cell-negative SCID. Science 274, 97-99Google Scholar
53Villa, A. et al. (1998) Partial V(D)J recombination activity leads to Omenn syndrome. Cell 93, 885-896Google Scholar
54Omenn, G.S. (1965) Familial reticuloendotheliosis with eosinophilia. New England Journal of Medicine 273, 427-432Google Scholar
55Villa, A. et al. (2001) V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations. Blood 97, 81-88Google Scholar
56Rieux-Laucat, F. et al. (1998) Highly restricted human T-cell repertoire beta (TCRB) chain diversity in peripheral blood and tissue-infiltrating lymphocytes in Omenn's syndrom (severe combined immunodeficiency with hypereosinophilia). Journal of Clinical Investigation 102, 312-321Google Scholar
57Ehl, S. et al. (2005) A variant of SCID with specific immune responses and predominance of gamma delta T cells. Journal of Clinical Investigation 115, 3140-3148Google Scholar
58de Villartay, J.P. et al. (2005) A novel immunodeficiency associated with hypomorphic RAG1 mutations and CMV infection. Journal of Clinical Investigation 115, 3291-3299Google Scholar
59Schuetz, C. et al. (2008) An immunodeficiency disease with RAG mutations and granulomas. New England Journal of Medicine 358, 2030-2038Google Scholar
60Chun, H.H., and Gatti, R.A. (2004) Ataxia-telangiectasia, an evolving phenotype. DNA Repair (Amsterdam) 3, 1187-1196Google Scholar
61Noordzij, J.G. et al. (2009) Ataxia-telangiectasia patients presenting with hyper-IgM syndrome. Archives of Disease in Childhood 94, 448-449Google Scholar
62Lefton-Greif, M.A. et al. (2000) Oropharyngeal dysphagia and aspiration in patients with ataxia-telangiectasia. Journal of Pediatrics 136, 225-231Google Scholar
63Staples, E.R. et al. (2008) Immunodeficiency in ataxia telangiectasia is correlated strongly with the presence of two null mutations in the ataxia telangiectasia mutated gene. Clinical and Experimental Immunology 153, 214-220Google Scholar
64Sanal, O. et al. (1999) Impaired IgG antibody production to pneumococcal polysaccharides in patients with ataxia-telangiectasia. Journal of Clinical Immunology 19, 326-334Google Scholar
65Tangsinmankong, N. et al. (2001) Lymphocytic interstitial pneumonitis, elevated IgM concentration, and hepatosplenomegaly in ataxia-telangiectasia. Journal of Pediatrics 138, 939-941Google Scholar
66Crawford, T.O. et al. (2006) Survival probability in ataxia telangiectasia. Archives of Disease in Childhood 91, 610-611Google Scholar
67Giovannetti, A. et al. (2002) Skewed T-cell receptor repertoire, decreased thymic output, and predominance of terminally differentiated T cells in ataxia telangiectasia. Blood 100, 4082-4089Google Scholar
68Reina-San-Martin, B. et al. (2004) ATM is required for efficient recombination between immunoglobulin switch regions. Journal of Experimental Medicine 200, 1103-1110Google Scholar
69Weemaes, C.M. et al. (1981) A new chromosomal instability disorder: the Nijmegen breakage syndrome. Acta Paediatrica Scandinavica 70, 557-564Google Scholar
70Digweed, M. and Sperling, K. (2004) Nijmegen breakage syndrome: clinical manifestation of defective response to DNA double-strand breaks. DNA Repair (Amsterdam) 3, 1207-1217Google Scholar
71Gregorek, H. et al. (2002) Heterogeneity of humoral immune abnormalities in children with Nijmegen breakage syndrome: an 8-year follow-up study in a single centre. Clinical and Experimental Immunology 130, 319-324Google Scholar
72Xu, Y. (1999) ATM in lymphoid development and tumorigenesis. Advances in Immunology 72, 179-189Google Scholar
73Kracker, S. et al. (2005) Nibrin functions in Ig class-switch recombination. Proceedings of the National Acadamy of Sciences of the United States of America 102, 1584-1589Google Scholar
74Reina-San-Martin, B. et al. (2005) Genomic instability, endoreduplication, and diminished Ig class-switch recombination in B cells lacking Nbs1. Proceedings of the National Acadamy of Sciences of the United States of America 102, 1590-1595Google Scholar
75Nakanishi, K. et al. (2002) Interaction of FANCD2 and NBS1 in the DNA damage response. Nature Cell Biology 4, 913-920Google Scholar
76Gennery, A.R. et al. (2004) The clinical and biological overlap between Nijmegen Breakage Syndrome and Fanconi anemia. Clinical Immunology 113, 214-219Google Scholar
77Stewart, G.S. et al. (1999) The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder. Cell 99, 577-587Google Scholar
78Delia, D. et al. (2004) MRE11 mutations and impaired ATM-dependent responses in an Italian family with ataxia-telangiectasia-like disorder. Human Molecular Genetics 13, 2155-2163Google Scholar
79Fernet, M. et al. (2005) Identification and functional consequences of a novel MRE11 mutation affecting 10 Saudi Arabian patients with the ataxia telangiectasia-like disorder. Human Molecular Genetics 14, 307-318Google Scholar
80Khan, A.O. et al. (2008) Ophthalmic features of ataxia telangiectasia-like disorder. Journal of American Association for Pediatric Ophthalmology and Strabismus 12, 186-189Google Scholar
81Uchisaka, N. et al. (2009) Two brothers with ataxia-telangiectasia-like disorder with lung adenocarcinoma. Journal of Pediatrics 155, 435-438Google Scholar
82Taylor, A.M., Groom, A. and Byrd, P.J. (2004) Ataxia-telangiectasia-like disorder (ATLD)-its clinical presentation and molecular basis. DNA Repair (Amsterdam) 3, 1219-1225Google Scholar
83Lahdesmaki, A. et al. (2004) Delineation of the role of the Mre11 complex in class switch recombination. The Journal of Biological Chemistry 279, 16479-16487Google Scholar
84Barbi, G. et al. (1991) Chromosome instability and X-ray hypersensitivity in a microcephalic and growth-retarded child. American Journal of Medical Genetics 40, 44-45Google Scholar
85Waltes, R. et al. (2009) Human RAD50 deficiency in a Nijmegen breakage syndrome-like disorder. American Journal of Medical Genetics 84, 605-616Google Scholar
86Donahue, S.L. et al. (2007) Defective signal joint recombination in fanconi anemia fibroblasts reveals a role for Rad50 in V(D)J recombination. Journal of Molecular Biology 370, 449-458Google Scholar
87Stewart, G.S. et al. (2007) RIDDLE immunodeficiency syndrome is linked to defects in 53BP1-mediated DNA damage signaling. Proceedings of the National Acadamy of Sciences of the United States of America 104, 16910-16915Google Scholar
88Stewart, G.S. et al. (2009) The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage. Cell 136, 420-434Google Scholar
89Difilippantonio, S. et al. (2008) 53BP1 facilitates long-range DNA end-joining during V(D)J recombination. Nature 456, 529-533Google Scholar
90Manis, J.P. et al. (2004) 53BP1 links DNA damage-response pathways to immunoglobulin heavy chain class-switch recombination. Nature Immunology 5, 481-487Google Scholar
91Ward, I.M. et al. (2004) 53BP1 is required for class switch recombination. Journal of Cellular Biology 165, 459-464Google Scholar
92van der Burg, M. et al. (2009) A DNA-PKcs mutation in a radiosensitive T-B- SCID patient inhibits Artemis activation and nonhomologous end-joining. Journal of Clinical Investigation 119, 91-98Google Scholar
93Moshous, D. et al. (2001) Artemis, a novel DNA double-strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency. Cell 105, 177-186Google Scholar
94Jones, J.F. et al. (1991) Severe combined immunodeficiency among the Navajo. I. Characterization of phenotypes, epidemiology, and population genetics. Human Biology 63, 669-682Google Scholar
95Cavazzana-Calvo, M. et al. (1993) Increased radiosensitivity of granulocyte macrophage colony-forming units and skin fibroblasts in human autosomal recessive severe combined immunodeficiency. Journal of Clinical Investigation 91, 1214-1218Google Scholar
96Ege, M. et al. (2005) Omenn syndrome due to ARTEMIS mutations. Blood 105, 4179-4186Google Scholar
97Moshous, D. et al. (2003) Partial T and B lymphocyte immunodeficiency and predisposition to lymphoma in patients with hypomorphic mutations in Artemis. Journal of Clinical Investigation 111, 381-387Google Scholar
98Evans, P.M. et al. (2006) Radiation-induced delayed cell death in a hypomorphic Artemis cell line. Human Molecular Genetics 15, 1303-1311Google Scholar
99Riballo, E. et al. (1999) Identification of a defect in DNA ligase IV in a radiosensitive leukaemia patient. Current Biology 9, 699-702Google Scholar
100O'Driscoll, M. et al. (2001) DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Molecular Cell 8, 1175-1185Google Scholar
101Unal, S. et al. (2009) A novel mutation in a family with DNA ligase IV deficiency syndrome. Pediatric Blood and Cancer 53, 482-484Google Scholar
102van der Burg, M. et al. (2006) A new type of radiosensitive T-B-NK+ severe combined immunodeficiency caused by a LIG4 mutation. Journal of Clinical Investigation 116, 137-145Google Scholar
103Buck, D. et al. (2006) Severe combined immunodeficiency and microcephaly in siblings with hypomorphic mutations in DNA ligase IV. European Journal of Immunology 36, 224-235Google Scholar
104Ben-Omran, T.I. et al. (2005) A patient with mutations in DNA Ligase IV: clinical features and overlap with Nijmegen breakage syndrome. American Journal of Medical Genetics A 137, 283-287Google Scholar
105Enders, A. et al. (2006) A severe form of human combined immunodeficiency due to mutations in DNA ligase IV. Journal of Immunology 176, 5060-5068Google Scholar
106Toita, N. et al. (2007) Epstein-Barr virus-associated B-cell lymphoma in a patient with DNA ligase IV (LIG4) syndrome. American Journal of Medical Genetics A 143, 742-745Google Scholar
107Grunebaum, E. et al. (2008) Omenn syndrome is associated with mutations in DNA ligase IV. Journal of Allergy and Clinical Immunology 122, 1219-1220Google Scholar
108Buck, D. et al. (2006) Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell 124, 287-299Google Scholar
109Ahnesorg, P. et al. (2006) XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining. Cell 124, 301-313Google Scholar
110Dai, Y. et al. (2003) Nonhomologous end joining and V(D)J recombination require an additional factor. Proceedings of the National Acadamy of Sciences of the United States of America 100, 2462-2467Google Scholar
111Faraci, M. et al. (2009) Unrelated hematopoietic stem cell transplantation for Cernunnos-XLF deficiency. Pediatric Transplantation 13, 785-789Google Scholar
112Schwartz, M. et al. (2009) Impaired replication stress response in cells from immunodeficiency patients carrying Cernunnos/XLF mutations. Public Library of Science ONE 4, e4516Google Scholar
113Berardinelli, F. et al. (2007) A case report of a patient with microcephaly, facial dysmorphism, chromosomal radiosensitivity and telomere length alterations closely resembling “Nijmegen breakage syndrome” phenotype. European Journal of Medical Genetics 50, 176-187Google Scholar
114Maraschio, P. et al. (2003) Genetic heterogeneity for a Nijmegen breakage-like syndrome. Clinical Genetics 63, 283-290Google Scholar
115Hiel, J.A. et al. (2001) Nijmegen breakage syndrome in a Dutch patient not resulting from a defect in NBS1. Journal of Medical Genetics 38, E19Google Scholar
116Wiegant, W.W. et al. (2010) A novel radiosensitive SCID patient with a pronounced G(2)/M sensitivity. DNA Repair (Amsterdam) Jan 13, [Epub ahead of print]Google Scholar
117Revy, P. et al. (2000) Activation-Induced cytidine Deaminase (AID) deficiency causes the autosomal recessive form of Hyper-IgM syndrome (HIGM2). Cell 102, 565-575Google Scholar
118Quartier, P. et al. (2004) Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to Activation-Induced Cytidine Deaminase deficiency. Clinical Immunology 110, 22-29Google Scholar
119Minegishi, Y. et al. (2000) Mutations in activation-induced cytidine deaminase in patients with hyper IgM syndrome. Clinical Immunology 97, 203-210Google Scholar
120Ta, V.T. et al. (2003) AID mutant analyses indicate requirement for class-switch-specific cofactors. Nature Immunology 4, 843-848Google Scholar
121Imai, K. et al. (2005) Analysis of class switch recombination and somatic hypermutation in patients affected with autosomal dominant hyper-IgM syndrome type 2. Clinical Immunology 115, 277-285Google Scholar
122Imai, K. et al. (2003) Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination. Nature Immunology 4, 1023-1028Google Scholar
123De Vos, M. et al. (2006) PMS2 mutations in childhood cancer. Journal of the National Cancer Institute 98, 358-361Google Scholar
124Kratz, C.P. et al. (2008) Childhood T-cell non-Hodgkin's lymphoma, colorectal carcinoma and brain tumor in association with café-au-lait spots caused by a novel homozygous PMS2 mutation. Leukemia 22, 1078-1080Google Scholar
125Imai, K. et al. (2003) Hyper-IgM syndrome type 4 with a B lymphocyte-intrinsic selective deficiency in Ig class-switch recombination Journal of Clinical Investigation 112, 136-142Google Scholar
126Péron, S. et al. (2007) A primary immunodeficiency characterized by defective immunoglobulin class switch recombination and impaired DNA repair. Journal of Experimental Medicine 204, 1207-1216Google Scholar
127Durandy, A. (2009) Immunoglobulin class switch recombination: study through human natural mutants. Philosophical Transactions of the Royal Society B 364, 577-582Google Scholar
128Kashef, S. et al. (2009) Isolated growth hormone deficiency in a patient with immunoglobulin class switch recombination deficiency. Journal of Investigational Allergology and Clinical Immunology 19, 233-236Google Scholar
129Ohzeki, T. et al. (1993) Immunodeficiency with increased immunoglobulin M associated with growth hormone insufficiency. Acta Paediatrica 82, 620-623Google Scholar
130Webster, A.D. et al. (1992) Growth retardation and immunodeficiency in a patient with mutations in the DNA ligase I gene. Lancet 339, 1508-1509Google Scholar
131Barnes, D.E. et al. (1992) Mutations in the DNA ligase I gene of an individual with immunodeficiencies and cellular hypersensitivity to DNA-damaging agents. Cell 69, 495-503Google Scholar
132Soza, S. et al. (2009) DNA ligase I deficiency leads to replication-dependent DNA damage and impacts cell morphology without blocking cell cycle progression. Molecular and Cellular Biology 29, 2032-2041Google Scholar
133Petrini, J.H. et al. (1994) Normal V(D)J coding junction formation in DNA ligase I deficiency syndromes. Journal of Immunology 152, 176-178Google Scholar
134Vago, R. et al. (2009) DNA ligase I and Nbs1 proteins associate in a complex and colocalize at replication factories. Cell Cycle 8, 2600-2607Google Scholar
135Hütteroth, T.H., Litwin, S.D. and German, J. (1975) Abnormal immune responses of Bloom's syndrome lymphocytes in vitro. Journal of Clinical Investigation 56, 1-7Google Scholar
136Van Kerckhove, C.W. et al. (1988) Bloom's syndrome. Clinical features and immunologic abnormalities of four patients. American Journal of Diseases of Children 142, 1089-1093Google Scholar
137German, J. (1995) Bloom's syndrome. Dermatological Clinics 13, 7-18Google Scholar
138Kondo, N. et al. (1992) Reduced secreted mu mRNA synthesis in selective IgM deficiency of Bloom's syndrome. Clinical and Experimental Immunology 88, 35-40Google Scholar
139Taniguchi, N. et al. (1982) Impaired B-cell differentiation and T-cell regulatory function in four patients with Bloom's syndrome. Clinical Immunology and Immunopathology 22, 247-258Google Scholar
140Hsieh, C.L., Arlett, C.F. and Lieber, M.R. (1993) V(D)J recombination in ataxia telangiectasia, Bloom's syndrome, and a DNA ligase I-associated immunodeficiency disorder. The Journal of Biological Chemistry 268, 20105-20109Google Scholar
141Alter, B.P. et al. (2003) Cancer in Fanconi Anemia. Blood 101, 2072Google Scholar
142Mohseni-Meybodi, A., Mozdarani, H. and Vosough, P. (2007) Cytogenetic sensitivity of G0 lymphocytes of Fanconi anemia patients and obligate carriers to mitomycin C and ionizing radiation. Cytogenetic Genome Research 119, 191-195Google Scholar
143Gruhn, B. et al. (2007) Successful bone marrow transplantation in a patient with DNA ligase IV deficiency and bone marrow failure. Orphanet Journal of Rare Diseases 2, 5Google Scholar
144Albert, M.H. et al. (2009) Successful Stem cell transplantation for Nijmegen breakage syndrome. Bone Marrow Transplantation Aug 17, [Epub ahead of print]Google Scholar
145Dembowska-Baginska, B. et al. (2009) Non-Hodgkin lymphoma (NHL) in children with Nijmegen Breakage syndrome (NBS). Pediatric Blood and Cancer 52, 186-190Google Scholar
146Benjelloun, F. et al. (2008) Stable and functional lymphoid reconstitution in artemis-deficient mice following lentiviral artemis gene transfer into hematopoietic stem cells. Molecular Therapy 16, 1490-1499Google Scholar
147Lai, C.H. et al. (2004) Correction of ATM gene function by aminoglycoside-induced read-through of premature termination codons. Proceedings of the National Acadamy of Sciences of the United States of America 101, 15676-15681Google Scholar
148Welch, E.M. et al. (2007) PTC124 targets genetic disorders caused by nonsense mutations. Nature 447, 87-91Google Scholar
149Schuetz, J.M. et al. (2009) Genetic variation in the NBS1, MRE11, RAD50 and BLM genes and susceptibility to non-Hodgkin lymphoma. BioMed Central Medical Genetics. 10, 117Google Scholar
150Margulis, V. et al. (2008) Genetic susceptibility to renal cell carcinoma: the role of DNA double-strand break repair pathway. Cancer Epidemiology, Biomarkers and Prevention 17, 2366-2373Google Scholar
151Pugh, T.J. et al. (2009) Sequence variant discovery in DNA repair genes from radiosensitive and radiotolerant prostate brachytherapy patients. Clinical Cancer Research 15, 5008-5016Google Scholar
152Okazaki, T. et al. (2008) Single-nucleotide polymorphisms of DNA damage response genes are associated with overall survival in patients with pancreatic cancer. Clinical Cancer Research 14, 2042-2048Google Scholar
153Girard, P.M. et al. (2004) Analysis of DNA ligase IV mutations found in LIG4 syndrome patients: the impact of two linked polymorphisms. Human Molecular Genetics 13, 2369-2376Google Scholar
154Roddam, P.L. et al. (2002) Genetic variants of NHEJ DNA ligase IV can affect the risk of developing multiple myeloma, a tumour characterised by aberrant class switch recombination. Journal of Medical Genetics 39, 900-905Google Scholar
155Ouyang, H. et al. (1997) Ku70 is required for DNA repair but not for T cell antigen receptor gene recombination In vivo. Journal of Experimental Medicine 186, 921-929Google Scholar
156Zhu, C. et al. (1996) Ku86-deficient mice exhibit severe combined immunodeficiency and defective processing of V(D)J recombination intermediates. Cell 86, 379-389Google Scholar
157Blunt, T. et al. (1995) Defective DNA-dependent protein kinase activity is linked to V(D)J recombination and DNA repair defects associated with the murine scid mutation. Cell 80, 813-823Google Scholar
158Meek, K. et al. (2001) SCID in Jack Russell terriers: a new animal model of DNA-PKcs deficiency. Journal of Immunology 167, 2142-2150Google Scholar
159Shin, E.K., Perryman, L.E. and Meek, K. (1997) A kinase-negative mutation of DNA-PK(CS) in equine SCID results in defective coding and signal joint formation. Journal of Immunology 158, 3565-3569Google Scholar
160Rooney, S. et al. (2002) Leaky Scid phenotype associated with defective V(D)J coding end processing in Artemis-deficient mice. Molecular Cell 10, 1379-1390Google Scholar
161Barnes, D.E. et al. (1998) Targeted disruption of the gene encoding DNA ligase IV leads to lethality in embryonic mice. Current Biology 8, 1395-1398Google Scholar
162Nijnik, A. et al. (2009) Impaired lymphocyte development and antibody class switching and increased malignancy in a murine model of DNA ligase IV syndrome. Journal of Clinical Investigation 119, 1696-1705Google Scholar
163Gao, Y.M. et al. (1998) A critical role for DNA end-joining proteins in both lymphogenesis and neurogenesis. Cell 95, 891-902Google Scholar
164Li, G. et al. (2008) Lymphocyte-specific compensation for XLF/cernunnos end-joining functions in V(D)J recombination. Molecular Cell 31, 631-640Google Scholar
165Kobayashi, Y. et al. (2002) Hydrocephalus, situs inversus, chronic sinusitis, and male infertility in DNA polymerase lambda-deficient mice: possible implication for the pathogenesis of immotile cilia syndrome. Molecular and Cellular Biology 22, 2769-2776Google Scholar
166Bertocci, B. et al. (2003) Immunoglobulin kappa light chain gene rearrangement is impaired in mice deficient for DNA polymerase mu. Immunity 19, 203-2011Google Scholar
167Komori, T. et al. (1996) Repertoires of antigen receptors in Tdt congenitally deficient mice. International Reviews in Immunology 13, 317-325Google Scholar

Further reading, resources and contacts

The primary immunodeficiency association website can be found at:

http://www.pia.org.ukGoogle Scholar
http://www.atsociety.org.ukGoogle Scholar
www.ncbi.nlm.nih.gov/omimGoogle Scholar
http://www.pia.org.ukGoogle Scholar
http://www.atsociety.org.ukGoogle Scholar
www.ncbi.nlm.nih.gov/omimGoogle Scholar