title: Screening exons 16 and 17 of the amyloid precursor protein gene in sporadic early-onset Alzheimer's disease.
abstract: Early-onset Alzheimer's disease (EOAD) can be familial (FAD) or sporadic EOAD (sEOAD); both have a disease onset ≤65 years of age. A total of 451 sEOAD samples were screened for known causative mutations in exons 16 and 17 of the amyloid precursor protein (APP) gene. Four samples were shown to be heterozygous for 1 of 3 known causative mutations: p.A713T, p.V717I, and p.V717G; this highlights the importance of screening EOAD patients for causative mutations. Additionally, we document an intronic 6 base pair (bp) deletion located 83 bp downstream of exon 17 (rs367709245, IVS17 83-88delAAGTAT), which has a nonsignificantly increased minor allele frequency in our sEOAD cohort (0.006) compared to LOAD (0.002) and controls (0.002). To assess the effect of the 6-bp deletion on splicing, COS-7 and BE(2)-C cells were transfected with a minigene vector encompassing exon 17. There was no change in splicing of exon 17 from constructs containing either wild type or deletion inserts. Sequencing of cDNA generated from cerebellum and temporal cortex of a patient harboring the deletion found no evidence of transcripts with exon 17 removed.
authors.affiliation: Schools of Life Sciences and Medicine, Human Genetics, University of Nottingham, Nottingham, UK.
authors.forename: Imelda S
authors.initials: IS
authors.lastname: Barber
authors.affiliation: Schools of Life Sciences and Medicine, Human Genetics, University of Nottingham, Nottingham, UK.
authors.forename: Jennyfer M
authors.initials: JM
authors.lastname: García-Cárdenas
authors.affiliation: Schools of Life Sciences and Medicine, Human Genetics, University of Nottingham, Nottingham, UK.
authors.forename: Chidchanok
authors.initials: C
authors.lastname: Sakdapanichkul
authors.affiliation: Schools of Life Sciences and Medicine, Human Genetics, University of Nottingham, Nottingham, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Deacon
authors.affiliation: Schools of Life Sciences and Medicine, Human Genetics, University of Nottingham, Nottingham, UK.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Zapata Erazo
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.
authors.forename: Rita
authors.initials: R
authors.lastname: Guerreiro
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.
authors.forename: Jose
authors.initials: J
authors.lastname: Bras
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Dena
authors.initials: D
authors.lastname: Hernandez
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Singleton
authors.affiliation: Schools of Life Sciences and Medicine, Human Genetics, University of Nottingham, Nottingham, UK.
authors.forename: Tamar
authors.initials: T
authors.lastname: Guetta-Baranes
authors.affiliation: Schools of Life Sciences and Medicine, Human Genetics, University of Nottingham, Nottingham, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Braae
authors.affiliation: Schools of Life Sciences and Medicine, Human Genetics, University of Nottingham, Nottingham, UK.
authors.forename: Naomi
authors.initials: N
authors.lastname: Clement
authors.affiliation: Schools of Life Sciences and Medicine, Human Genetics, University of Nottingham, Nottingham, UK.
authors.forename: Tulsi
authors.initials: T
authors.lastname: Patel
authors.affiliation: Schools of Life Sciences and Medicine, Human Genetics, University of Nottingham, Nottingham, UK.
authors.forename: Keeley
authors.initials: K
authors.lastname: Brookes
authors.affiliation: Schools of Life Sciences and Medicine, Human Genetics, University of Nottingham, Nottingham, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Medway
authors.affiliation: Schools of Life Sciences and Medicine, Human Genetics, University of Nottingham, Nottingham, UK.
authors.forename: Sally
authors.initials: S
authors.lastname: Chappell
authors.affiliation: Clinical and Cognitive Sciences Research Group, Faculty of Medical and Human Sciences, Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, UK.
authors.forename: David M
authors.initials: DM
authors.lastname: Mann
authors.affiliation: Schools of Life Sciences and Medicine, Human Genetics, University of Nottingham, Nottingham, UK. Electronic address: kevin.morgan@nottingham.ac.uk.
authors.forename: Kevin
authors.initials: K
authors.lastname: Morgan
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D020029:Base Pairing / Q000235:genetics; D015331:Cohort Studies; D005091:Exons / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D005787:Gene Frequency; D056726:Genetic Association Studies; D005820:Genetic Testing; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017422:Sequence Analysis, DNA
chemical_list: D016564:Amyloid beta-Protein Precursor
keywords: APP; Alzheimer's disease; Early-onset; Screening; Sporadic; rs367709245