Mutation in the 3'untranslated region of APP as a genetic determinant of cerebral amyloid angiopathy

Eur J Hum Genet. 2016 Jan;24(1):92-8. doi: 10.1038/ejhg.2015.61. Epub 2015 Apr 1.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Adult
  • Age of Onset
  • Amyloid beta-Protein Precursor / genetics*
  • Amyloid beta-Protein Precursor / metabolism
  • Base Sequence*
  • Binding Sites
  • Cerebral Amyloid Angiopathy / genetics*
  • Cerebral Amyloid Angiopathy / metabolism
  • Cerebral Amyloid Angiopathy / pathology
  • Computational Biology
  • Female
  • Gene Expression Regulation
  • Humans
  • Male
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Middle Aged
  • Molecular Sequence Data
  • Nucleic Acid Conformation
  • Sequence Analysis, DNA
  • Sequence Deletion*


  • 3' Untranslated Regions
  • APP protein, human
  • Amyloid beta-Protein Precursor
  • MIRN582 microRNA, human
  • MIRN892 microRNA, human
  • MicroRNAs