Two unrelated patients with MRE11A mutations and Nijmegen breakage syndrome-like severe microcephaly
Yoshiyuki Matsumoto1, Tatsuo Miyamoto, Hiromi Sakamoto
1Department of Genetics and Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Kasumi 1-2-3, Hiroshima 734-8553, Japan.
Abstract:
MRE11 and NBS1 function together as components of a MRE11/RAD50/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 MRE11A 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 MRE11A 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.
Insights
Mutations in the MRE11A gene can cause severe microcephaly, a condition previously linked only to Nijmegen breakage syndrome (NBS). This finding expands our understanding of NBS-like disorders and MRE11A gene function.
Area of Science:
- Genetics
- Molecular Biology
- Genomic Instability Syndromes
Background:
- The MRE11/RAD50/NBS1 complex is crucial for DNA repair, with mutations in NBS1 causing Nijmegen breakage syndrome (NBS) and MRE11A mutations causing ataxia-telangiectasia-like disorder (ATLD).
- NBS is characterized by microcephaly, developmental delays, and radiosensitivity, while ATLD presents as a late-onset ataxia without microcephaly.
Observation:
- Two unrelated patients presented with severe microcephaly (head circumference -10.2 and -12.8 SD), exhibiting NBS-like features.
- Genetic analysis revealed compound heterozygous mutations in the MRE11A gene in both patients.
Findings:
- Both patients carried a functionally debilitating truncating or missense MRE11A mutation alongside a common translationally silent mutation.
- The silent mutation impacted splicing efficiency, reducing MRE11 protein levels but not to a critical deficiency.
- Radiation-induced ATM activation levels in these patients were higher compared to ATLD cells, suggesting a distinct molecular mechanism.
Implications:
- This study identifies MRE11A mutations as a cause of NBS-like microcephaly, broadening the clinical spectrum associated with this gene.
- The findings highlight the complex genotype-phenotype correlations in DNA repair disorders and emphasize the importance of considering MRE11A in differential diagnosis.
- Understanding the specific impact of MRE11A mutations on ATM activation provides insights into DNA damage response pathways and potential therapeutic targets.
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