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Open Access 01-09-2017 | Original Paper

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

Authors: Arne De Roeck, Tobi Van den Bossche, Julie van der Zee, Jan Verheijen, Wouter De Coster, Jasper Van Dongen, Lubina Dillen, Yalda Baradaran-Heravi, Bavo Heeman, Raquel Sanchez-Valle, Albert Lladó, Benedetta Nacmias, Sandro Sorbi, Ellen Gelpi, Oriol Grau-Rivera, Estrella Gómez-Tortosa, Pau Pastor, Sara Ortega-Cubero, Maria A. Pastor, Caroline Graff, Håkan Thonberg, Luisa Benussi, Roberta Ghidoni, Giuliano Binetti, Alexandre de Mendonça, Madalena Martins, Barbara Borroni, Alessandro Padovani, Maria Rosário Almeida, Isabel Santana, Janine Diehl-Schmid, Panagiotis Alexopoulos, Jordi Clarimon, Alberto Lleó, Juan Fortea, Magda Tsolaki, Maria Koutroumani, Radoslav Matěj, Zdenek Rohan, Peter De Deyn, Sebastiaan Engelborghs, Patrick Cras, Christine Van Broeckhoven, Kristel Sleegers, On behalf of the European Early-Onset Dementia (EU EOD) consortium

Published in: Acta Neuropathologica | Issue 3/2017

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.

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Allen M, Lincoln SJ, Corda M, Watzlawik JO, Carrasquillo MM, Reddy JS et al (2017) ABCA7 loss-of-function variants, expression, and neurologic disease risk. Neurol Genet 3:e126. doi:10.1212/NXG.0000000000000126 CrossRefPubMedPubMedCentral

Allen M, Zou F, Chai HS, Younkin CS, Crook J, Pankratz VS et al (2012) Novel late-onset Alzheimer disease loci variants associate with brain gene expression. Neurology 79:221–228. doi:10.1212/WNL.0b013e3182605801 CrossRefPubMedPubMedCentral

Aronesty E (2011) ea-utils: Command-line tools for processing biological sequencing data. In: Expression analysis, Durham, NC. https://github.com/ExpressionAnalysis/ea-utils

Barbosa-Morais NL, Irimia M, Pan Q, Xiong HY, Gueroussov S, Lee LJ et al (2012) The evolutionary landscape of alternative splicing in vertebrate species. Science 338:1587–1593. doi:10.1126/science.1230612 CrossRefPubMed

Bidou L, Allamand V, Rousset JP, Namy O (2012) Sense from nonsense: therapies for premature stop codon diseases. Trends Mol Med 18:679–688. doi:10.1016/j.molmed.2012.09.008 CrossRefPubMed

Bolger AM, Lohse M, Usadel B (2014) Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 30:2114–2120. doi:10.1093/bioinformatics/btu170 CrossRefPubMedPubMedCentral

Van den Bossche T, Sleegers K, Cuyvers E, Engelborghs S, Sieben A, De Roeck A et al (2016) Phenotypic characteristics of Alzheimer patients carrying an ABCA7 mutation. Neurology 86:2126–2133. doi:10.1212/WNL.0000000000002628 CrossRefPubMedPubMedCentral

Cacace R, Sleegers K, Van Broeckhoven C (2016) Molecular genetics of early-onset Alzheimer disease revisited. Alzheimers Dement 12:733–748. doi:10.1016/j.jalz.2016.01.012 CrossRefPubMed

Cingolani P, Platts A, Wang LL, Coon M, Nguyen T, Wang L et al (2012) A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff. Fly (Austin) 6:80–92. doi:10.4161/fly.19695 CrossRef

10.

Cukier HN, Kunkle BW, Vardarajan BN, Rolati S, Hamilton-Nelson KL, Kohli MA et al (2016) ABCA7 frameshift deletion associated with Alzheimer disease in African Americans. Neurol Genet 2:e79. doi:10.1212/NXG.0000000000000079 CrossRefPubMedPubMedCentral

11.

Cuyvers E, De Roeck A, Van den Bossche T, Van Cauwenberghe C, Bettens K, Vermeulen S et al (2015) Mutations in ABCA7 in a Belgian cohort of Alzheimer’s disease patients: a targeted resequencing study. Lancet Neurol 14:814–822. doi:10.1016/S1474-4422(15)00133-7 CrossRefPubMed

12.

Cuyvers E, Sleegers K (2016) Genetic variations underlying Alzheimer’s disease: evidence from genome-wide association studies and beyond. Lancet Neurol 15:857–868. doi:10.1016/S1474-4422(16)00127-7 CrossRefPubMed

13.

Del-Aguila JL, Fernández MV, Jimenez J, Black K, Ma S, Deming Y et al (2015) Role of ABCA7 loss-of-function variant in Alzheimer’s disease: a replication study in European-Americans. Alzheimers Res Ther 7:73. doi:10.1186/s13195-015-0154-x CrossRefPubMedPubMedCentral

14.

Douglas AGL, Wood MJA (2013) Splicing therapy for neuromuscular disease. Mol Cell Neurosci 56:169–185. doi:10.1016/j.mcn.2013.04.005 CrossRefPubMedPubMedCentral

15.

Fu Y, Hsiao J-HT, Paxinos G, Halliday GM, Kim WS (2016) ABCA7 mediates phagocytic clearance of amyloid-β in the brain. J Alzheimers Dis 54:569–584. doi:10.3233/JAD-160456 CrossRefPubMed

16.

Le Guennec K, Nicolas G, Quenez O, Charbonnier C, Wallon D, Bellenguez C et al (2016) ABCA7 rare variants and Alzheimer disease risk. Neurology 86:2134–2137. doi:10.1212/WNL.0000000000002627 CrossRefPubMedPubMedCentral

17.

Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML et al (2009) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet 41:1088–1093. doi:10.1038/ng.440 CrossRefPubMedPubMedCentral

18.

Hollingworth P, Harold D, Sims R, Gerrish A, Lambert J-C, Carrasquillo MM et al (2011) Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Genet 43:429–435. doi:10.1038/ng.803 CrossRefPubMedPubMedCentral

19.

Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC et al (2012) National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement 8:1–13. doi:10.1016/j.jalz.2011.10.007 CrossRefPubMedPubMedCentral

20.

Iwamoto N, Abe-Dohmae S, Sato R, Yokoyama S (2006) ABCA7 expression is regulated by cellular cholesterol through the SREBP2 pathway and associated with phagocytosis. J Lipid Res 47:1915–1927. doi:10.1194/jlr.M600127-JLR200 CrossRefPubMed

21.

Jehle AW, Gardai SJ, Li S, Linsel-Nitschke P, Morimoto K, Janssen WJ et al (2006) ATP-binding cassette transporter A7 enhances phagocytosis of apoptotic cells and associated ERK signaling in macrophages. J Cell Biol 174:547–556. doi:10.1083/jcb.200601030 CrossRefPubMedPubMedCentral

22.

Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg SL (2013) TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol 14:R36. doi:10.1186/gb-2013-14-4-r36 CrossRefPubMedPubMedCentral

23.

Kim WS, Li H, Ruberu K, Chan S, Elliott DA, Low JK et al (2013) Deletion of Abca7 increases cerebral amyloid-β accumulation in the J20 mouse model of Alzheimer’s disease. J Neurosci 33:4387–4394. doi:10.1523/JNEUROSCI.4165-12.2013 CrossRefPubMed

24.

Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J (2014) A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 46:310–315. doi:10.1038/ng.2892 CrossRefPubMedPubMedCentral

25.

Krzywinski M, Schein J, Birol I, Connors J, Gascoyne R, Horsman D et al (2009) Circos: an information aesthetic for comparative genomics. Genome Res 19:1639–1645. doi:10.1101/gr.092759.109 CrossRefPubMedPubMedCentral

26.

Lambert J-C, Heath S, Even G, Campion D, Sleegers K, Hiltunen M et al (2009) Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet 41:1094–1099. doi:10.1038/ng.439 CrossRefPubMed

27.

Lambert J-C, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C et al (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 45:1452–1458. doi:10.1038/ng.2802 CrossRefPubMedPubMedCentral

28.

Laver TW, Caswell RC, Moore KA, Poschmann J, Johnson MB, Owens MM et al (2016) Pitfalls of haplotype phasing from amplicon-based long-read sequencing. Nat Publ Gr. doi:10.1038/srep21746

29.

Lee S (2015) MetaSKAT: Meta analysis for SNP-Set (sequence) Kernel Association Test

30.

Li H, Durbin R (2010) Fast and accurate long-read alignment with Burrows–Wheeler transform. Bioinformatics 26:589–595. doi:10.1093/bioinformatics/btp698 CrossRefPubMedPubMedCentral

31.

Li H, Karl T, Garner B (2015) Understanding the function of ABCA7 in Alzheimer’s disease. Biochem Soc Trans 43:920–923. doi:10.1042/BST20150105 CrossRefPubMed

32.

Linsel-Nitschke P, Jehle AW, Shan J, Cao G, Bacic D, Lan D et al (2005) Potential role of ABCA7 in cellular lipid efflux to apoA-I. J Lipid Res 46:86–92. doi:10.1194/jlr.M400247-JLR200 CrossRefPubMed

33.

Loman N, Quinlan A (2014) Poretools: a toolkit for analyzing nanopore sequence data. Bioinformatics. doi:10.1101/007401 PubMedPubMedCentral

34.

McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:939–944CrossRefPubMed

35.

McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas CH et al (2011) The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:263–269. doi:10.1016/j.jalz.2011.03.005 CrossRefPubMedPubMedCentral

36.

Morgan M, Pagès H, Obenchain V and Hayden N (2017) Rsamtools: Binary alignment (BAM), FASTA, variant call (BCF), and tabix file import. R package version 1.26.2. http://bioconductor.org/packages/release/bioc/html/Rsamtools.html

37.

Naj AC, Jun G, Beecham GW, Wang L, Vardarajan BN, Buros J et al (2011) Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat Genet 43:436–441. doi:10.1038/ng.801 CrossRefPubMedPubMedCentral

38.

Nyholt DR (2004) A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am J Hum Genet 74:765–769. doi:10.1086/383251 CrossRefPubMedPubMedCentral

39.

Oikonomopoulos S, Wang YC, Djambazian H, Badescu D, Ragoussis J (2016) Benchmarking of the Oxford Nanopore MinION sequencing for quantitative and qualitative assessment of cDNA populations. Sci Rep 6:31602. doi:10.1038/srep31602 CrossRefPubMedPubMedCentral

40.

Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D et al (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575. doi:10.1086/519795 CrossRefPubMedPubMedCentral

41.

Reitz C, Jun G, Naj A, Rajbhandary R, Vardarajan BN, Wang L-S et al (2013) Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E e4, and the risk of late-onset Alzheimer disease in African Americans. JAMA 309:1483–1492. doi:10.1001/jama.2013.2973 CrossRefPubMedPubMedCentral

42.

Reumers J, De Rijk P, Zhao H, Liekens A, Smeets D, Cleary J et al (2012) Optimized filtering reduces the error rate in detecting genomic variants by short-read sequencing. Nat Biotechnol 30:61–68. doi:10.1038/nbt.2053 CrossRef

43.

Sakae N, Liu C-C, Shinohara M, Frisch-Daiello J, Ma L, Yamazaki Y et al (2016) ABCA7 deficiency accelerates amyloid-beta generation and Alzheimer’s neuronal pathology. J Neurosci 36:3848–3859. doi:10.1523/JNEUROSCI.3757-15.2016 CrossRefPubMedPubMedCentral

44.

Sassi C, Nalls MA, Ridge PG, Gibbs JR, Ding J, Lupton MK et al (2016) ABCA7 p. G215S as potential protective factor for Alzheimer’s disease. Neurobiol Aging 46:235.e1–235.e9. doi:10.1016/j.neurobiolaging.2016.04.004 CrossRef

45.

Satoh K, Abe-Dohmae S, Yokoyama S, St. George-Hyslop P, Fraser PE (2015) ATP-binding cassette transporter A7 (ABCA7) loss of function alters Alzheimer amyloid processing. J Biol Chem 290:24152–24165. doi:10.1074/jbc.M115.655076 CrossRefPubMedPubMedCentral

46.

Seshadri S, Fitzpatrick AL, Ikram MA, DeStefano AL, Gudnason V, Boada M et al (2010) Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA 303:1832–1840. doi:10.1001/jama.2010.574 CrossRefPubMedPubMedCentral

47.

Steinberg S, Stefansson H, Jonsson T, Johannsdottir H, Ingason A, Helgason H et al (2015) Loss-of-function variants in ABCA7 confer risk of Alzheimer’s disease. Nat Genet 47:445–447. doi:10.1038/ng.3246 CrossRefPubMed

48.

Tanaka N, Abe-Dohmae S, Iwamoto N, Yokoyama S (2011) Roles of ATP-binding cassette transporter A7 in cholesterol homeostasis and host defense system. J Atheroscler Thromb 18:274–281CrossRefPubMed

49.

Vardarajan BN, Ghani M, Kahn A, Sheikh S, Sato C, Barral S et al (2015) Rare coding mutations identified by sequencing of Alzheimer disease genome-wide association studies loci. Ann Neurol 78:487–498. doi:10.1002/ana.24466 CrossRefPubMedPubMedCentral

50.

Vasquez JB, Fardo DW, Estus S (2013) ABCA7 expression is associated with Alzheimer’s disease polymorphism and disease status. Neurosci Lett 556:58–62. doi:10.1016/j.neulet.2013.09.058 CrossRefPubMed

51.

Verheijen J, Van den Bossche T, van der Zee J, Engelborghs S, Sanchez-Valle R, Lladó A et al (2016) A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer’s disease. Acta Neuropathol 132:213–224. doi:10.1007/s00401-016-1566-9 CrossRefPubMedPubMedCentral

52.

Weckx S, Del-Favero J, Rademakers R, Claes L, Cruts M, De Jonghe P et al (2005) novoSNP, a novel computational tool for sequence variation discovery. Genome Res 15:436–442CrossRefPubMedPubMedCentral

53.

Wu TD, Watanabe CK (2005) GMAP: a genomic mapping and alignment program for mRNA and EST sequences. Bioinformatics 21:1859–1875. doi:10.1093/bioinformatics/bti310 CrossRefPubMed

54.

Zetoune AB, Fontanière S, Magnin D, Anczuków O, Buisson M, Zhang CX et al (2008) Comparison of nonsense-mediated mRNA decay efficiency in various murine tissues. BMC Genet 9:83. doi:10.1186/1471-2156-9-83 CrossRefPubMedPubMedCentral

Title: Deleterious ABCA7 mutations and transcript rescue mechanisms in early onset Alzheimer’s disease
Authors: Arne De Roeck
Tobi Van den Bossche
Julie van der Zee
Jan Verheijen
Wouter De Coster
Jasper Van Dongen
Lubina Dillen
Yalda Baradaran-Heravi
Bavo Heeman
Raquel Sanchez-Valle
Albert Lladó
Benedetta Nacmias
Sandro Sorbi
Ellen Gelpi
Oriol Grau-Rivera
Estrella Gómez-Tortosa
Pau Pastor
Sara Ortega-Cubero
Maria A. Pastor
Caroline Graff
Håkan Thonberg
Luisa Benussi
Roberta Ghidoni
Giuliano Binetti
Alexandre de Mendonça
Madalena Martins
Barbara Borroni
Alessandro Padovani
Maria Rosário Almeida
Isabel Santana
Janine Diehl-Schmid
Panagiotis Alexopoulos
Jordi Clarimon
Alberto Lleó
Juan Fortea
Magda Tsolaki
Maria Koutroumani
Radoslav Matěj
Zdenek Rohan
Peter De Deyn
Sebastiaan Engelborghs
Patrick Cras
Christine Van Broeckhoven
Kristel Sleegers
On behalf of the European Early-Onset Dementia (EU EOD) consortium
Publication date: 01-09-2017
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 3/2017
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-017-1714-x

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Springer Medicine

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

Abstract

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Springer Medicine

Abstract

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