Detailed Phenotyping and Therapeutic Strategies for Intronic ABCA4 Variants in Stargardt Disease.
ABCA4
Stargardt disease
antisense oligonucleotides
iPSC
intronic mutations
organoids
photoreceptors
retina
splicing
stem cells
Journal
Molecular therapy. Nucleic acids
ISSN: 2162-2531
Titre abrégé: Mol Ther Nucleic Acids
Pays: United States
ID NLM: 101581621
Informations de publication
Date de publication:
04 Sep 2020
04 Sep 2020
Historique:
received:
06
03
2020
revised:
15
04
2020
accepted:
09
06
2020
pubmed:
13
7
2020
medline:
13
7
2020
entrez:
13
7
2020
Statut:
ppublish
Résumé
Stargardt disease is a progressive retinal disorder caused by bi-allelic mutations in the ABCA4 gene that encodes the ATP-binding cassette, subfamily A, member 4 transporter protein. Over the past few years, we and others have identified several pathogenic variants that reside within the introns of ABCA4, including a recurrent variant in intron 36 (c.5196+1137G>A) of which the pathogenicity so far remained controversial. Detailed clinical characterization of this variant confirmed its pathogenic nature, and classified it as an allele of intermediate severity. Moreover, we discovered several additional ABCA4 variants clustering in intron 36. Several of these variants resulted in aberrant splicing of ABCA4, i.e., the inclusion of pseudoexons, while the splicing defects caused by the recurrent c.5196+1137G>A variant strongly increased upon differentiation of patient-derived induced pluripotent stem cells into retina-like cells. Finally, all splicing defects could be rescued by the administration of antisense oligonucleotides that were designed to specifically block the pseudoexon insertion, including rescue in 3D retinal organoids harboring the c.5196+1137G>A variant. Our data illustrate the importance of intronic variants in ABCA4 and expand the therapeutic possibilities for overcoming splicing defects in Stargardt disease.
Identifiants
pubmed: 32653833
pii: S2162-2531(20)30168-2
doi: 10.1016/j.omtn.2020.06.007
pmc: PMC7352060
pii:
doi:
Types de publication
Journal Article
Langues
eng
Pagination
412-427Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Références
Cell Stem Cell. 2012 Jun 14;10(6):771-785
pubmed: 22704518
BMC Biol. 2009 May 14;7:23
pubmed: 19442261
Doc Ophthalmol. 2015 Feb;130(1):1-12
pubmed: 25502644
Science. 2004 Dec 3;306(5702):1796-9
pubmed: 15528407
Cell Stem Cell. 2016 Jun 2;18(6):769-781
pubmed: 27151457
Biochem Soc Trans. 2016 Oct 15;44(5):1245-1251
pubmed: 27911706
J Comput Biol. 1997 Fall;4(3):311-23
pubmed: 9278062
Annu Rev Biochem. 2015;84:291-323
pubmed: 25784052
Am J Hum Genet. 2017 Jan 5;100(1):75-90
pubmed: 28041643
Invest Ophthalmol Vis Sci. 2016 Nov 1;57(14):5963-5973
pubmed: 27820952
Curr Gene Ther. 2019;19(3):172-196
pubmed: 31566126
Hum Mutat. 2015 Jan;36(1):43-7
pubmed: 25363634
Methods Mol Biol. 2012;867:117-29
pubmed: 22454058
Nat Commun. 2012 Jun 26;3:925
pubmed: 22735453
Genes (Basel). 2019 Jun 14;10(6):
pubmed: 31197102
Nucleic Acids Res. 1987 Sep 11;15(17):7155-74
pubmed: 3658675
Invest Ophthalmol Vis Sci. 2019 Oct 1;60(13):4249-4256
pubmed: 31618761
Hum Mol Genet. 1998 Mar;7(3):355-62
pubmed: 9466990
J Comput Biol. 2004;11(2-3):377-94
pubmed: 15285897
Cold Spring Harb Mol Case Stud. 2018 Aug 1;4(4):
pubmed: 29848554
Cell. 2006 Aug 25;126(4):663-76
pubmed: 16904174
Curr Opin Ophthalmol. 2017 May;28(3):260-266
pubmed: 28151748
Hum Mol Genet. 2016 Jun 15;25(12):2552-2563
pubmed: 27106101
Hum Mutat. 2015 Jan;36(1):39-42
pubmed: 25346251
Hum Mutat. 2017 Apr;38(4):400-408
pubmed: 28044389
Mol Ther Nucleic Acids. 2018 Sep 7;12:730-740
pubmed: 30114557
Invest Ophthalmol Vis Sci. 2016 Sep 1;57(11):4668-78
pubmed: 27583828
Nat Methods. 2012 Jun 28;9(7):676-82
pubmed: 22743772
Genome Res. 2018 Jan;28(1):100-110
pubmed: 29162642
J Med Genet. 2017 Jun;54(6):404-412
pubmed: 28446513
Ophthalmology. 2016 Jun;123(6):1375-85
pubmed: 26976702
Nucleic Acids Res. 2001 Mar 1;29(5):1185-90
pubmed: 11222768
Invest Ophthalmol Vis Sci. 2018 Jul 2;59(8):3220-3231
pubmed: 29971439
Hum Mutat. 2003 Nov;22(5):395-403
pubmed: 14517951
Arch Ophthalmol. 2001 Mar;119(3):359-69
pubmed: 11231769
Hum Mol Genet. 2013 Dec 20;22(25):5136-45
pubmed: 23918662
Br J Ophthalmol. 2017 Jan;101(1):25-30
pubmed: 27491360
Int J Mol Sci. 2019 Oct 11;20(20):
pubmed: 31614660
Nucleic Acids Res. 2009 May;37(9):e67
pubmed: 19339519
Genet Med. 2019 Aug;21(8):1751-1760
pubmed: 30643219
Biochim Biophys Acta. 2012 Jul;1822(7):1169-79
pubmed: 22033104
F1000Res. 2014 Nov 18;3:282
pubmed: 25717368
Am J Hum Genet. 2018 Apr 5;102(4):517-527
pubmed: 29526278
Genet Med. 2019 Aug;21(8):1761-1771
pubmed: 30670881
Hum Mol Genet. 2014 Dec 20;23(25):6797-806
pubmed: 25082829
Methods Mol Biol. 2018;1715:61-78
pubmed: 29188506
Curr Opin Organ Transplant. 2011 Feb;16(1):96-100
pubmed: 21150614
Mol Ther. 2009 Mar;17(3):548-53
pubmed: 18813282
Nat Genet. 1997 Mar;15(3):236-46
pubmed: 9054934
Nat Med. 2019 Feb;25(2):225-228
pubmed: 30559420
Invest Ophthalmol Vis Sci. 2017 Jan 1;58(1):394-403
pubmed: 28118664