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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-017-1714-x) contains supplementary material, which is available to authorized users.

Weighted burden analysis of exome‐sequenced late‐onset Alzheimer's cases and controls provides further evidence for a role for PSEN1 and suggests involvement of the PI3K/Akt/GSK‐3β and WNT signalling pathways

“…The variants in TREM2 have been reported in a previous analysis of this dataset (Song et al., ). Likewise, deleterious mutations in ABCA7 are known to be risk factors for both early‐ and late‐onset AD (De Roeck et al., ). The variants in SORL1 at 11:121348842 (rs140888526), 11:121421313 (rs148430425), and 11:121421361 (rs146438170) have not previously been implicated in LOAD susceptibility and although the gene‐based SLP of 4.42 suggests that overall there is an excess of functionally significant variants among cases, the numbers are too small to draw any definitive conclusions about any of these variants individually.…”

Inflammation: the link between comorbidities, genetics, and Alzheimer’s disease

“…ABCA1, ABCA7, and ABCB1 (also known as P-glycoprotein) are members of the ABC family of transporters that are important for the clearance of Aβ, and hence, their loss of function results in the accumulation of plaques in the brain. ABCA7 is particularly relevant, as recent studies have shown that loss-of-function polymorphisms at its gene increase the risk for late- [ 75 ] and early-onset AD [ 76 ]. These transporters use the binding and hydrolysis of ATP to power the translocation of several substrates ranging from ions to macromolecules across membranes.…”

Weighted burden analysis of exome-sequenced late onset Alzheimer’s cases and controls provides further evidence for a role for PSEN1 and suggests involvement of the PI3K/Akt/GSK-3β and WNT signalling pathways

“…The variants in TREM2 have been reported in a previous analysis of this dataset (Song et al, 2017). Likewise, deleterious mutations in ABCA7 are known to be risk factors for both early and late onset Alzheimer's disease (De Roeck et al, 2017). The variants in SORL1 at 11:121348842 (rs140888526), 11:121421313 (rs148430425) and 11:121421361 (rs146438170) have not previously been implicated in LOAD susceptibility and although the gene-based SLP of 4.42 suggests that overall there is an excess of functionally significant variants among cases the numbers are too small to draw any definitive conclusions about any of these variants individually.…”