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

Bolduc, V, Foley, A.R., Solomon-Degefa, H., Sarathy, A., Donkervoort, S., Hu, Y., Chen, G.S., Sizov, K., Nalls, M., Zhou, H., Aguti, S., Cummings, B.B., Lek, M., Tukiainen, T., Marshall, J.L., Regev, O., Marek-Yagel, D., Sarkozy, A., Butterfield, R.J., Jou, C., Jimenez-Mallebrera, C., Li, Y., Gartioux, C., Mamchaoui, K., Allamand, V., Gualandi, F., Ferlini, A., Hanssen, E., Wilton, S.D., Lamandé, S.R., MacArthur, D.G., Wagener, R., Muntoni, F. and Bönnemann, C.G. (2019) A recurrent COL6A1 pseudoexon insertion causes muscular dystrophy and is effectively targeted by splice-correction therapies. JCI Insight, 4 (6). art. no. e124403.

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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.

Item Type: Journal Article
Publisher: American Society for Clinical Investigation
Copyright: © 2019 American Society for Clinical Investigation
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