Severe combined immunodeficiency and microcephaly in siblings with hypomorphic mutations in DNA ligase IV

Buck, Dietke; Moshous, Despina; Chasseval, Régina de; Ma, Yunmei; Deist, Françoise Le; Cavazzana‐Calvo, Marina; Fischer, Alain; Casanova, Jean‐Laurent; Lieber, Michael R.; Villartay, Jean‐Pierre de

doi:10.1002/eji.200535401

Cited by 185 publications

(131 citation statements)

References 36 publications

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“…In vitro studies revealed no residual LIG4 adenylation or ligation activity in that combination of mutations (Girard et al, 2004). Two siblings who presented with SCID, growth defects and microcephaly were found to harbor compound heterozygous mutations conferring a Q280R substitution on one allele and a K424 frame-shift mutation that resulted in truncation of the C terminus on the other allele (Buck et al, 2006b). Identification of only hypomorphic mutations in LIG4 syndrome individuals suggests that loss of LIG4 would be incompatible with viability, as partially attenuated activity has a profound developmental defect.…”

Section: Defective Nhej Deficiency and Human Diseasementioning

confidence: 95%

DNA double-strand break repair and development

Phillips

McKinnon

2007

Oncogene

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Normal development of an organism requires the ability to respond to DNA damage. A particularly deleterious lesion is a DNA double-strand break (DSB). The cellular response to DNA DSBs occurs via an integrated sensing and signaling network that maintains genomic stability. The outcomes of defective DNA DSB repair are related to the developmental stage of an organism, and often show striking tissue specificity. Many human diseases are associated with deficiencies in DNA DSB repair and can be characterized by neuropathology, immune deficiency, growth retardation or predisposition to cancer. This review will focus on the requirements of the DNA DSB response that function to maintain homeostasis during mammalian development.

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Section: Defective Nhej Deficiency and Human Diseasementioning

confidence: 95%

DNA double-strand break repair and development

Phillips

McKinnon

2007

Oncogene

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“…Several cases of B‐cell leukaemia and lymphoma were identified in patients with mutations in the ligase IV gene 67, 100. Moreover, murine models with hypomorphic ligase IV mutations develop thymic lymphoma, which further indicates the importance of ligase IV in the prevention of malignant transformation 101.…”

Section: Mechanisms Of Cancer Developmentmentioning

confidence: 99%

“…In most patients, this leads to severe ablation of T and B lymphocytes and cells derived from these patients have impaired V(D)J recombination. However, in some patients, ligase IV residual activity is sufficient for recombining TCRα and TCRβ regions 67. In summary, ligase IV deficiencies present with various phenotypes where the degree of immune deficiency and neurological defects is highly variable.…”

Section: Genes and Diseases Associated With Defective Recombination Imentioning

confidence: 99%

Programmed DNA breaks in lymphoid cells: repair mechanisms and consequences in human disease

Procházková

Loizou

2015

Immunology

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SummaryIn recent years, several novel congenital human disorders have been described with defects in lymphoid B‐cell and T‐cell functions that arise due to mutations in known and/or novel components of DNA repair and damage response pathways. Examples include impaired DNA double‐strand break repair, as well as compromised DNA damage‐induced signal transduction, including phosphorylation and ubiquitination. These disorders reinforce the importance of genome stability pathways in the development of lymphoid cells in humans. Furthermore, these conditions inform our knowledge of the biology of the mechanisms of genome stability and in some cases may provide potential routes to help exploit these pathways therapeutically. Here we review the mechanisms that repair programmed DNA lesions that occur during B‐cell and T‐cell development, as well as human diseases that arise through defects in these pathways.

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“…In contrast to RS-SCIDs, these patients are not completely devoid of B and T lymphocytes, although their numbers can be drastically reduced. Several other reports of DNA-LigaseIV deficiency further demonstrated the high heterogeneity of this syndrome for its impact on immunodeficiency (from no deficiency to SCID) as well as on its developmental consequences (with or without microcephaly) and cancer incidence (Ben-Omran et al, 2005;Enders et al, 2006;van der Burg et al, 2006;Buck et al, 2006b). In the more severe forms, the V(D)J recombination is strongly affected both quantitatively and qualitatively as a consequence of the DNA rejoining deficiency.…”

Section: Artemismentioning

confidence: 92%

V(D)J and immunoglobulin class switch recombinations: a paradigm to study the regulation of DNA end-joining

et al. 2007

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The immune system is the site of intense DNA damage/ modification, which occur during the development and maturation of B and T lymphocytes. V(D)J recombination is initiated by the Rag1 and Rag2 proteins and the formation of a DNA double-strand break (DNA dsb). This DNA lesion is repaired through the use of the nonhomologous end-joining (NHEJ) pathway, several factors of which have been identified through the survey of immunodeficient conditions in humans and mice. Upon antigenic recognition in secondary lymphoid organs, mature B cells further diversify their repertoire through class switch recombination (CSR). CSR is a region-specific rearrangement process triggered by the activation-induced cytidine deaminase factor and also proceeds through the introduction of DNA dsb. However, unlike V(D)J recombination, CSR does not rely strictly on NHEJ for the repair of the DNA lesion. Instead, CSR, but not V(D)J recombination, requires the major factors of the DNA damage response. V(D)J recombination and CSR thus represent an interesting paradigm to study the regulation among the various DNA repair pathways. Oncogene (2007) 26, 7780-7791; doi:10.1038/sj.onc.1210875 Keywords: V(D)J recombination; class switch recombination; SCID; Artemis; Cernunnos; NHEJ V(D)J recombination and CSR: two rearrangement processes that shape the immune system repertoire B and T lymphocytes respond to foreign pathogens through specialized antigenic receptors, the B-cell receptor and T-cell receptor, respectively. The required diversity of these receptors is ensured by the V(D)J recombination process (Figure 1) which assembles previously scattered Variable (V), Diversity (D) and Joining (J) encoding gene segments through a specialized somatic DNA rearrangement mechanism (Tonegawa, 1983). The reaction is initiated by the lymphoid-specific factors, Rag1 and Rag2, which recognize recombination signal sequences (RSS) that flank all V, D and J gene units and introduce a DNA dsb at the border of the RSS (see Dudley et al. (2005) for a review on V(D)J recombination). The resulting DNA double-strand break (DNA dsb) is resolved by the ubiquitous DNA repair machinery known as non-homologous end-joining (NHEJ). The convergent efforts of scientists in the immunology and DNA repair fields were decisive in defining the various actors and molecular mechanisms of this DNA repair pathway over the years as will be discussed below.The terminal maturation of B lymphocytes, which occurs in germinal centres of secondary lymphoid organs upon antigen recognition, is accompanied by two additional molecular processing of immunoglobulin genes that increase the efficiency of the humoral response: (1) the class switch recombination (CSR, Figure 2) exchanges the immunoglobulin (Ig) constant region (CH), thus modifying the function of the Ig without altering its antigenic specificity (Manis et al., 2002b) and (2) somatic hypermutations are introduced in the Ig variable domains, thus increasing their affinity for antigen (Papavasiliou and Schatz, 2002). These two events ar...

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Severe combined immunodeficiency and microcephaly in siblings with hypomorphic mutations in DNA ligase IV

Cited by 185 publications

References 36 publications

DNA double-strand break repair and development

DNA double-strand break repair and development

Programmed DNA breaks in lymphoid cells: repair mechanisms and consequences in human disease

V(D)J and immunoglobulin class switch recombinations: a paradigm to study the regulation of DNA end-joining

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