Three new cases of ataxia‐telangiectasia‐like disorder: No impairment of the ATM pathway, but S‐phase checkpoint defect. Issue 10 (15th May 2019)

• Record Type: Journal Article
• Authors: Fiévet, Alice; Bellanger, Dorine; Valence, Stéphanie; Mobuchon, Lenha; Afenjar, Alexandra; Giuliano, Fabienne; Dubois d'Enghien, Catherine; Parfait, Béatrice; Pedespan, Jean‐Michel; Auger, Nathalie; Rieunier, Guillaume; Collet, Agnès; Burglen, Lydie; Stoppa‐Lyonnet, Dominique; Stern, Marc‐Henri
• Is Part Of: Human mutation. Volume 40:Issue 10(2019)
• Page Start: 1690
• Page End: 1699
• Publication Date: 2019-05-15
• Subjects: ataxia -- ataxia‐telangiectasia‐like disorder (ATLD) -- ataxia‐telangiectasia mutated (ATM) -- checkpoint -- meiotic recombination 11 (MRE11) -- MRN; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23773
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract: 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. Abstract : 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. We describe the first three French patients with progressive cerebellar ataxia diagnosed with ATLD, associated with compound heterozygosity for unreported MRE11 variants. Functional consequences were evaluated on activation of the ataxia‐telangiectasia mutated (ATM) pathway via phosphorylation of ATM targets, but no consistent defect was observed. However, an S‐phase checkpoint activation defect after camptothecin was observed in these ATLD patients.