Abstract
Mre11/Rad50/Nbs1 protein complex plays a crucial role in DNA double strand break repair. Mutations in the NBS gene underlies Nijmegen breakage syndrome (NBS), a chromosomal instability syndrome characterized by microcephaly, growth and mental retardation, cellular radiosensitivity, and cancer predisposition, while mutations in the MRE11 gene lead to an ataxia-telangiectasia-like disorder (ATLD), a slowly progressive variant of A-T without microcephaly.
Here we studied two unrelated patients with clinical features resembling NBS and identified mutations in the MRE11 gene. Both patients were compound heterozygotes for a truncating or missense mutation plus a translationally silent mutation. The translationally silent mutation common to them had a profound effect on splicing efficiency, resulting in reduced but normal Mre11protein. Their levels of ATM activation by γ-radiation and the following apoptosis were significantly higher than those in ATLD cells. These findings suggest that both patients during development underwent ATM-dependent neuronal apoptosis of DNA damaged cells in the presence of reduced but normal Mre11 protein, and resulted in reduced numbers of neuronal progenitor cells and NBS-like severe microcephaly.
