Abstract for presentation at 11th International Congress of Human Genetics

Nijmegen Breakage Syndrome: hypomorphic mutation, protein expression and phenotypic variability

  • Martin Digweed, Institut für Humangenetik, Charité - Universitätsmedizin Berlin., Germany
  • Lars Krüger, Institut für Humangenetik, Charité - Universitätsmedizin Berlin., Germany
  • Ilja Demuth, Institut für Humangenetik, Charité - Universitätsmedizin Berlin., Germany
  • Raymonda Varon, Institut für Humangenetik, Charité - Universitätsmedizin Berlin., Germany
  • Krystyna Chrzanowska, Department of Genetics, Memorial Hospital-Child Health Center, Warsaw, Poland
  • Eva Seemanova, Department of Clinical Genetics, Institute of Biology and Medical Genetics, Second Medical School of Charles University, Czech Republic
  • Karl Sperling, Institut für Humangenetik, Charité - Universitätsmedizin Berlin., Germany

    • The gene mutated in the autosomal recessive disorder, Nijmegen Breakage Syndrome (NBS), is a major player in the cellular response to ionising radiation. The gene’s product, nibrin, is involved both directly in the repair of DNA double-strand breaks and also in a signalling cascade to cell cycle checkpoints. The involvement of nibrin in DNA-repair can readily explain the characteristic radiosensitivity of NBS patients, their immunodeficiency, and the chromosome instability observed in their cells. Nibrin’s additional functions in cell cycle control can be made responsible for the particularly high risk of cancer in NBS, predominantly, B-cell lymphoma.
    The major founder mutation in NBS is a five base pair deletion which, through alternative translation at a cryptic start codon, is actually hypomorphic. Alternative translation leads to an approximately 70kDa nibin-fragment able to maintain some of the full-length protein’s cellular functions; this we have demonstrated by rescue of null-mutant mouse cells by the human 70kDa nibin-fragment. We hypothesized that the level of expression of this fragment might influence the clinical manifestation of the disease. To this end, measured the relative levels of p70-nibrin in lymphoblastoid cell lines from 26 NBS patients using immunoprecipitation. We found that p70-nibrin expression levels varied ten-fold in these cell lines. In the expectation that these measurements reflect patient-specific constitutive p70-nibrin expression, we attempted a correlation with clinical manifestation. Indeed, under the 26 NBS patients analysed, those expressing low levels of p70-nibrin had developed neoplasms whilst those with higher expression levels were cancer-free.
    Combining these data with the investigation of NBS heterozygotes and of homozygous patients with other NBS1-mutations, suggests a model in which decreasing expression levels of functional nibrin protein correlate with increased cancer risk and/or phenotypic manifestation.

    Conference Organiser - ICMS Pty Ltd