Accéder directement au contenu Accéder directement à la navigation
Nouvelle interface
Article dans une revue

Mutation in the 3’untranslated region of APP as a genetic determinant of cerebral amyloid angiopathy

Abstract : Aβ-related cerebral amyloid angiopathy (CAA) is a major cause of primary non-traumatic brain hemorrhage. In families with an early onset of the disease, CAA can be due to amyloid precursor protein (APP) pathogenic variants or duplications. APP duplications lead to a ~1.5-fold increased APP expression, resulting in Aβ overproduction and deposition in the walls of leptomeningeal vessels. We hypothesized that rare variants in the 3’untranslated region (UTR) of APP might lead to APP overexpression in patients with CAA and no APP pathogenic variant or duplication. We performed direct sequencing of the whole APP 3’UTR in 90 patients with CAA and explored the functional consequences of one previously unreported variant. We identified three sequence variants in four patients, of which a two-base pair deletion (c.*331_*332del) was previously unannotated and absent from 175 controls of same ethnicity. This latter variant was associated with increased APP expression in vivo and in vitro. Bioinformatics and functional assays showed that the APP c.*331_*332del variant affected APP messenger RNA (mRNA) structure and binding of two microRNAs (miR-582-3p and miR-892b), providing a mechanism for the observed effects on APP expression. These results identify APP 3’UTR sequence variants as genetic determinants of Aβ-CAA.
Type de document :
Article dans une revue
Liste complète des métadonnées
Contributeur : Elisabeth Grelier Connectez-vous pour contacter le contributeur
Soumis le : jeudi 26 novembre 2015 - 11:57:37
Dernière modification le : mardi 22 novembre 2022 - 14:26:16

Lien texte intégral



Gaël Nicolas, David Wallon, Claudia Goupil, Anne-Claire Richard, Cyril Pottier, et al.. Mutation in the 3’untranslated region of APP as a genetic determinant of cerebral amyloid angiopathy. European Journal of Human Genetics, 2015, 24 (1), pp.92-98. ⟨10.1038/ejhg.2015.61⟩. ⟨hal-01234142⟩



Consultations de la notice