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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11110%2F17%3A10364317" target="_blank" >RIV/00216208:11110/17:10364317 - isvavai.cz</a>

Alternative codes found

RIV/00216208:11120/17:43913371 RIV/00064190:_____/17:N0000020

Result on the web

<a href="http://dx.doi.org/10.1007/s00401-017-1714-x" target="_blank" >http://dx.doi.org/10.1007/s00401-017-1714-x</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1007/s00401-017-1714-x" target="_blank" >10.1007/s00401-017-1714-x</a>

Result language

angličtina

Original language name

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

Original language description

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&apos;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.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

30109 - Pathology

Project

—

Continuities

V - Vyzkumna aktivita podporovana z jinych verejnych zdroju

Publication year

2017

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Acta Neuropathologica

ISSN

0001-6322

e-ISSN

—

Volume of the periodical

134

Issue of the periodical within the volume

3

Country of publishing house

DE - GERMANY

Number of pages

13

Pages from-to

475-487

UT code for WoS article

000407931900009

EID of the result in the Scopus database

2-s2.0-85018272631