Premium
Functional classification of ATM variants in ataxia‐telangiectasia patients
Author(s) -
Fiévet Alice,
Bellanger Dorine,
Rieunier Guillaume,
Dubois d'Enghien Catherine,
Sophie Julia,
Calvas Patrick,
Carriere JeanPaul,
Anheim Mathieu,
Castrioto Anna,
Flabeau Olivier,
Degos Bertrand,
Ewenczyk Claire,
Mahlaoui Nizar,
Touzot Fabien,
Suarez Felipe,
Hully Marie,
Roubertie Agathe,
Aladjidi Nathalie,
Tison François,
AntoinePoirel Hélène,
Dahan Karine,
Doummar Diane,
Nougues MarieChristine,
Ioos Christine,
Rougeot Christelle,
Masurel Alice,
Bourjault Caroline,
Ginglinger Emmanuelle,
Prieur Fabienne,
Siri Aurélie,
Bordigoni Pierre,
Nguyen Karine,
Philippe Noel,
Bellesme Céline,
Demeocq François,
Altuzarra Cecilia,
MathieuDramard Michèle,
Couderc Fanny,
Dörk Thilo,
Auger Nathalie,
Parfait Béatrice,
Abidallah Khadija,
Moncoutier Virginie,
Collet Agnès,
StoppaLyonnet Dominique,
Stern MarcHenri
Publication year - 2019
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23778
Subject(s) - ataxia telangiectasia , biology , phenotype , ataxia , genetics , mutation , cancer research , gene , dna damage , neuroscience , dna
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.