NBS is an autosomal recessive condition. NBS1 is the only gene known to be associated with NBS and encodes a protein nibrin (Cerosaletti et al. 1998; Featherstone and Jackson 1998). Cells from NBS patients are sensitive to radiation and radiomimetic compounds (Taalman et al. 1983). For instance, peripheral blood lymphocytes display spontaneous and radiation-induced chromosomal instability that frequently involves the immunoglobulin and T cell receptor loci on chromosomes 7 and 14 (Weemaes et al. 1981; Taalman et al. 1989).
DNA damage triggers specific cellular responses that ensure the maintenance of genomic integrity. The induction of DNA strand breakage by ionizing radiation (IR) results in activation of signaling pathways that lead either to elimination of damaged cells by programmed cell death or arrest of cell-cycle progression and repair of the DNA breaks (Elledge 1996; Zhou and Elledge 2000). Among the various proteins that contribute to DNA damage response, (ATM (serine-threonine kinase) protein plays a prominent role. Cells from individuals with ataxia telangiectasia exhibit defects in cell-cycle checkpoints operative in Gi, S, and G2 phases, as well as radiation hypersensitivity and an increased frequency of chromosome breakage (Kastan and Lim 2000; Kastan et al. 2000). Activated ATM, in turn, triggers the activation of cell-cycle checkpoints and DNA repair through the phosphorylation of various proteins, including nibrin (Petrini 1999; Lim et al. 2000; Wu et al. 2000; D'Amours and Jackson 2002). Mutations in the NBS1 gene encoding nibrin are responsible for molecular and clinical features of NBS (Varon et al. 1998). IR induces the formation of nuclear foci that contain a complex of NBS1 with MRE11 and RAD50 proteins, and these foci may represent sites of ongoing repair of DNA double-strand breaks (Mirzoeva and Petrini 2001; Howlett et al. 2006).
Genetic studies have provided evidence for a common haplotype of markers present in the families of Eastern European origins, suggesting a common original effect with regard to mutations causing the disorder. After identification of the gene, mutation detection has revealed a truncating 5 bp deletion, 657-661delACAAA, which was proven to be responsible for the disease. However, a few additional truncating mutations were identified in patients with other distinct haplotypes (2000).
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