De novo deleterious genetic variations ...
Type de document :
Article dans une revue scientifique: Article original
DOI :
PMID :
URL permanente :
Titre :
De novo deleterious genetic variations target a biological network centered on a? peptide in early-onset alzheimer disease
Auteur(s) :
Rovelet-Lecrux, Anne [Auteur]
Charbonnier, Camille [Auteur]
Wallon, David [Auteur]
Nicolas, Gael [Auteur]
Seaman, M N J. [Auteur]
Pottier, Cyril [Auteur]
Breusegem, S Y. [Auteur]
Mathur, P P. [Auteur]
Jenardhanan, P. [Auteur]
Le Guennec, Kilan [Auteur]
Mukadam, A S. [Auteur]
Quenez, Olivier [Auteur]
Coutant, Sophie [Auteur]
Rousseau, Stéphane [Auteur]
Richard, Anne-Claire [Auteur]
Boland, Anne [Auteur]
Deleuze, Jean-François [Auteur]
Frebourg, Thierry [Auteur]
Hannequin, Didier [Auteur]
Campion, Dominique [Auteur]
Charbonnier, Camille [Auteur]
Wallon, David [Auteur]
Nicolas, Gael [Auteur]
Seaman, M N J. [Auteur]
Pottier, Cyril [Auteur]
Breusegem, S Y. [Auteur]
Mathur, P P. [Auteur]
Jenardhanan, P. [Auteur]
Le Guennec, Kilan [Auteur]
Mukadam, A S. [Auteur]
Quenez, Olivier [Auteur]
Coutant, Sophie [Auteur]
Rousseau, Stéphane [Auteur]
Richard, Anne-Claire [Auteur]
Boland, Anne [Auteur]
Deleuze, Jean-François [Auteur]
Frebourg, Thierry [Auteur]
Hannequin, Didier [Auteur]
Campion, Dominique [Auteur]
Titre de la revue :
Molecular psychiatry
Nom court de la revue :
Mol. Psychiatry
Numéro :
20
Pagination :
1046-56
Date de publication :
2015-09-01
ISSN :
1476-5578
Discipline(s) HAL :
Sciences du Vivant [q-bio]
Résumé en anglais : [en]
We hypothesized that de novo variants (DNV) might participate in the genetic determinism of sporadic early-onset Alzheimer disease (EOAD, onset before 65 years). We investigated 14 sporadic EOAD trios first by array-comparative ...
Lire la suite >We hypothesized that de novo variants (DNV) might participate in the genetic determinism of sporadic early-onset Alzheimer disease (EOAD, onset before 65 years). We investigated 14 sporadic EOAD trios first by array-comparative genomic hybridization. Two patients carried a de novo copy number variation (CNV). We then performed whole-exome sequencing in the 12 remaining trios and identified 12 non-synonymous DNVs in six patients. The two de novo CNVs (an amyloid precursor protein (APP) duplication and a BACE2 intronic deletion) and 3/12 non-synonymous DNVs (in PSEN1, VPS35 and MARK4) targeted genes from a biological network centered on the Amyloid beta (Aβ) peptide. We showed that this a priori-defined genetic network was significantly enriched in amino acid-altering DNV, compared with the rest of the exome. The causality of the APP de novo duplication (which is the first reported one) was obvious. In addition, we provided evidence of the functional impact of the following three non-synonymous DNVs targeting this network: the novel PSEN1 variant resulted in exon 9 skipping in patient's RNA, leading to a pathogenic missense at exons 8-10 junction; the VPS35 missense variant led to partial loss of retromer function, which may impact neuronal APP trafficking and Aβ secretion; and the MARK4 multiple nucleotide variant resulted into increased Tau phosphorylation, which may trigger enhanced Aβ-induced toxicity. Despite the difficulty to recruit Alzheimer disease (AD) trios owing to age structures of the pedigrees and the genetic heterogeneity of the disease, this strategy allowed us to highlight the role of de novo pathogenic events, the putative involvement of new genes in AD genetics and the key role of Aβ network alteration in AD.Lire moins >
Lire la suite >We hypothesized that de novo variants (DNV) might participate in the genetic determinism of sporadic early-onset Alzheimer disease (EOAD, onset before 65 years). We investigated 14 sporadic EOAD trios first by array-comparative genomic hybridization. Two patients carried a de novo copy number variation (CNV). We then performed whole-exome sequencing in the 12 remaining trios and identified 12 non-synonymous DNVs in six patients. The two de novo CNVs (an amyloid precursor protein (APP) duplication and a BACE2 intronic deletion) and 3/12 non-synonymous DNVs (in PSEN1, VPS35 and MARK4) targeted genes from a biological network centered on the Amyloid beta (Aβ) peptide. We showed that this a priori-defined genetic network was significantly enriched in amino acid-altering DNV, compared with the rest of the exome. The causality of the APP de novo duplication (which is the first reported one) was obvious. In addition, we provided evidence of the functional impact of the following three non-synonymous DNVs targeting this network: the novel PSEN1 variant resulted in exon 9 skipping in patient's RNA, leading to a pathogenic missense at exons 8-10 junction; the VPS35 missense variant led to partial loss of retromer function, which may impact neuronal APP trafficking and Aβ secretion; and the MARK4 multiple nucleotide variant resulted into increased Tau phosphorylation, which may trigger enhanced Aβ-induced toxicity. Despite the difficulty to recruit Alzheimer disease (AD) trios owing to age structures of the pedigrees and the genetic heterogeneity of the disease, this strategy allowed us to highlight the role of de novo pathogenic events, the putative involvement of new genes in AD genetics and the key role of Aβ network alteration in AD.Lire moins >
Langue :
Anglais
Audience :
Internationale
Vulgarisation :
Non
Établissement(s) :
CHU Lille
CNRS
Inserm
Université de Lille
CNRS
Inserm
Université de Lille
Collections :
Équipe(s) de recherche :
Troubles cognitifs dégénératifs et vasculaires
Date de dépôt :
2019-11-27T14:29:46Z