Title | Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Hsu S, Pimenova AA, Hayes K, Villa JA, Rosene MJ, Jere M, Goate AM, Karch CM |
Journal | Neurobiol Dis |
Volume | 139 |
Pagination | 104817 |
Date Published | 2020 06 |
ISSN | 1095-953X |
Keywords | Alzheimer Disease, Amyloid beta-Protein Precursor, Humans, Mutation, Presenilin-1, Presenilin-2 |
Abstract | Alzheimer's disease (AD) is a neurodegenerative disease that is clinically characterized by progressive cognitive decline. More than 200 pathogenic mutations have been identified in amyloid-β precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2). Additionally, common and rare variants occur within APP, PSEN1, and PSEN2 that may be risk factors, protective factors, or benign, non-pathogenic polymorphisms. Yet, to date, no single study has carefully examined the effect of all of the variants of unknown significance reported in APP, PSEN1 and PSEN2 on Aβ isoform levels in vitro. In this study, we analyzed Aβ isoform levels by ELISA in a cell-based system in which each reported pathogenic and risk variant in APP, PSEN1, and PSEN2 was expressed individually. In order to classify variants for which limited family history data is available, we have implemented an algorithm for determining pathogenicity using available information from multiple domains, including genetic, bioinformatic, and in vitro analyses. We identified 90 variants of unknown significance and classified 19 as likely pathogenic mutations. We also propose that five variants are possibly protective. In defining a subset of these variants as pathogenic, individuals from these families may eligible to enroll in observational studies and clinical trials. |
DOI | 10.1016/j.nbd.2020.104817 |
Pubmed Link | https://www.ncbi.nlm.nih.gov/pubmed/32087291?dopt=Abstract |
page_expo | External |
Alternate Journal | Neurobiol Dis |
PubMed ID | 32087291 |
PubMed Central ID | PMC7236786 |
Grant List | P30 AG066444 / AG / NIA NIH HHS / United States U01 AG058922 / AG / NIA NIH HHS / United States RF1 AG054011 / AG / NIA NIH HHS / United States UF1 AG032438 / AG / NIA NIH HHS / United States RF1 AG044546 / AG / NIA NIH HHS / United States U19 AG032438 / AG / NIA NIH HHS / United States U01 AG052411 / AG / NIA NIH HHS / United States RF1 AG053303 / AG / NIA NIH HHS / United States P01 AG003991 / AG / NIA NIH HHS / United States P50 AG005681 / AG / NIA NIH HHS / United States |
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