title: De novo deleterious genetic variations target a biological network centered on Aβ peptide in early-onset Alzheimer disease.
abstract: 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.
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.
authors.forename: A
authors.initials: A
authors.lastname: Rovelet-Lecrux
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.
authors.forename: C
authors.initials: C
authors.lastname: Charbonnier
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.|Department of Neurology, Rouen University Hospital, Rouen, France.
authors.forename: D
authors.initials: D
authors.lastname: Wallon
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.|Department of Genetics, Rouen University Hospital, Rouen, France.
authors.forename: G
authors.initials: G
authors.lastname: Nicolas
authors.affiliation: Cambridge Institute for Medical Research/Dept of Clinical Biochemistry, University of Cambridge, Addenbrookes Hospital, Cambridge, UK.
authors.forename: M N J
authors.initials: MN
authors.lastname: Seaman
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.
authors.forename: C
authors.initials: C
authors.lastname: Pottier
authors.affiliation: Cambridge Institute for Medical Research/Dept of Clinical Biochemistry, University of Cambridge, Addenbrookes Hospital, Cambridge, UK.
authors.forename: S Y
authors.initials: SY
authors.lastname: Breusegem
authors.affiliation: Centre of Bioinformatics and Department of Biochemistry & Molecular Biology, School of Life Sciences, Pondicherry University, Pondicherry, India.|KIIT University, Bhubaneshwar, Odisha, India.
authors.forename: P P
authors.initials: PP
authors.lastname: Mathur
authors.affiliation: Centre of Bioinformatics and Department of Biochemistry & Molecular Biology, School of Life Sciences, Pondicherry University, Pondicherry, India.
authors.forename: P
authors.initials: P
authors.lastname: Jenardhanan
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.
authors.forename: K
authors.initials: K
authors.lastname: Le Guennec
authors.affiliation: Cambridge Institute for Medical Research/Dept of Clinical Biochemistry, University of Cambridge, Addenbrookes Hospital, Cambridge, UK.
authors.forename: A S
authors.initials: AS
authors.lastname: Mukadam
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.
authors.forename: O
authors.initials: O
authors.lastname: Quenez
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.
authors.forename: S
authors.initials: S
authors.lastname: Coutant
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.
authors.forename: S
authors.initials: S
authors.lastname: Rousseau
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.
authors.forename: A-C
authors.initials: AC
authors.lastname: Richard
authors.affiliation: Centre National de Génotypage, Evry, France.
authors.forename: A
authors.initials: A
authors.lastname: Boland
authors.affiliation: Centre National de Génotypage, Evry, France.
authors.forename: J-F
authors.initials: JF
authors.lastname: Deleuze
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.|Department of Genetics, Rouen University Hospital, Rouen, France.
authors.forename: T
authors.initials: T
authors.lastname: Frebourg
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.|Department of Neurology, Rouen University Hospital, Rouen, France.|Department of Genetics, Rouen University Hospital, Rouen, France.
authors.forename: D
authors.initials: D
authors.lastname: Hannequin
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.|Department of Research, Centre Hospitalier du Rouvray, Sotteville-Les-Rouen, France.
authors.forename: D
authors.initials: D
authors.lastname: Campion
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics* / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D059472:Exome; D005260:Female; D053263:Gene Regulatory Networks; D006801:Humans; D008297:Male; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction; D010375:Pedigree; D053764:Presenilin-1 / Q000235:genetics
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D053764:Presenilin-1