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Acta Neuropathol. 2017 Sep;134(3):475-487. doi: 10.1007/s00401-017-1714-x. Epub 2017 Apr 27.

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

Author information

1
Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
2
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
3
Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
4
Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium.
5
Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Department, Hospital Clínic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
6
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy.
7
IRCCS Don Gnocchi, Florence, Italy.
8
Neurological Tissue Bank of the Biobanc, Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
9
Department of Neurology, Fundación Jiménez Díaz, Madrid, Spain.
10
Memory Unit, Department of Neurology, University Hospital Mútua de Terrassa, University of Barcelona School of Medicine, Terrassa, Barcelona, Spain.
11
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
12
Neuroimaging Laboratory, Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
13
Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain.
14
Department of Neurobiology, Care Sciences and Society (NVS), Division of Neurogeriatrics, Center for Alzheimer Research, Karolinska Institutet, Huddinge, Stockholm, Sweden.
15
Genetics Unit, Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden.
16
Molecular Markers Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy.
17
MAC Memory Center, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy.
18
Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
19
Neurology Unit, Department of Clinical and Experimental Sciences, Centre for Neurodegenerative Disorders, University of Brescia, Brescia, Italy.
20
Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
21
Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany.
22
Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
23
3rd Department of Neurology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.
24
Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki, Greece.
25
Department of Pathology, First Medical Faculty, Charles University, Prague, Czech Republic.
26
Department of Pathology and Molecular Medicine, Thomayer Hospital, Prague, Czech Republic.
27
Institute of Pathology, Third Medical Faculty, Charles University, Prague, Czech Republic.
28
Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium. christine.vanbroeckhoven@molgen.vib-ua.be.
29
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. christine.vanbroeckhoven@molgen.vib-ua.be.
30
Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium. kristel.sleegers@molgen.vib-ua.be.
31
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. kristel.sleegers@molgen.vib-ua.be.

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.

KEYWORDS:

ATP-Binding Cassette; Early Onset Alzheimer’s disease; Loss-of-function; Member 7 (ABCA7); Modifier; RNA sequencing; Sub-Family A; Third-generation long-read sequencing

PMID:
28447221
PMCID:
PMC5563332
DOI:
10.1007/s00401-017-1714-x
[Indexed for MEDLINE]
Free PMC Article

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