Oligonucleotide correction of an intronic TIMMDC1 variant in cells of patients with severe neurodegenerative disorder
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Date
2022
Authors
Kumar, R.
Corbett, M.A.
Smith, N.J.C.
Hock, D.H.
Kikhtyak, Z.
Semcesen, L.N.
Morimoto, A.
Lee, S.
Stroud, D.A.
Gleeson, J.G.
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Journal article
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npj Genomic Medicine, 2022; 7(1):9-1-9-12
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Raman Kumar, Mark A. Corbett, Nicholas J. C. Smith, Daniella H. Hock, Zoya Kikhtyak, Liana N. Semcesen, Atsushi Morimoto, Sangmoon Lee, David A. Stroud, Joseph G. Gleeson, Eric A. Haan, and Jozef Gecz
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Abstract
TIMMDC1 encodes the Translocase of Inner Mitochondrial Membrane Domain-Containing protein 1 (TIMMDC1) subunit of complex I of the electron transport chain responsible for ATP production. We studied a consanguineous family with two affected children, now deceased, who presented with failure to thrive in the early postnatal period, poor feeding, hypotonia, peripheral neuropathy and drug-resistant epilepsy. Genome sequencing data revealed a known, deep intronic pathogenic variant TIMMDC1 c.597- 1340A>G, also present in gnomAD (~1/5000 frequency), that enhances aberrant splicing. Using RNA and protein analysis we show almost complete loss of TIMMDC1 protein and compromised mitochondrial complex I function. We have designed and applied two different splice-switching antisense oligonucleotides (SSO) to restore normal TIMMDC1 mRNA processing and protein levels in patients’ cells. Quantitative proteomics and real-time metabolic analysis of mitochondrial function on patient fibroblasts treated with SSOs showed restoration of complex I subunit abundance and function. SSO-mediated therapy of this inevitably fatal TIMMDC1 neurologic disorder is an attractive possibility.
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© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.