Clinical variability and novel mutations in the NHEJ1 gene in patients with a Nijmegen breakage syndrome-like phenotype

Dutrannoy, Véronique; Demuth, Ilja; Baumann, Ulrich; Schindler, Detlev; Konrat, Kateryna; Neitzel, Heidemarie; Gillessen‐Kaesbach, Gabriele; Radszewski, Janina; Rothe, Susanne; Schellenberger, Mario T.; Nürnberg, Gudrun; Nürnberg, Peter; Teik, Keng Wee; Nallusamy, Revathy; Reis, André; Sperling, Karl; Digweed, Martin; Varon, Raymonda

doi:10.1002/humu.21315

Cited by 28 publications

(20 citation statements)

References 56 publications

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“…Mutations in NHEJ1 have been associated with a Nijmegen breakage syndrome-like phenotype. 16 Moreover Cantagrel et al 17 described a patient with hydrocephalus, polymicrogyria and syndactyly of the fingers and toes, who carried a balanced translocation t(2;7)(q36;p22), the breakpoint on chromosome 2 disrupting NHEJ1, a gene also located within the duplicated region in our cases. 17 Seen as the mechanism underlying these phenotypes is rather loss-of-function, we consider NHEJ1 unlikely to be primarily involved in the phenotype seen in this study.…”

Section: Ihh Duplication In Acsmentioning

confidence: 54%

A large duplication involving the IHH locus mimics acrocallosal syndrome

et al. 2012

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Indian hedgehog (Ihh) signaling is a major determinant of various processes during embryonic development and has a pivotal role in embryonic skeletal development. A specific spatial and temporal expression of Ihh within the developing limb buds is essential for accurate digit outgrowth and correct digit number. Although missense mutations in IHH cause brachydactyly type A1, small tandem duplications involving the IHH locus have recently been described in patients with mild syndactyly and craniosynostosis. In contrast, a B600-kb deletion 5¢ of IHH in the doublefoot mouse mutant (Dbf) leads to severe polydactyly without craniosynostosis, but with craniofacial dysmorphism. We now present a patient resembling acrocallosal syndrome (ACS) with extensive polysyndactyly of the hands and feet, craniofacial abnormalities including macrocephaly, agenesis of the corpus callosum, dysplastic and low-set ears, severe hypertelorism and profound psychomotor delay. Single-nucleotide polymorphism (SNP) array copy number analysis identified a B900-kb duplication of the IHH locus, which was confirmed by an independent quantitative method. A fetus from a second pregnancy of the mother by a different spouse showed similar craniofacial and limb malformations and the same duplication of the IHH-locus. We defined the exact breakpoints and showed that the duplications are identical tandem duplications in both sibs. No copy number changes were observed in the healthy mother. To our knowledge, this is the first report of a human phenotype similar to the Dbf mutant and strikingly overlapping with ACS that is caused by a copy number variation involving the IHH locus on chromosome 2q35.

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Section: Ihh Duplication In Acsmentioning

confidence: 54%

A large duplication involving the IHH locus mimics acrocallosal syndrome

et al. 2012

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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%

“…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. The XLF-deficient patients suffered from recurrent (opportunistic) infections, but in contrast to patients with "classical" severe combined immunodeficiency with defects in RAG or ARTEMIS, in whom the outcome is usually fatal within the first year of life, unless they receive hematopoietic stem cell transplantation (SCT), the XLF-deficient patients survived beyond the first year of life without SCT.…”

Section: Resultsmentioning

confidence: 99%

“…7,16,17 XLF deficiency in human results in extreme sensitivity to IR, microcephaly, and growth retardation, but the effect on the immune system is variable (mild to severe immunodeficiency). 6,7,18 Studies in XLF-deficient mouse models have confirmed the severe sensitivity to IR and chromosomal instability, but the V(D)J recombination defect seemed relatively mild. 19,20 So far, the most important action of XLF seems to be the stimulation of LIG4 activity, 21,22 probably by stabilizing the XRCC4-LIG4 complex on DNA and promotion of DNA strand alignment.…”

Section: Introductionmentioning

confidence: 98%

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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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“…NBS1 gene analysis was found to be negative; therefore, it was thought to be a different diagnosis. Finally, because of phenotypical and laboratory similarities with previously reported Cernunnos deficient patients, genetic analysis for Cernunnos/DNA ligase IV deficiency was performed and homozygous NHEJ1 (Cernunnos) mutation, which is common in Turkish patients, was identified [7, 8]. …”

Section: Discussionmentioning

confidence: 99%

Cernunnos/XLF Deficiency: A Syndromic Primary Immunodeficiency

Çipe

Aydoğmuş

Hocaoğlu

et al. 2014

Case Reports in Pediatrics

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Artemis, DNA ligase IV, DNA protein kinase catalytic subunit, and Cernunnos/XLF genes in nonhomologous end joining pathways of DNA repair mechanisms have been identified as responsible for radiosensitive SCID. Here, we present a 3-year-old girl patient with severe growth retardation, bird-like face, recurrent perianal abscess, pancytopenia, and polydactyly. Firstly, she was thought as Fanconi anemia and spontaneous DNA breaks were seen on chromosomal analysis. After that DEB test was found to be normal and Fanconi anemia was excluded. Because of that she had low IgG and IgA levels, normal IgM level, and absence of B cells in peripheral blood; she was considered as primary immunodeficiency, Nijmegen breakage syndrome. A mutation in NBS1 gene was not found; then Cernunnos/XLF deficiency was investigated due to clinical similarities with previously reported cases. Homozygous mutation in Cernunnos/XLF gene (NHEJ1) was identified. She is now on regular IVIG prophylaxis and has no new infection. Fully matched donor screening is in progress for bone marrow transplantation which is curative treatment of the disease. In conclusion, the patients with microcephaly, bird-like face, and severe growth retardation should be evaluated for hypogammaglobulinemia and primary immunodeficiency diseases.

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Clinical variability and novel mutations in the NHEJ1 gene in patients with a Nijmegen breakage syndrome-like phenotype

Cited by 28 publications

References 56 publications

A large duplication involving the IHH locus mimics acrocallosal syndrome

A large duplication involving the IHH locus mimics acrocallosal syndrome

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

Cernunnos/XLF Deficiency: A Syndromic Primary Immunodeficiency

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