uORF-introducing variants in the 5'UTR of the NIPBL gene as a cause of Cornelia de Lange syndrome.
Fiche publication
Date publication
avril 2022
Journal
Human mutation
Auteurs
Membres identifiés du Cancéropôle Est :
Dr BONNET Céline
Tous les auteurs :
Coursimault J, Rovelet-Lecrux A, Cassinari K, Brischoux-Boucher E, Saugier-Veber P, Goldenberg A, Lecoquierre F, Drouot N, Richard AC, Vera G, Coutant S, Quenez O, Rolain M, Bonnet C, Bronner M, Lecourtois M, Nicolas G
Lien Pubmed
Résumé
Cornelia de Lange syndrome (CdLS) is a clinically-recognizable rare developmental disorder. About 70% of patients carry a missense or loss-of-function pathogenic variant in the NIPBL gene. We hypothesized that some variants in the 5' Untranslated Region (UTR) of NIPBL may create an upstream open reading frame (uORF), putatively leading to a loss of function. We searched for NIPBL 5'UTR variants potentially introducing uORF by (i) reannotating NGS data of 102 unsolved CdLS patients and (ii) literature and variant databases search. We set up a GFP reporter assay and studied NIPBL expression in a lymphoblastoid cell line (LCL). We identified two variants introducing a novel ATG codon sequence in the 5'UTR of NIPBL, both predicted to introduce uORF: a novel c.-457_-456delinsAT de novo mutation in a 15-year-old male with classic CdLS, and a c.-94C>T variant in a published family. Our reporter assay showed a significant decrease of GFP levels in both mutant contexts, with similar levels of mRNA as compared to wt constructs. Assessment of LCL of one patient showed consistent results with decreased NIPBL protein and unchanged mRNA levels. 5'UTR uORF-introducing NIPBL variants may represent a rare source of pathogenic variants in unsolved CdLS patients. This article is protected by copyright. All rights reserved.
Mots clés
5'UTR, cornelia de lange syndrome, de novo mutation, neurodevelopmental disorder, uORF
Référence
Hum Mutat. 2022 Apr 21;: