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.

A non-coding variant in the 5ʹ UTR of DLG3 attenuates protein translation to cause non-syndromic intellectual disability

“…16,17 Variants in these elements, particularly those effecting 5ʹ and 3ʹ UTR mRNA secondary structures have been linked to disease. [17][18][19][20] Taken together, our combined genetic, experimental and modelling evidence suggests that NC_000023.10:g.69665044dupG variant alters SAP102 protein abundance, which is the most plausible cause of moderate non-syndromic ID this family.…”

Increased serum microRNAs are closely associated with the presence of microvascular complications in type 2 diabetes mellitus

“…Only one study has demonstrated the role of miR-770-5p, and bioinformatic analysis revealed that it likely contributed to apoptosis and hippocampal signaling pathways and was involved in the molecular mechanisms underlying temporal lobe epilepsy memory disorders 28 . Like miR-770-5p, recent study suggested that miR-892b was correlated with retinopathy and neurological diseases 29 30 . These results suggest that this miRNA is a potential contributor to diabetic neuropathy and retinopathy.…”

APP mouse models for Alzheimer's disease preclinical studies

“…Absence of non‐coding regions of the App gene precludes the analysis of splicing of APP mRNA and transcriptional regulation involving these gene regions (Nicolas et al , 2016). …”