MRE11 mutations and impaired ATM-dependent responses in an Italian family with ataxia-telangiectasia-like disorder

Abstract

Hypomorphic mutations of the MRE11 gene are the hallmark of the radiosensitive ataxia-telangiectasia-like disorder (ATLD). Here, we describe a new family with two affected siblings, ATLD5 and ATLD6, now aged 37 and 36, respectively. They presented with late onset cerebellar degeneration slowly progressing until puberty and absence of telangiectasias, and were cancer-free. Both patients were wild-type for ATM and NBS1, but compound heterozygotes for MRE11 gene mutations [1422C-->A, T481K; 1714C-->T, R571X]. The 1422C-->A allele was inherited from the mother, whereas the 1714C-->T, allele paternally inherited, was apparently null as a result of nonsense-mediated mRNA decay (NMD). Interestingly, the 1714C-->T mutation is the same as previously identified in an unrelated English ATLD family (probands ATLD3 and ATLD4), suggesting an important role for NMD in saving potentially lethal mutations. Lymphoblastoid cell lines (LCLs) derived from ATLD5 and ATLD6 were normal for ATM, but defective for Mre11, Rad50 and Nbs1 (the MRN complex) protein expression. Their response to gamma-radiation was abnormal, as evidenced by the enhanced radiosensitivity, attenuated autophosphorylation of ATM-S1981 and phosphorylation of the ATM targets p53-S15 and Smc1-S966, failure to form Mre11 nuclear foci and defective G1 checkpoint arrest. The fibroblasts, but not LCLs, from ATLD5 and ATLD6 showed an impaired ATM-dependent Chk2 phosphorylation. These findings further underscore the interconnection between ATM activity and MRN function, which rationalizes the clinical similarity between ataxia-telangiectasia (A-T) and ATLD.

Programmed DNA breaks in lymphoid cells: repair mechanisms and consequences in human disease

“…This disease is characterized by neurodegeneration and cancer predisposition, in a similar way to AT 57. In most patients, MRE11 mutations affect the ability of the MRN complex to activate ATM.…”

Autosomal recessive ataxias: 20 types, and counting

“…No ocular or facial telangiectasias are detected and cognition is preserved 39,42,43 . Reflexes might be initially brisk and became reduced 42 .…”

“…Reflexes might be initially brisk and became reduced 42 . At advanced stages of disease, tongue and facial dyskinesia, choreoathetosis, and dystonia, suggesting basal ganglia compromise, might be seen 42,43 . ATL is progressive up to the adolescence, when it stabilizes 43 .…”

“…At advanced stages of disease, tongue and facial dyskinesia, choreoathetosis, and dystonia, suggesting basal ganglia compromise, might be seen 42,43 . ATL is progressive up to the adolescence, when it stabilizes 43 . There is no increased risk for infections or neoplasias, as is seen in AT, but occasionally microcephaly is present 39,42 .…”

“…Brain MRI detects cerebellar atrophy, and laboratory tests are non-informative 43 . Radiosensitivity test is usually present but in a lesser degree than in AT 35,[42][43][44] .…”