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Nijmegen breakage syndrome

Written2002-10Nancy Uhrhammer, Jacques-Olivier Bay, Richard A Gatti
Centre Jean-Perrin, BP 392, 63000 Clermont-Ferrand, France
This article is an update of :
1999-10Nancy Uhrhammer, Jacques-Olivier Bay, Richard A Gatti
Centre Jean-Perrin, BP 392, 63000 Clermont-Ferrand, France
1998-10Jérôme Couturier
Department of Pathology, Institut Curie, Paris, France

(Note : for Links provided by Atlas : click)


Other namesAtaxia-telangiectasia, variant VI
Seemanova syndrome II
Microcephaly with normal intelligence, immunodeficiency, lymphoreticular malignancies
Immunodeficiency, microcephaly, chromosomal instability
Atlas_Id 10020
Genes implicated inNBN   RAD50  
Note belongs to the group of inherited chromosomal instability syndromes including
  • Bloom's syndrome,
  • Fanconi's disease, and
  • ataxia telangiectasia(AT); see also, in Deep Insight section: Ataxia-Telangiectasia and variants
  • Inheritance autosomal recessive disease; since the recognition of the Nijmegen breakage syndrome (NBS) in 1981, about 70 patients are included in the NBS Registry in Nijmegen; the disease appears to have originated in central Europe, in the Slavic population, and to have spread through a founder effect.


    Note the condition is characterised by growth and mental retardation, craniofacial dysmorphy, ovarian failure, immunodeficiency, chromosome instability, predisposition to lymphoid malignancies, and radiosensitivity.
    Phenotype and clinics
  • growth and mental development: 30 % of children have low birth weight and short stature, and 75% a head circumference at birth below the 3rd percentile; all patients develop a severe microcephaly during the first months of life; mental development is normal in 35% of the patients, moderately retarded in the others, though the mental retardation appears to be progressive; cerebellar ataxia is absent; alphafoetoprotein levels are normal, in contrast to AT patients.
  • craniofacial dysmorphy: progressive and severe microcephaly, "bird-like" face with prominent midface, long nose and receding mandible
  • immunodeficiency: severe combined deficiency with agammaglobulinemia, IgA, IgG2 and IgG4 deficiencies, decreased CD3+ and CD4+ lymphocytes, and decreased CD4+ / CD8+ ratio; these disturbances are responsible of frequent respiratory, garstrointestinal and urinary infections.
  • Neoplastic risk high frequency and early development of lymphomas, more often involving B-cells, in contrast with those found in AT.
    other forms of cancer may also be at higher risk


    Inborn conditions
  • lymphocyte cultures often show low mitotic index
  • structural chromosome aberrations are observed in 10-30% of metaphases; most of the rearrangements occur in or between chromosomes 7 and 14, at bands 7p13, 7q35, 14q11, and 14q32, as in AT; these bands contain immunoglobulin and T-cell receptor genes; the most frequent rearrangement is the inv(7)(p13q35)
  • Other findings

    Note radiosensitivity: increased sensitivity of both lymphocytes and fibroblasts to ionising radiations and radiomimetics, radio-resistant DNA synthesis.

    Genes involved and Proteins

    Gene NameNBN (Nijmegen breakage syndrome 1)
    Location 8q21.3
    Description 16 exons
    Function the product of NBS1, nibrin (p95), associates with Mre and Rad50 to control the repair of double-strand DNA breaks involved, for example, in VDJ joining in immunoglobulin and T-cell receptor genes recombination process, in meiotic recombination, and in radio-induced DNA lesions; this suggests that nibrin and the product of ATM could act in a common pathway of detection or repair of double-strand breaks, and indeed, ATM phosphorylates nibrin in response to DNA damage. Nibrin/p95 is found associated with Rad50 and Mre11 at sites of DNA double-strand breaks and is essential for the nuclear localization of the complex.
    Germinal all NBS patients show truncating mutations. The common 657del5 allele has been shown to produce a short N-terminal protein of no detectable function, and also a C-terminal protein produced through an alternative translation initiation signal in the deleted mRNA. Data from knockout mice indicates that this C-terminal protein is partially functional, as Nbs1 null alleles are lethal.
    Somatic Missence mutations in NBS1 have been associated with childhood acute lymphoblastic leukemia.


    Chk2 activation dependence on Nbs1 after DNA damage.
    Buscemi G, Savio C, Zannini L, Miccichè F, Masnada D, Nakanishi M, Tauchi H, Komatsu K, Mizutani S, Khanna K, Chen P, Concannon P, Chessa L, Delia D
    Molecular and cellular biology. 2001 ; 21 (15) : 5214-5222.
    PMID 11438675
    The Nijmegen breakage syndrome protein is essential for Mre11 phosphorylation upon DNA damage.
    Dong Z, Zhong Q, Chen PL
    The Journal of biological chemistry. 1999 ; 274 (28) : 19513-19516.
    PMID 10391882
    Nijmegen breakage syndrome cells fail to induce the p53-mediated DNA damage response following exposure to ionizing radiation.
    Jongmans W, Vuillaume M, Chrzanowska K, Smeets D, Sperling K, Hall J
    Molecular and cellular biology. 1997 ; 17 (9) : 5016-5022.
    PMID 9271379
    hMre11 and hRad50 nuclear foci are induced during the normal cellular response to DNA double-strand breaks.
    Maser RS, Monsen KJ, Nelms BE, Petrini JH
    Molecular and cellular biology. 1997 ; 17 (10) : 6087-6096.
    PMID 9315668
    An alternative mode of translation permits production of a variant NBS1 protein from the common Nijmegen breakage syndrome allele.
    Maser RS, Zinkel R, Petrini JH
    Nature genetics. 2001 ; 27 (4) : 417-421.
    PMID 11279524
    Positional cloning of the gene for Nijmegen breakage syndrome.
    Matsuura S, Tauchi H, Nakamura A, Kondo N, Sakamoto S, Endo S, Smeets D, Solder B, Belohradsky BH, Der Kaloustian VM, Oshimura M, Isomura M, Nakamura Y, Komatsu K
    Nature genetics. 1998 ; 19 (2) : 179-181.
    PMID 9620777
    Ataxia-telangiectasia and the Nijmegen breakage syndrome: related disorders but genes apart.
    Shiloh Y
    Annual review of genetics. 1997 ; 31 : 635-662.
    PMID 9442910
    Mutations in the Nijmegen Breakage Syndrome gene (NBS1) in childhood acute lymphoblastic leukemia (ALL).
    Varon R, Reis A, Henze G, von Einsiedel HG, Sperling K, Seeger K
    Cancer research. 2001 ; 61 (9) : 3570-3572.
    PMID 11325820
    Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome.
    Varon R, Vissinga C, Platzer M, Cerosaletti KM, Chrzanowska KH, Saar K, Beckmann G, Seemanov´ E, Cooper PR, Nowak NJ, Stumm M, Weemaes CM, Gatti RA, Wilson RK, Digweed M, Rosenthal A, Sperling K, Concannon P, Reis A
    Cell. 1998 ; 93 (3) : 467-476.
    PMID 9590180
    A murine model of Nijmegen breakage syndrome.
    Williams BR, Mirzoeva OK, Morgan WF, Lin J, Dunnick W, Petrini JH
    Current biology : CB. 2002 ; 12 (8) : 648-653.
    PMID 11967151
    Characterization of cell cycle checkpoint responses after ionizing radiation in Nijmegen breakage syndrome cells.
    Yamazaki V, Wegner RD, Kirchgessner CU
    Cancer research. 1998 ; 58 (11) : 2316-2322.
    PMID 9622065
    Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response.
    Zhong Q, Chen CF, Li S, Chen Y, Wang CC, Xiao J, Chen PL, Sharp ZD, Lee WH
    Science (New York, N.Y.). 1999 ; 285 (5428) : 747-750.
    PMID 10426999
    Decreased immunoglobulin class switching in Nijmegen Breakage syndrome due to the DNA repair defect.
    van Engelen BG, Hiel JA, Gabreëls FJ, van den Heuvel LP, van Gent DC, Weemaes CM
    Human immunology. 2001 ; 62 (12) : 1324-1327.
    PMID 11756000
    Nijmegen breakage syndrome.
    van der Burgt I, Chrzanowska KH, Smeets D, Weemaes C
    Journal of medical genetics. 1996 ; 33 (2) : 153-156.
    PMID 8929954


    This paper should be referenced as such :
    Uhrhammer, N ; Bay, JO ; Gatti, RA
    Nijmegen breakage syndrome
    Atlas Genet Cytogenet Oncol Haematol. 2003;7(1):55-56.
    Free journal version : [ pdf ]   [ DOI ]
    On line version :
    History of this paper:
    Couturier, J. Nijmegen breakage syndrome. Atlas Genet Cytogenet Oncol Haematol. 1999;3(1):46-47.
    Uhrhammer, N ; Bay, JO ; Gatti, RA. Nijmegen breakage syndrome. Atlas Genet Cytogenet Oncol Haematol. 1999;3(4):215-216.

    Other genes implicated (Data extracted from papers in the Atlas) [ 4 ]


    External links

    OrphanetNijmegen breakage syndrome
    Other databaseNijmegen breakage syndrome (GARD)
    Genes implicated inNBN   [ Atlas ]   [ Entrez ]  [ LOVD ]  [ GeneReviews ]  
    Genes implicated inRAD50   [ Atlas ]   [ Entrez ]  [ LOVD ]  [ GeneReviews ]  

    REVIEW articlesautomatic search in PubMed
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