Journal
DNA REPAIR
Volume 10, Issue 3, Pages 314-321Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.dnarep.2010.12.002
Keywords
Nijmegen breakage syndrome (NBS); Ataxia-telangiectasia-like disorder (ATLD); Nijmegen breakage syndrome-like disorder (NBSLD); ATM; MRE11; NBS1; Microcephaly
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Funding
- Ministry of Education, Culture, Sports, Science and Technology
- Grants-in-Aid for Scientific Research [23650626, 23300363, 23710068, 22710056] Funding Source: KAKEN
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MRE11 and NBS1 function together as components of a MRE11/RAD5O/NBS1 protein complex, however deficiency of either protein does not result in the same clinical features. Mutations in the NBN gene underlie Nijmegen breakage syndrome (NBS), a chromosomal instability syndrome characterized by microcephaly, bird-like faces, growth and mental retardation, and cellular radiosensitivity. Additionally, mutations in the MRE1 1A gene are known to lead to an ataxia-telangiectasia-like disorder (ATLD), a late-onset, slowly progressive variant of ataxia-telangiectasia without microcephaly. Here we describe two unrelated patients with NBS-like severe microcephaly (head circumference -10.2 SD and -12.8 SD) and mutations in the MRE1 1A gene. Both patients were compound heterozygotes for a truncating or missense mutation and carried a translationally silent mutation. The truncating and missense mutations were assumed to be functionally debilitating. The translationally silent mutation common to both patients had an effect on splicing efficiency resulting in reduced but normal MRE11 protein. Their levels of radiation-induced activation of ATM were higher than those in ATLD cells. (C) 2010 Elsevier B.V. All rights reserved.
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