A recurrent COL6A1 pseudoexon insertion causes muscular dystrophy and is effectively targeted by splice-correction therapies

V Bolduc; A.R. Foley; H. Solomon-Degefa; A. Sarathy; S. Donkervoort; Y. Hu; G.S. Chen; K. Sizov; M. Nalls; H. Zhou; S. Aguti; B.B. Cummings; M. Lek; T. Tukiainen; J.L. Marshall; O. Regev; D. Marek-Yagel; A. Sarkozy; R.J. Butterfield; C. Jou; C. Jimenez-Mallebrera; Y. Li; C. Gartioux; K. Mamchaoui; V. Allamand; F. Gualandi; A. Ferlini; E. Hanssen; S.D. Wilton; S.R. Lamandé; D.G. MacArthur; R. Wagener; F. Muntoni; C.G. Bönnemann

doi:10.1172/jci.insight.124403

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A recurrent COL6A1 pseudoexon insertion causes muscular dystrophy and is effectively targeted by splice-correction therapies

Journal article

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A recurrent COL6A1 pseudoexon insertion causes muscular dystrophy and is effectively targeted by splice-correction therapies

V Bolduc, A.R. Foley, H. Solomon-Degefa, A. Sarathy, S. Donkervoort, Y. Hu, G.S. Chen, K. Sizov, M. Nalls, H. Zhou, …

JCI Insight, Vol.4(6), art. no. e124403

2019

DOI: https://doi.org/10.1172/jci.insight.124403

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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 (COL6-RD), inserts an in-frame pseudoexon into COL6A1 mRNA, encodes a mutant collagen α1(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.

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Title: A recurrent COL6A1 pseudoexon insertion causes muscular dystrophy and is effectively targeted by splice-correction therapies
Authors/Creators: V Bolduc (Author/Creator) - National Institute of Neurological Disorders and Stroke
A.R. Foley (Author/Creator) - National Institute of Neurological Disorders and Stroke
H. Solomon-Degefa (Author/Creator) - University of Cologne
A. Sarathy (Author/Creator) - National Institute of Neurological Disorders and Stroke
S. Donkervoort (Author/Creator) - National Institute of Neurological Disorders and Stroke
Y. Hu (Author/Creator) - National Institute of Neurological Disorders and Stroke
G.S. Chen (Author/Creator) - National Institute of Neurological Disorders and Stroke
K. Sizov (Author/Creator) - National Institute of Neurological Disorders and Stroke
M. Nalls (Author/Creator) - National Institute of Neurological Disorders and Stroke
H. Zhou (Author/Creator) - UCL Institute of Child Health
S. Aguti (Author/Creator) - UCL Institute of Child Health
B.B. Cummings (Author/Creator) - Massachusetts General Hospital
M. Lek (Author/Creator) - Massachusetts General Hospital
T. Tukiainen (Author/Creator) - Massachusetts General Hospital
J.L. Marshall (Author/Creator) - Broad Institute
O. Regev (Author/Creator) - Courant Institute of Mathematical Sciences
D. Marek-Yagel (Author/Creator) - Edmond and Lily Safra Children's Hospital
A. Sarkozy (Author/Creator) - UCL Institute of Child Health
R.J. Butterfield (Author/Creator) - University of Utah
C. Jou (Author/Creator) - Hospital Sant Joan de Déu Barcelona
C. Jimenez-Mallebrera (Author/Creator) - Hospital Sant Joan de Déu Barcelona
Y. Li (Author/Creator) - National Institute of Neurological Disorders and Stroke
C. Gartioux (Author/Creator) - Inserm
K. Mamchaoui (Author/Creator) - Inserm
V. Allamand (Author/Creator) - Inserm
F. Gualandi (Author/Creator) - University of Ferrara
A. Ferlini (Author/Creator) - University of Ferrara
E. Hanssen (Author/Creator) - The University of Melbourne
S.D. Wilton (Author/Creator) - Murdoch University
S.R. Lamandé (Author/Creator) - The University of Melbourne
D.G. MacArthur (Author/Creator) - Massachusetts General Hospital
R. Wagener (Author/Creator) - University of Cologne
F. Muntoni (Author/Creator) - Great Ormond Street Hospital
C.G. Bönnemann (Author/Creator) - National Institute of Neurological Disorders and Stroke
Publication Details: JCI Insight, Vol.4(6), art. no. e124403
Publisher: American Society for Clinical Investigation
Identifiers: 991005542456707891
Copyright: © 2019 American Society for Clinical Investigation
Murdoch Affiliation: Murdoch University
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.255 Musculoskeletal Disorders; 1.255.628 Duchenne Muscular Dystrophy
Web Of Science research areas: Medicine, Research & Experimental
ESI research areas: Clinical Medicine