ATAXIA-TELANGIECTASIA-LIKE DISORDER (ATLD)
A small proportion of “AT” cases have mutations in the MRE11 gene rather than ATM, causing a disorder known as ATLD. The lymphocytes of such patients show increased levels of translocations involving immune system genes, and chromosomal radiosensitivity is seen, but B lymphocytes may not be affected and the cancer risk is less (Stewart et al. 1999; Duker 2002; De la Torre et al. 2003). MRE11 is part of the MRN (MRE11–RAD50–NBN) complex. MRN appears to be the primary sensor of DNA damage, signaling ATM to sites of double-strand breaks to initiate the DNA damage response (Lavin 2007). It also has important downstream functions that include tethering and processing the two broken ends of the DNA strand to generate 3′ overhangs for either non-homologous end-joining or homologous repair.
Its role in maintaining genome integrity is underscored by chromosome instability and cell-cycle checkpoint defects common to all patients with recessive loss of any one of these components. Heterozygous mutations in NBN and RAD50 (Heikkinen et al. 2006) have been associated with an increased risk for breast cancer (mainly in countries where founder mutations in these genes have been identified). Rare germline mutations in MRE11 have also been proposed to be breast cancer alleles – in one study of eight Tumours showing concomitant reduction/loss of all three MRN-complex proteins, mutation analysis revealed two germline mutations in MRE11: a missense mutation Arg202Gly and a truncating mutation Arg633X (Bartkova et al. 2008). This study remains to be verified in large case-control studies.
One likely truncating mutation in MRE11A was identified in 360 women with ovarian carcinoma (Walsh et al. 2011).