title: 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.
authors.affiliation: INSERM U1079, University of Rouen, Normandy Univ, Institute for Research and Innovation in Biomedicine, Rouen, France.|Rouen University Hospital, Department of Genetics, Rouen, France.|CNR-MAJ, Rouen, France.
authors.forename: Gaël
authors.initials: G
authors.lastname: Nicolas
authors.affiliation: INSERM U1079, University of Rouen, Normandy Univ, Institute for Research and Innovation in Biomedicine, Rouen, France.|CNR-MAJ, Rouen, France.|Rouen University Hospital, Department of Neurology, Rouen, France.
authors.forename: David
authors.initials: D
authors.lastname: Wallon
authors.affiliation: Centre de Recherche du CHU de Québec, CHUL, Axe Neurosciences, Québec, QC, Canada.|Département de Psychiatrie et de Neurosciences, Faculté de Médecine, Université Laval, Québec, Canada.
authors.forename: Claudia
authors.initials: C
authors.lastname: Goupil
authors.affiliation: INSERM U1079, University of Rouen, Normandy Univ, Institute for Research and Innovation in Biomedicine, Rouen, France.
authors.forename: Anne-Claire
authors.initials: AC
authors.lastname: Richard
authors.affiliation: INSERM U1079, University of Rouen, Normandy Univ, Institute for Research and Innovation in Biomedicine, Rouen, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Pottier
authors.affiliation: Centre de Recherche du CHU de Québec, CHUL, Axe Neurosciences, Québec, QC, Canada.|Département de Psychiatrie et de Neurosciences, Faculté de Médecine, Université Laval, Québec, Canada.
authors.forename: Véronique
authors.initials: V
authors.lastname: Dorval
authors.affiliation: Department of Neurology, Bicêtre Hospital, Kremlin-Bicêtre, France.
authors.forename: Mariana
authors.initials: M
authors.lastname: Sarov-Rivière
authors.affiliation: AP-HP, Service de Génétique Moléculaire Neurovasculaire, Hôpital Lariboisière, Paris, France.|INSERM, U1161, Université Paris 7, Diderot, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Riant
authors.affiliation: Department of Neurology, Lariboisiere Hospital, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Hervé
authors.affiliation: UMR1167 Inserm, Lille, France.|Université de Lille, Lille, France.|Institut Pasteur de Lille, Lille, France.|Lille University Hospital, Lille, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Amouyel
authors.affiliation: INSERM, UMR 1094, Tropical Neuroepidemiology, Limoges, France.|Université de Limoges, School of Medicine, Institute of Neuroepidemiology and Tropical Neurology, Limoges, France.
authors.forename: Maelenn
authors.initials: M
authors.lastname: Guerchet
authors.affiliation: Department of Neurology, Amitiés Hospital, Bangui, Central African Republic.
authors.forename: Bebene
authors.initials: B
authors.lastname: Ndamba-Bandzouzi
authors.affiliation: INSERM, UMR 1094, Tropical Neuroepidemiology, Limoges, France.|Université de Limoges, School of Medicine, Institute of Neuroepidemiology and Tropical Neurology, Limoges, France.|Department of Neurology, Brazzaville University Hospital, Brazzaville, Republic of Congo.
authors.forename: Pascal
authors.initials: P
authors.lastname: Mbelesso
authors.affiliation: INSERM, U897, Victor Salengro Bordeaux II University, Bordeaux, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dartigues
authors.affiliation: UMR1167 Inserm, Lille, France.|Université de Lille, Lille, France.|Institut Pasteur de Lille, Lille, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Lambert
authors.affiliation: INSERM, UMR 1094, Tropical Neuroepidemiology, Limoges, France.|Université de Limoges, School of Medicine, Institute of Neuroepidemiology and Tropical Neurology, Limoges, France.|CHU, Department of Medical Information & Evaluation, Clinical Research and Biostatistic Unit, Limoges, France.
authors.forename: Pierre-Marie
authors.initials: PM
authors.lastname: Preux
authors.affiliation: INSERM U1079, University of Rouen, Normandy Univ, Institute for Research and Innovation in Biomedicine, Rouen, France.|Rouen University Hospital, Department of Genetics, Rouen, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Frebourg
authors.affiliation: INSERM U1079, University of Rouen, Normandy Univ, Institute for Research and Innovation in Biomedicine, Rouen, France.|CNR-MAJ, Rouen, France.|Department of Research, Rouvray Psychiatric Hospital, Sotteville-lès-Rouen, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Campion
authors.affiliation: INSERM U1079, University of Rouen, Normandy Univ, Institute for Research and Innovation in Biomedicine, Rouen, France.|Rouen University Hospital, Department of Genetics, Rouen, France.|CNR-MAJ, Rouen, France.|Rouen University Hospital, Department of Neurology, Rouen, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Hannequin
authors.affiliation: AP-HP, Service de Génétique Moléculaire Neurovasculaire, Hôpital Lariboisière, Paris, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Tournier-Lasserve
authors.affiliation: Centre de Recherche du CHU de Québec, CHUL, Axe Neurosciences, Québec, QC, Canada.|Département de Psychiatrie et de Neurosciences, Faculté de Médecine, Université Laval, Québec, Canada.
authors.forename: Sébastien S
authors.initials: SS
authors.lastname: Hébert
authors.affiliation: INSERM U1079, University of Rouen, Normandy Univ, Institute for Research and Innovation in Biomedicine, Rouen, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Rovelet-Lecrux
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D017668:Age of Onset; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019295:Computational Biology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion
chemical_list: D020413:3' Untranslated Regions; C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; C000593706:MIRN582 microRNA, human; C574666:MIRN892 microRNA, human; D035683:MicroRNAs
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