Bolduc, Veronique, Foley, A. Reghan, Solomon-Degefa, Herimela, Sarathy, Apurva, Donkervoort, Sandra, Hu, Ying, Chen, Grace S., Sizov, Katherine, Nalls, Matthew, Zhou, Haiyan ORCID: 0000-0001-8440-3074, Aguti, Sara, Cummings, Beryl B., Lek, Monkol, Tukiainen, Taru, Marshall, Jamie L., Regev, Oded, Marek-Yagel, Dina, Sarkozy, Anna, Butterfield, Russell J., Jou, Cristina, Jimenez-Mallebrera, Cecilia ORCID: 0000-0001-8203-7103, Li, Yan, Gartioux, Corine, Mamchaoui, Kamel, Allamand, Valerie, Gualandi, Francesca, Ferlini, Alessandra, Hanssen, Eric ORCID: 0000-0002-4064-1844, Wilton, Steve D., Lamande, Shireen R., MacArthur, Daniel G., Wagener, Raimund, Muntoni, Francesco and Bonnemann, Carsten G. (2019). A recurrent COL6A1 pseudoexon insertion causes muscular dystrophy and is effectively targeted by splice-correction therapies. JCI Insight, 4 (6). ANN ARBOR: AMER SOC CLINICAL INVESTIGATION INC. ISSN 2379-3708

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Abstract

The clinical application of advanced next-generation sequencing technologies is increasingly uncovering novel classes of mutations that may serve as potential targets for precision medicine therapeutics. Here, we show that a deep intronic splice defect in the COL6A1 gene, originally discovered by applying muscle RNA sequencing in patients with clinical findings of collagen VI-related dystrophy (COLE-RD), inserts an in-frame pseudoexon into COL6A1 mRNA, encodes a mutant collagen alpha 1(VI) protein that exerts a dominant-negative effect on collagen VI matrix assembly, and provides a unique opportunity for splice-correction approaches aimed at restoring normal gene expression. Using splice-modulating antisense oligomers, we efficiently skipped the pseudoexon in patient-derived fibroblast cultures and restored a wild-type matrix. Similarly, we used CRISPR/Cas9 to precisely delete an intronic sequence containing the pseudoexon and efficiently abolish its inclusion while preserving wild-type splicing. Considering that this splice defect is emerging as one of the single most frequent mutations in COL6-RD, the design of specific and effective splice-correction therapies offers a promising path for clinical translation.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Bolduc, VeroniqueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Foley, A. ReghanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Solomon-Degefa, HerimelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sarathy, ApurvaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Donkervoort, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hu, YingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, Grace S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sizov, KatherineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nalls, MatthewUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhou, HaiyanUNSPECIFIEDorcid.org/0000-0001-8440-3074UNSPECIFIED
Aguti, SaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cummings, Beryl B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lek, MonkolUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tukiainen, TaruUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marshall, Jamie L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Regev, OdedUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marek-Yagel, DinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sarkozy, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Butterfield, Russell J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jou, CristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jimenez-Mallebrera, CeciliaUNSPECIFIEDorcid.org/0000-0001-8203-7103UNSPECIFIED
Li, YanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gartioux, CorineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mamchaoui, KamelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Allamand, ValerieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gualandi, FrancescaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ferlini, AlessandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hanssen, EricUNSPECIFIEDorcid.org/0000-0002-4064-1844UNSPECIFIED
Wilton, Steve D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lamande, Shireen R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
MacArthur, Daniel G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wagener, RaimundUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muntoni, FrancescoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bonnemann, Carsten G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-153486
DOI: 10.1172/jci.insight.124403
Journal or Publication Title: JCI Insight
Volume: 4
Number: 6
Date: 2019
Publisher: AMER SOC CLINICAL INVESTIGATION INC
Place of Publication: ANN ARBOR
ISSN: 2379-3708
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
COLLAGEN-VI; ANTISENSE OLIGONUCLEOTIDES; MOUSE MODEL; MATRIX DEPOSITION; NATURAL-HISTORY; IN-VITRO; MUSCLE; ULLRICH; MUTATIONS; GENEMultiple languages
Medicine, Research & ExperimentalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/15348

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