MRE11A Gene Mutations Responsible for the Rare Ataxia Telangiectasia-Like Disorder

Abstract

Ataxia telangiectasia like disorder (ATLD) is a rare variant of ataxia telangiectasia (A-T) that share a number of clinical features and similar cellular characteristics with the hallmark of increased sensitivity to ionizing radiation (Taylor et al., 1975; Taylor, 2001; Tauchi et al., 2002). These conditions are typically diagnosed at young age at about the time the affected children start to walk. A-T and ATLD patients develop progressive cerebellar ataxia which is required for their clinical diagnosis. Although classified as another variant of A-T, Nijmegen breakage syndrome (NBS) is characterized by microcephaly and growth retardation without ataxia. The other major clinical characteristics are variable and include dilated blood vessels (telangiectasia) usually in the eyes, immunodeficiency, high level of spontaneously occurring chromosome abnormalities, and predisposition to cancer particularly lymphoreticular malignancies. Genetically, the A-T is caused by biallelic inactivating mutations in the ATM gene at 11q22-23, the NBS is caused by mutation in the NBS1 gene mapped at 8q21, and the ATLD is caused by mutation in the MRE11A gene located at 11q21. Therefore, a disorder virtually indistinguishable from A-T is caused by mutation in the MRE11A gene. In view of the fact that the ATM and the MRE11A loci are situated nearby (11q22-23 and 11q21) only a very detailed linkage analysis would have historically separated ATLD from A-T on the basis of genetic data. Assuming that the mutation rate is proportional to the length of the coding sequence of the two genes, about 6% of A-T cases might be expected to have MRE11A mutations (Stewart et al., 1999). Thus, ATLD patients were first recognized as a subset of A-T who does not have mutations in the ATM gene. Hence, Stewart et al. had designated this syndrome as ataxia-telagnietasia-like disorder (Stewart et al., 1999). The clinical features are very similar to those of A-T; with the clearest similarity being the progressive cerebellar ataxia. In contrast to A-T, however, ATLD patients show no telangiectasia (Hernandez et al., 1993; Klein et al., 1996). In addition, the patients show later onset of the neurological features, and slower progression of the disorder giving the overall appearance of a milder A-T condition in early years. The function of Mre11 protein is linked to Nbs1 and both are members of the Mre11/Rad50/Nbs1 (MRN) complex involved in different DNA healing mechanisms due to innate processes or in responses to damage induced by ionizing radiation and radiomimetic chemicals (Carney et al., 1998; Petrini, 2000), including complexing with chromatin and