Functional classification of ATM variants in ataxia‐telangiectasia patients
2 Institut Curie [Paris]
3 Equipe BIOETHICS (CERPOP)
4 Service Génétique Médicale [CHU Toulouse]
5 Service Neurologie Pédiatrique [CHU Toulouse]
6 Service de Neurologie [Strasbourg]
7 Pôle Psychiatrie et Neurologie [Grenoble]
8 Neurologie - Côte Basque
9 CHU Charles Foix [AP-HP]
10 CHU Pitié-Salpêtrière [AP-HP]
11 Service d'immuno-hématologie pédiatrique [CHU Necker]
12 RAISE - Centre de Référence pour les Maladies Rhumatologiques Auto-Immunes et Systémiques [CHU Necker]
13 Service d'Hématologie Adultes [CHU Necker]
14 Service de neurologie pédiatrique [CHU Necker]
15 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
16 INM - Institut des Neurosciences de Montpellier
17 CHU de Bordeaux Pellegrin [Bordeaux]
18 Service de neurologie [Bordeaux]
19 Cliniques Universitaires Saint-Luc [Bruxelles]
20 UCLouvain - Université Catholique de Louvain = Catholic University of Louvain
21 CHU Trousseau [APHP]
22 CHIC - Centre Hospitalier Intercommunal de Créteil
23 Hôpital Raymond Poincaré [AP-HP]
24 HFME - Hôpital Femme Mère Enfant [CHU - HCL]
25 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
26 CH Lorient - Centre Hospitalier de Lorient
27 CH E.Muller Mulhouse - Centre Hospitalier Emile Muller [Mulhouse]
28 CHU ST-E - Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne]
29 Service de neurologie [CHRU Nancy]
30 Service d'Oncologie Pédiatrique [CHRU Nancy]
31 Département de génétique médicale [Hôpital de la Timone - APHM]
32 Hôpital Debrousse
33 Service d'Endocrinologie [CHU Cochin]
34 Service de Pédiatrie Générale [CHU Clermont-Ferrand]
35 CHRU Besançon - Centre Hospitalier Régional Universitaire de Besançon
36 Unité de génétique médicale et oncogénétique [CHU Amiens Picardie]
37 CHIAP - Centre Hospitalier d'Aix en Provence [Aix-en-Provence]
38 MHH - Department of Obstetrics and Gynaecology
39 IGR - Institut Gustave Roussy
40 IC UM3 (UMR 8104 / U1016) - Institut Cochin
41 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
- Fonction : Auteur
- PersonId : 803001
- ORCID : 0000-0003-2096-8708
- Fonction : Auteur
- PersonId : 1105631
- ORCID : 0000-0001-8121-0605
- IdRef : 110246675
- Fonction : Auteur
- PersonId : 760657
- ORCID : 0000-0002-6889-3891
- Fonction : Auteur
- PersonId : 807138
- ORCID : 0000-0002-8100-2272
- IdRef : 074099191
Résumé
Ataxia-telangiectasia (A-T) is a recessive disorder caused by biallelic pathogenic variants of ataxia-telangiectasia mutated (ATM). This disease is characterized by progressive ataxia, telangiectasia, immune deficiency, predisposition to malignancies, and radiosensitivity. However, hypomorphic variants may be discovered associated with very atypical phenotypes, raising the importance of evaluating their pathogenic effects. In this study, multiple functional analyses were performed on lymphoblastoid cell lines from 36 patients, comprising 49 ATM variants, 24 being of uncertain significance. Thirteen patients with atypical phenotype and presumably hypomorphic variants were of particular interest to test strength of functional analyses and to highlight discrepancies with typical patients. Western-blot combined with transcript analyses allowed the identification of one missing variant, confirmed suspected splice defects and revealed unsuspected minor transcripts. Subcellular localization analyses confirmed the low level and abnormal cytoplasmic localization of ATM for most A-T cell lines. Interestingly, atypical patients had lower kinase defect and less altered cell-cycle distribution after genotoxic stress than typical patients. In conclusion, this study demonstrated the pathogenic effects of the 49 variants, highlighted the strength of KAP1 phosphorylation test for pathogenicity assessment and allowed the establishment of the Ataxia-TeLangiectasia Atypical Score to predict atypical phenotype. Altogether, we propose strategies for ATM variant detection and classification.