Nijmegen breakage syndrome

2002-10-01   Nancy Uhrhammer  , Jacques-Olivier Bay  , Richard A Gatti  

Centre Jean-Perrin, BP 392, 63000 Clermont-Ferrand, France

Identity

Name

Nijmegen breakage syndrome

Alias

Ataxia-telangiectasia, variant VI , Seemanova syndrome II , Microcephaly with normal intelligence, immunodeficiency, lymphoreticular malignancies , Immunodeficiency, microcephaly, chromosomal instability

Note

belongs to the group of inherited chromosomal instability syndromes including
  • Blooms syndrome,
  • Fanconis 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.

    Omim

    251260 , 613078

    Mesh

    C531759;D049932

    Orphanet

    647 Nijmegen breakage syndrome

    Umls

    C0398791;C2930831

    Clinics

    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

    Cytogenetics

    Inborn condition

  • 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

    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.

    To be noted

    Hgmd

    9598211

    Article Bibliography

    Pubmed IDLast YearTitleAuthors
    114386752001Chk2 activation dependence on Nbs1 after DNA damage.Buscemi G et al
    103918821999The Nijmegen breakage syndrome protein is essential for Mre11 phosphorylation upon DNA damage.Dong Z et al
    92713791997Nijmegen breakage syndrome cells fail to induce the p53-mediated DNA damage response following exposure to ionizing radiation.Jongmans W et al
    93156681997hMre11 and hRad50 nuclear foci are induced during the normal cellular response to DNA double-strand breaks.Maser RS et al
    112795242001An alternative mode of translation permits production of a variant NBS1 protein from the common Nijmegen breakage syndrome allele.Maser RS et al
    96207771998Positional cloning of the gene for Nijmegen breakage syndrome.Matsuura S et al
    94429101997Ataxia-telangiectasia and the Nijmegen breakage syndrome: related disorders but genes apart.Shiloh Y et al
    113258202001Mutations in the Nijmegen Breakage Syndrome gene (NBS1) in childhood acute lymphoblastic leukemia (ALL).Varon R et al
    95901801998Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome.Varon R et al
    119671512002A murine model of Nijmegen breakage syndrome.Williams BR et al
    96220651998Characterization of cell cycle checkpoint responses after ionizing radiation in Nijmegen breakage syndrome cells.Yamazaki V et al
    104269991999Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response.Zhong Q et al
    117560002001Decreased immunoglobulin class switching in Nijmegen Breakage syndrome due to the DNA repair defect.van Engelen BG et al
    89299541996Nijmegen breakage syndrome.van der Burgt I et al