Journal article
A recurrent COL6A1 pseudoexon insertion causes muscular dystrophy and is effectively targeted by splice-correction therapies
V Bolduc, A Reghan Foley, H Solomon-Degefa, A Sarathy, S Donkervoort, Y Hu, GS Chen, K Sizov, M Nalls, H Zhou, S Aguti, BB Cummings, M Lek, T Tukiainen, JL Marshall, O Regev, D Marek-Yagel, A Sarkozy, RJ Butterfield, C Jou Show all
Jci Insight | AMER SOC CLINICAL INVESTIGATION INC | Published : 2019
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-modulati..
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Awarded by Horizon 2020 Framework Programme
Funding Acknowledgements
The authors thank Mon-Li Chu for providing the collagen VI antibody, Dragan Maric for sharing his expertise in fluorescence-activated cell sorting, and Gina Norato for reviewing the statistical analyses. This study was supported by National Institute of Neurological Disorders and Stroke intramural funds to CGB (1ZIANS003129-08), and by the German Research Council (CRC 829-B2, FOR 2722-B1) to RW. We acknowledge contributing funding and support from CureCMD and Muscular Dystrophy UK. VB is the recipient of a Canadian Institutes of Health Research Fellowship, a Fonds de Recherche Quebec - Sante Fellowship, and of a Muscular Dystrophy Association Development Grant (MDA513460). FM is supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. FM gratefully acknowledges the support of the Centre for Neuromuscular Disease Biobank, and of the Muscular Dystrophy UK. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. CJM is funded by the Plan Nacional de I+D+ I and Instituto de Salud Carlos III Subdireccion General de Evaluacion y Fomento de la Investigacion Sanitaria (projects PI16/PI16/00579 and CP09/00011 to CJM), and the European Regional Development Fund (FEDER, A way to make Europe). CJM is indebted to the "Biobanc de l'Hospital Infantil Sant Joan de Deu per a la Investigacio" integrated in the Spanish Biobank Network of ISCIII for the sample and data procurement. DGM was supported by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung and Blood Institute grant UM1 HG008900. See supplemental material for the COL6A1 Intron 11 Study Group consortium details.