| Title: |
A recurrent COL6A1 pseudoexon insertion causes muscular dystrophy and is effectively targeted by splice-correction therapies |
| Authors: |
Bolduc, Véronique; Foley, A. Reghan, Reghan; Solomon-Degefa, Herimela; Sarathy, Apurva; Donkervoort, Sandra; Hu, Ying; Chen, Grace, S; Sizov, Katherine; Nalls, Matthew; Zhou, Haiyan; 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; Li, Yan; Gartioux, Corine; Mamchaoui, Kamel; Allamand, Valérie; Gualandi, Francesca; Ferlini, Alessandra; Hanssen, Eric; Wilton, Steve, D; Lamandé, Shireen, R; Macarthur, Daniel, G; Wagener, Raimund; Muntoni, Francesco; Bönnemann, Carsten, G |
| Contributors: |
National Institute of Neurological Disorders and Stroke Bethesda (NINDS); National Institutes of Health Bethesda, MD, USA (NIH); University of Cologne; Centre de recherche en Myologie – U974 SU-INSERM; Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU); Institut de Recherche Mathématique de Rennes (IRMAR); Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes); Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École normale supérieure - Rennes (ENS Rennes)-Université de Rennes 2 (UR2)-Centre National de la Recherche Scientifique (CNRS)-INSTITUT AGRO Agrocampus Ouest; Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro); Cardiac Unit, Institute of Child Health (UCL); University College of London London (UCL); Massachusetts General Hospital Boston; Broad Institute of MIT and Harvard (BROAD INSTITUTE); Harvard Medical School Boston (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital Boston; New York University New York (NYU); NYU System (NYU); Chaim Sheba Medical Center; School of Medicine University of Utah, Salt Lake City; University of Utah; Hospital Sant Joan de Déu Barcelona; Università degli Studi di Ferrara = University of Ferrara (UniFE); University of Melbourne; Murdoch University Perth; Murdoch Children's Research Institute (MCRI); ANR-11-LABX-0020,LEBESGUE,Centre de Mathématiques Henri Lebesgue : fondements, interactions, applications et Formation(2011) |
| Source: |
ISSN: 2379-3708 ; JCI Insight ; https://hal.sorbonne-universite.fr/hal-03285227 ; JCI Insight, 2019, 4 (6), ⟨10.1172/jci.insight.124403⟩. |
| Publisher Information: |
HAL CCSD; American Society for Clinical Investigation |
| Publication Year: |
2019 |
| Collection: |
Université de Rennes 1: Publications scientifiques (HAL) |
| Subject Terms: |
[SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] |
| Description: |
International audience ; 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 a1(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 splicemodulating 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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1172/jci.insight.124403 |
| Availability: |
https://hal.sorbonne-universite.fr/hal-03285227; https://hal.sorbonne-universite.fr/hal-03285227/document; https://hal.sorbonne-universite.fr/hal-03285227/file/Bolduc%20et%20al.%20-%20A%20recurrent%20COL6A1%20pseudoexon%20insertion%20causes%20mus.pdf; https://doi.org/10.1172/jci.insight.124403 |
| Rights: |
info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.8AA4DE11 |
| Database: |
BASE |