Deleterious ABCA7 mutations and transcript rescue mechanisms in early onset Alzheimer’s disease

Abstract: Premature termination codon (PTC) mutations in the ATP-Binding Cassette, Sub-Family A, Member 7 gene (ABCA7) have recently been identified as intermediate-to-high penetrant risk factor for late-onset Alzheimer's disease (LOAD). High variability, however, is observed in downstream ABCA7 mRNA and protein expression, disease penetrance, and onset age, indicative of unknown modifying factors. Here, we investigated the prevalence and disease penetrance of ABCA7 PTC mutations in a large early onset AD (EOAD)-control cohort, and examined the effect on transcript level with comprehensive third-generation long-read sequencing. We characterized the ABCA7 coding sequence with next-generation sequencing in 928 EOAD patients and 980 matched control individuals. With MetaSKAT rare variant association analysis, we observed a fivefold enrichment (p = 0.0004) of PTC mutations in EOAD patients (3%) versus controls (0.6%). Ten novel PTC mutations were only observed in patients, and PTC mutation carriers in general had an increased familial AD load. In addition, we observed nominal risk reducing trends for three common coding variants. Seven PTC mutations were further analyzed using targeted long-read cDNA sequencing on an Oxford Nanopore MinION platform. PTC-containing transcripts for each investigated PTC mutation were observed at varying proportion (5-41% of the total read count), implying incomplete nonsense-mediated mRNA decay (NMD). Furthermore, we distinguished and phased several previously unknown alternative splicing events (up to 30% of transcripts). In conjunction with PTC mutations, several of these novel ABCA7 isoforms have the potential to rescue deleterious PTC effects. In conclusion, ABCA7 PTC mutations play a substantial role in EOAD, warranting genetic screening of ABCA7 in genetically unexplained patients. Long-read cDNA sequencing revealed both varying degrees of NMD and transcript-modifying events, which may influence ABCA7 dosage, disease severity, and may create opportunities for therapeutic interventions in AD

The Bristol CMIP6 Data Hackathon

This is the final version. Available on open access from Wiley via the DOI in this recordThe Bristol CMIP6 Data Hackathon formed part of the Met Office Climate Data Challenge Hackathon series during 2021, bringing together around 100 UK early career researchers from a wide range of environmental disciplines. The purpose was to interrogate the under-utilised but currently most advanced climate model inter-comparison project datasets to develop new research ideas, create new networks and outreach opportunities in the lead up to COP26. Experts in different science fields, supported by a core team of scientists and data specialists at Bristol, had the unique opportunity to explore together interdisciplinary environmental topics summarised in this article

G018 Evaluation of IKr blocking properties of different molecules with or without torsadogenic properties

Currently, industrials and regulatory authorities are worried by Torsades de Pointes (TdP), a type of ventricular tachycardia, which can lead to sudden death. The most recent guidelines from the International Committee of Harmonization, recommend to assess properly the risk of TdP, by different approaches, among others an in vitro method. This method consists on studying the blockade of a voltage-dependant potassium channel, called hERG. Indeed, hERG channel, responsible for the IKr current, seems to be blocked by the majority of the torsadogenic molecules and, is thus considered as an important marker of pro arrhythmic risk.CERB developed a bio-computerized database named TdPScreen® to predict the risk of TdP. Known molecules are classified according to their pro arrhythmic potential, from group A to C. The group A corresponds to drugs with numerous or several reports of TdP, the group B to compounds causing QT prolongation with TdP at very low frequency; and in group C to drugs with no report of TdP or QT prolongation. This database suggests that other factors than a single blockade of IKr could be involved in the genesis of druginduced TdP.We performed experiments in patch-clamp using HEK cells expressing stably the hERG channel. Different compounds from the different groups, above mentioned, were evaluated for their IKr blocking potency and compared to the TdPScreen® database.Results show some torsadogenic drugs might exhibit very low IKr blocking properties (e.g. D-sotalol), whereas other non-torsadogenic drugs are potent IKr inhibitors (e.g. verapamil, diltiazem…).These results, and others, indicate that drugs can block hERG current without any influence on TdP appearance.We conclude that assessing pro arrhythmic potential of compounds, only on the blocking effects of IKr, in vitro, can lead to the eviction of interesting molecules