Omenn syndrome due to ARTEMIS mutations

Ege, Markus; Ma, Yunmei; Manfras, Burkhard; Kałwak, Krzysztof; Lu, Haihui; Lieber, Michael R.; Schwarz, Klaus; Pannicke, Ulrich

doi:10.1182/blood-2004-12-4861

Cited by 203 publications

(133 citation statements)

References 41 publications

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“…P-1 and P-2 as well as the previously described Lig4-deficient patients exhibit hypomorhic Lig4 mutations. Hypomorphic mutations provide residual protein function often causing a heterogeneous phenotype, like hypomorphic Artemis mutations, which have been found to cause partial T and B lymphocyte immunodeficiency associated with lymphoma predisposition [29] or Omenn syndrome [30]. In contrast, null mutations lead to a complete loss of protein function inducing a homogenous phenotype like Artemis RS-SCID.…”

Section: Germ-line Sequences A)mentioning

confidence: 99%

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

et al. 2005

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DNA double-strand breaks (dsb) during V(D)J recombination of T and B lymphocyte receptor genes are resolved by the non-homologous DNA end joining pathway (NHEJ) including at least six factors: Ku70, Ku80, DNA-PK cs , Artemis, Xrcc4, and DNA ligase IV (Lig4). Artemis and Lig4 are the only known V(D)J/NHEJ factors found deficient in human genetic disorders. Null mutations of the Artemis gene result in a complete absence of T and B lymphocytes and increased cellular sensitivity to ionizing radiations, causing radiosensitive-SCID. Mutations of Lig4 are exclusively hypomorphic and have only been described in six patients, four exhibiting mild immunodeficiency associated with microcephaly and developmental delay, while two patient had leukemia. Here we report a SCID associated with microcephaly caused by compound heterozygous hypomorphic mutations in Lig4. Residual activity of Lig4 in these patients is underscored by a normal pattern of TCR-a and -b junctions in the T cells of the patients and a moderate impairment of V(D)J recombination as tested in vitro. These observations contrast with the severity of the clinical immunodeficiency, suggesting that Lig4 may have additional critical roles in lymphocyte survival beyond V(D)J recombination.

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Section: Germ-line Sequences A)mentioning

confidence: 99%

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

et al. 2005

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“…The inactivation of the Artemis gene in mice recapitulates the clinical and biological features of RS-SCID patients (Rooney et al, 2002;Li et al, 2005). Hypomorphic Artemis mutations have been identified in patients presenting a leaky SCID phenotype (Ege et al, 2005;Gennery et al, 2005) as well as in one patient characterized by a progressive combined immune deficiency resulting from an elevated lymphocyte apoptosis but a delayed cell death of IR-treated fibroblasts in vitro (Evans et al, 2006).…”

Section: Artemismentioning

confidence: 93%

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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“…Interestingly, such patients frequently display progressive immunodeficiency. One patient displayed Omenn's Syndrome, due to oligoclonal expansion of a reduced number of T or B cells [68]. Interestingly, lymphomas, often EBV-associated, can be observed in such patients, which is rarely seen in Artemis-null patients due to their lack of B cells [55,69].…”

Section: Clinical Manifestation Of Hypomorphic Mutations In Artemismentioning

confidence: 99%

“…X X X X √ X X X X X p.M1T/p.H35D Unknown Died of aspergillosis [68] Defect at earl y and lat e t imes post IR vicinity and activates processes, such as cell cycle checkpoint arrest, which influence but are not essential for NHEJ. The kinase, ataxia telangiectasia mutated (ATM), is central to the DSB signalling response.…”

Section: Related Radiosensitive Immunodeficiency Disordersmentioning

confidence: 99%

Reprint of “The clinical impact of deficiency in DNA non-homologous end-joining”

2014

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Double strand break repair V(D)J recombination (Severe) combined immunodeficiency -(S)CID Human syndromes a b s t r a c t DNA non-homologous end-joining (NHEJ) is the major DNA double strand break (DSB) repair pathway in mammalian cells. Defects in NHEJ proteins confer marked radiosensitivity in cell lines and mice models, since radiation potently induces DSBs. The process of V(D)J recombination functions during the development of the immune response, and involves the introduction and rejoining of programmed DSBs to generate an array of diverse T and B cells. NHEJ rejoins these programmed DSBs. Consequently, NHEJ deficiency confers (severe) combined immunodeficiency -(S)CID -due to a failure to carry out V(D)J recombination efficiently. NHEJ also functions in class switch recombination, another step enhancing T and B cell diversity. Prompted by these findings, a search for radiosensitivity amongst (S)CID patients revealed a radiosensitive sub-class, defined as RS-SCID. Mutations in NHEJ genes, defining human syndromes deficient in DNA ligase IV (LIG4 Syndrome), XLF-Cernunnos, Artemis or DNA-PKcs, have been identified in such patients. Mutations in XRCC4 or Ku70,80 in patients have not been identified. RS-SCID patients frequently display additional characteristics including microcephaly, dysmorphic facial features and growth delay. Here, we overview the clinical spectrum of RS-SCID patients and discuss our current understanding of the underlying biology.

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Omenn syndrome due to ARTEMIS mutations

Cited by 203 publications

References 41 publications

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

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

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

Reprint of “The clinical impact of deficiency in DNA non-homologous end-joining”

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