Radiosensitive SCID patients with Artemis gene mutations show a complete B-cell differentiation arrest at the pre-B-cell receptor checkpoint in bone marrow

Noordzij, Jeroen G.; Verkaik, Nicole S.; Burg, Mirjam van der; Veelen, Lieneke R. van; Bruin-Versteeg, Sandra de; Wiegant, Wouter W.; Vossen, Jaak M.; Weemaes, C.M.R.; Groot, Ronald de; Zdzienicka, Małgorzata Z.; Gent, Dik C. van; Dongen, Jacques J. M. van

doi:10.1182/blood-2002-01-0187

Cited by 91 publications

(84 citation statements)

References 28 publications

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“…Human SCID with increased IR sensitivity has thus far been described in patients with null mutations in the Artemis gene and is characterized by a complete absence of T and B lymphocytes [16][17][18][19]. We herein report the occurrence of a RS-SCID, characterized by a virtual absence of B lymphocytes and a residual number of T cells, associated with microcephaly in two siblings as a consequence of mutations in the V(D)J/NHEJ factor Lig4-encoding gene.…”

Section: Discussionmentioning

confidence: 99%

“…The second group is additionally characterized by increased cellular sensitivity to ionizing radiations (IR), which points to a general DNA repair deficiency [15]. This radiosensitive SCID (RS-SCID) is caused by null mutations in the V(D)J/NHEJ factor Artemis [16][17][18][19]. Given the embryonic lethality of both Lig4 and Xrcc4 KO mice one does not expect to identify patients with complete loss of function in either gene.…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2005

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“…Flow cytometric analysis of peripheral blood and BM was performed as previously described. 16,18,45 Cell lines and tissue culture Primary fibroblasts were cultured from a skin biopsy of patient 1 and 2. Furthermore, fibroblasts from controls (C5RO and VH10), Artemis-deficient patients (Artemis-5 and Artemis-6; both having genomic deletions of exon 1-3 27 ), a patient with mutant Artemis (Artemis-8 (c.1391_1395delGAATC)) and a RAG-deficient patient (RAG-SCID12) (c.1782C4A)) were used.…”

Section: Methodsmentioning

confidence: 99%

“…15 Mutations in the Artemis, LIG4 and DNA-PKcs genes have been identified in these patients. 14,[16][17][18][19] Furthermore, mutations in the XLF gene have been found in radiosensitive patients with growth retardation, microcephaly and immunodeficiency due to profound T-and B-cell lymphocytopenia. 13 Not all mutations in V(D)J recombination genes give rise to the classical SCID phenotype.…”

Section: Introductionmentioning

confidence: 99%

Artemis splice defects cause atypical SCID and can be restored in vitro by an antisense oligonucleotide

IJspeert

Lankester

et al. 2011

Genes Immun

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Artemis deficiency is known to result in classical TÀBÀ severe combined immunodeficiency (SCID) in case of Artemis null mutations, or Omenn's syndrome in case of hypomorphic mutations in the Artemis gene. We describe two unrelated patients with a relatively mild clinical TÀBÀ SCID phenotype, caused by different homozygous Artemis splice-site mutations. The splice-site mutations concern either dysfunction of a 5 0 splice-site or an intronic point mutation creating a novel 3 0 splice-site, resulting in mutated Artemis protein with residual activity or low levels of wild type (WT) Artemis transcripts. During the first 10 years of life, the patients suffered from recurrent infections necessitating antibiotic prophylaxis and intravenous immunoglobulins. Both mutations resulted in increased ionizing radiation sensitivity and insufficient variable, diversity and joining (V(D)J) recombination, causing B-lymphopenia and exhaustion of the naive T-cell compartment. The patient with the novel 3 0 splice-site had progressive granulomatous skin lesions, which disappeared after stem cell transplantation (SCT). We showed that an alternative approach to SCT can, in principle, be used in this case; an antisense oligonucleotide (AON) covering the intronic mutation restored WT Artemis transcript levels and non-homologous end-joining pathway activity in the patient fibroblasts.

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“…The majority of the remaining patients show hypersensitivity to ionizing radiation, because the V(D)J recombination deficiency results from a defect in NHEJ. The majority of these patients have mutations in Artemis (Moshous et al, 2001;Li et al, 2002;Kobayashi et al, 2003;Noordzij et al, 2003). The clinical phenotype of RAG1, RAG2 and Artemis-deficient patients is similar and can be mimicked in mice (Table 1).…”

Section: Intersection Of Nhej With Other Cellular Processesmentioning

confidence: 99%

Non-homologous end-joining, a sticky affair

2007

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Rejoining of broken chromosomes is crucial for cell survival and prevention of malignant transformation. Most mammalian cells rely primarily on the non-homologous end-joining pathway of DNA double-strand break (DSB) repair to accomplish this task. This review focuses both on the core non-homologous end-joining machinery, which consists of DNA-dependent protein kinase and the ligase IV/XRCC4 complex, and on accessory factors that facilitate rejoining of a subset of the DSBs. We discuss how the ATM protein kinase and the Mre11/Rad50/Nbs1 complex might function in DSB repair and what role ionizing radiation-induced foci may play in this process.

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Radiosensitive SCID patients with Artemis gene mutations show a complete B-cell differentiation arrest at the pre-B-cell receptor checkpoint in bone marrow

Cited by 91 publications

References 28 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

Artemis splice defects cause atypical SCID and can be restored in vitro by an antisense oligonucleotide

Non-homologous end-joining, a sticky affair

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