Institut Curie, PSL Research University, Paris, France.
INSERM U830, D.R.U.M. team, Paris, France.
Hum Mutat. 2019 Oct;40(10):1690-1699. doi: 10.1002/humu.23773. Epub 2019 May 15.
Ataxia-telangiectasia-like disorder (ATLD) is a rare genomic instability syndrome caused by biallelic variants of MRE11 (meiotic recombination 11) characterized by progressive cerebellar ataxia and typical karyotype abnormalities. These symptoms are common to those of ataxia-telangiectasia, which is consistent with the key role of MRE11 in ataxia-telangiectasia mutated (ATM) activation after DNA double-strand breaks. Three unrelated French patients were referred with ataxia. Only one had typical karyotype abnormalities. Unreported biallelic MRE11 variants were found in these three cases. Interestingly, one variant (c.424G>A) was present in two cases and haplotype analysis strongly suggested a French founder variant. Variants c.544G>A and c.314+4_314+7del lead to splice defects. The level of MRE11 in lymphoblastoid cell lines was consistently and dramatically reduced. Functional consequences were evaluated on activation of the ATM pathway via phosphorylation of ATM targets (KAP1 and CHK2), but no consistent defect was observed. However, an S-phase checkpoint activation defect after camptothecin was observed in these patients with ATLD. In conclusion, we report the first three French ATLD patients and a French founder variant, and propose an S-phase checkpoint activation study to evaluate the pathogenicity of MRE11 variants.
共济失调毛细血管扩张症样疾病（ATLD）是一种罕见的基因组不稳定性综合征，由 MRE11（减数分裂重组 11）的双等位基因突变引起，其特征为进行性小脑共济失调和典型的核型异常。这些症状与共济失调毛细血管扩张症相似，这与 MRE11 在 DNA 双链断裂后激活共济失调毛细血管扩张症突变（ATM）的关键作用一致。有 3 名法国无关患者因共济失调而就诊。只有 1 名患者存在典型的核型异常。在这 3 例患者中发现了未报道的 MRE11 双等位基因突变。有趣的是，一个变异（c.424G>A）存在于两个病例中，单倍型分析强烈提示存在法国创始变异。变异 c.544G>A 和 c.314+4_314+7del 导致剪接缺陷。淋巴母细胞系中 MRE11 的水平持续且显著降低。通过 ATM 靶标（KAP1 和 CHK2）的磷酸化评估 ATM 通路的激活来评估功能后果，但未观察到一致的缺陷。然而，在这些 ATLD 患者中，在用喜树碱处理后观察到 S 期检查点激活缺陷。总之，我们报告了法国的前 3 例 ATLD 患者和一个法国创始变异，并提出了 S 期检查点激活研究来评估 MRE11 变异的致病性。
