Cernunnos/XLF Deficiency: A Syndromic Primary Immunodeficiency

Çipe, Funda; Aydoğmuş, Çiğdem; Hocaoğlu, Arzu Babayiğit; Kılıç, Merve; Kaya, Gul Demet; Güleç, Elif Yılmaz

doi:10.1155/2014/614238

Cited by 16 publications

(16 citation statements)

References 9 publications

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“…6,7,18,[37][38][39] In this study, we describe 9 additional patients (Table 1). All patients (except P3) 18 had microcephaly and growth retardation.…”

Section: Resultsmentioning

confidence: 99%

XLF deficiency results in reduced N-nucleotide addition during V(D)J recombination

IJspeert

Rozmus

Schwarz

et al. 2016

Blood

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Key Points• XLF belongs to the NHEJ ligation complex and has a dual role in DNA doublestrand break repair and V(D)J recombination.• XLF is involved in Nnucleotide addition, and thereby contributes to junctional diversity of the antigen receptors.Repair of DNA double-strand breaks (DSBs) by the nonhomologous end-joining pathway (NHEJ) is important not only for repair of spontaneous breaks but also for breaks induced in developing lymphocytes during V(D)J (variable [V], diversity [D], and joining [J] genes) recombination of their antigen receptor loci to create a diverse repertoire. Mutations in the NHEJ factor XLF result in extreme sensitivity for ionizing radiation, microcephaly, and growth retardation comparable to mutations in LIG4 and XRCC4, which together form the NHEJ ligation complex. However, the effect on the immune system is variable (mild to severe immunodeficiency) and less prominent than that seen in deficiencies of NHEJ factors ARTEMIS and DNA-dependent protein kinase catalytic subunit, with defects in the hairpin opening step, which is crucial and unique for V(D)J recombination. Therefore, we aimed to study the role of XLF during V(D)J recombination. We obtained clinical data from 9 XLF-deficient patients and performed immune phenotyping and antigen receptor repertoire analysis of immunoglobulin (Ig) and T-cell receptor (TR) rearrangements, using next-generation sequencing in 6 patients. The results were compared with XRCC4 and LIG4 deficiency. Both Ig and TR rearrangements showed a significant decrease in the number of nontemplated (N) nucleotides inserted by terminal deoxynucleotidyl transferase, which resulted in a decrease of 2 to 3 amino acids in the CDR3. Such a reduction in the number of N-nucleotides has a great effect on the junctional diversity, and thereby on the total diversity of the Ig and TR repertoire. This shows that XLF has an important role during V(D)J recombination in creating diversity of the repertoire by stimulating N-nucleotide insertion. (Blood. 2016;128(5):650-659)

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“…6,7,18,[37][38][39] In this study, we describe 9 additional patients (Table 1). All patients (except P3) 18 had microcephaly and growth retardation.…”

Section: Resultsmentioning

confidence: 99%

XLF deficiency results in reduced N-nucleotide addition during V(D)J recombination

IJspeert

Rozmus

Schwarz

et al. 2016

Blood

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“…Growth retardation, frequently accompanied by microcephaly and craniofacial abnormalities, is seen in patients who are deficient in LIG4, XRCC4, or NHEJ1, which encode subunits of the complex responsible for the ligation step in c-NHEJ [41–43], and in patients who are deficient in NBS1, which encodes a different DSB repair factor [44]. Reduced body size is also seen in mice lacking XRCC5 and XRCC6, which encode the two subunits of Ku protein [45, 46].…”

Section: Discussionmentioning

confidence: 99%

Cell-type specific role of the RNA-binding protein, NONO, in the DNA double-strand break response in the mouse testes

Fang

et al. 2017

DNA Repair

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The tandem RNA recognition motif protein, NONO, was previously identified as a candidate DNA double-strand break (DSB) repair factor in a biochemical screen for proteins with end-joining stimulatory activity. Subsequent work showed that NONO and its binding partner, SFPQ, have many of the properties expected for bona fide repair factors in cell-based assays. Their contribution to the DNA damage response in intact tissue in vivo has not, however, been demonstrated. Here we compare DNA damage sensitivity in the testes of wild-type mice versus mice bearing a null allele of the NONO homologue (Nonogt). In wild-type mice, NONO protein was present in Sertoli, peritubular myoid, and interstitial cells, with an increase in expression following induction of DNA damage. As expected for the product of an X-linked gene, NONO was not detected in germ cells. The Nonogt/0 mice had at most a mild testis developmental phenotype in the absence of genotoxic stress. However, following irradiation at sublethal, 2–4 Gy doses, Nonogt/0 mice displayed a number of indicators of radiosensitivity as compared to their wild-type counterparts. These included higher levels of persistent DSB repair foci, increased numbers of apoptotic cells in the seminiferous tubules, and partial degeneration of the blood-testis barrier. There was also an almost complete loss of germ cells at later times following irradiation, evidently arising as an indirect effect reflecting loss of stromal support. Results demonstrate a role for NONO protein in protection against direct and indirect biological effects of ionizing radiation in the whole animal.

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“…NEHJ1 is one of the four genes responsible (along with the DCLRE1C , LIG4 and PRKDC ) for severe combined immunodeficiency (SCID) in humans (Cipe et al . ). DNA double‐strand breaks are DNA lesions produced by cell sources, such as replication errors, or external damaging agents.…”

Section: Resultsmentioning

confidence: 97%

A genome‐wide association study for the incidence of persistent bovine viral diarrhea virus infection in cattle

Casas

Hessman²,

Keele

et al. 2014

Animal Genetics

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Bovine viral diarrhea viruses (BVDV) comprise a diverse group of viruses that cause disease in cattle. BVDV may establish both transient and persistent infections depending on the developmental stage of the animal at exposure. The objective was to determine whether genomic regions harboring single nucleotide polymorphisms (SNPs) could be associated with the presence or absence of persistent BVDV infection. A genome-wide association approach based on 777,000 SNP markers was used. Samples of animals identified as positive (n = 1200) or negative (n = 1200) for the presence of BVDV in skin samples (n = 1200) were used. DNA samples were combined in 24 pools (100 animals per pool). One SNP, significant at the 5 percent genome-wide level (P = 9.41 × 10(-8) ), was detected on chromosome 14, located at position 80 675 176 bp. Fifteen SNPs, residing on chromosomes 1, 2, 6, 8, 10, 15 and 18, were moderately associated (P < 1 × 10(-5) ) with persistent BVDV infection. Results show that genes harboring or neighboring significant SNPs are involved in leucopenia, signal transduction, RNA splicing and DNA methylation processes.

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Cernunnos/XLF Deficiency: A Syndromic Primary Immunodeficiency

Cited by 16 publications

References 9 publications

XLF deficiency results in reduced N-nucleotide addition during V(D)J recombination

XLF deficiency results in reduced N-nucleotide addition during V(D)J recombination

Cell-type specific role of the RNA-binding protein, NONO, in the DNA double-strand break response in the mouse testes

A genome‐wide association study for the incidence of persistent bovine viral diarrhea virus infection in cattle

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