Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/119823
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Type: Journal article
Title: Alternative splicing in a presenilin 2 variant associated with Alzheimer disease
Author: Braggin, J.
Bucks, S.
Course, M.
Smith, C.
Sopher, B.
Osnis, L.
Shuey, K.
Domoto-Reilly, K.
Caso, C.
Kinoshita, C.
Scherpelz, K.
Cross, C.
Grabowski, T.
Nik, S.H.
Newman, M.
Garden, G.
Leverenz, J.
Tsuang, D.
Latimer, C.
Gonzalez-Cuyar, L.
et al.
Citation: Annals of Clinical and Translational Neurology, 2019; 6(4):762-777
Publisher: Wiley
Issue Date: 2019
ISSN: 2328-9503
2328-9503
Statement of
Responsibility: 
Jacquelyn E. Braggin, Stephanie A. Bucks, Meredith M. Course, Carole L. Smith, Bryce Sopher, Leah Osnis, Kiel D. Shuey, Kimiko Domoto-Reilly, Christina Caso, Chizuru Kinoshita, Kathryn P. Scherpelz, Chloe Cross, Thomas Grabowski, Seyyed H.M. Nik, Morgan Newman, Gwenn A. Garden, James B. Leverenz, Debby Tsuang, Caitlin Latimer, Luis F. Gonzalez-Cuyar, Christopher Dirk Keene, Richard S. Morrison, Kristoffer Rhoads, Ellen M. Wijsman, Michael O. Dorschner, Michael Lardelli, Jessica E. Young, Paul N. Valdmanis, Thomas D. Bird, Suman Jayadev
Abstract: Objective: Autosomal-dominant familial Alzheimer disease (AD) is caused by by variants in presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP). Previously, we reported a rare PSEN2 frameshift variant in an early-onset AD case (PSEN2 p.K115Efs*11). In this study, we characterize a second family with the same variant and analyze cellular transcripts from both patient fibroblasts and brain lysates. Methods: We combined genomic, neuropathological, clinical, and molecular techniques to characterize the PSEN2 K115Efs*11 variant in two families. Results: Neuropathological and clinical evaluation confirmed the AD diagnosis in two individuals carrying the PSEN2 K115Efs*11 variant. A truncated transcript from the variant allele is detectable in patient fibroblasts while levels of wild-type PSEN2 transcript and protein are reduced compared to controls. Functional studies to assess biological consequences of the variant demonstrated that PSEN2 K115Efs*11 fibroblasts secrete less Aβ₁-₄₀ compared to controls, indicating abnormal γ-secretase activity. Analysis of PSEN2 transcript levels in brain tissue revealed alternatively spliced PSEN2 products in patient brain as well as in sporadic AD and age-matched control brain. Interpretation: These data suggest that PSEN2 K115Efs*11 is a likely pathogenic variant associated with AD. We uncovered novel PSEN2 alternative transcripts in addition to previously reported PSEN2 splice isoforms associated with sporadic AD. In the context of a frameshift, these alternative transcripts return to the canonical reading frame with potential to generate deleterious protein products. Our findings suggest novel potential mechanisms by which PSEN variants may influence AD pathogenesis, highlighting the complexity underlying genetic contribution to disease risk.
Keywords: Humans; Alzheimer Disease; Peptide Fragments; Amyloid beta-Protein Precursor; Alternative Splicing; Mutation; Adult; Middle Aged; Male; Amyloid Precursor Protein Secretases; Presenilin-1; Presenilin-2; Amyloid beta-Peptides
Rights: © 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
RMID: 0030113885
DOI: 10.1002/acn3.755
Grant ID: http://purl.org/au-research/grants/nhmrc/1126422
Appears in Collections:Molecular and Biomedical Science publications

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