1. TEFM variants impair mitochondrial transcription causing childhood-onset neurological disease
- Author
-
Lindsey Van Haute, Emily O’Connor, Héctor Díaz-Maldonado, Benjamin Munro, Kiran Polavarapu, Daniella H. Hock, Gautham Arunachal, Alkyoni Athanasiou-Fragkouli, Mainak Bardhan, Magalie Barth, Dominique Bonneau, Nicola Brunetti-Pierri, Gerarda Cappuccio, Nikeisha J. Caruana, Natalia Dominik, Himanshu Goel, Guy Helman, Henry Houlden, Guy Lenaers, Karine Mention, David Murphy, Bevinahalli Nandeesh, Catarina Olimpio, Christopher A. Powell, Veeramani Preethish-Kumar, Vincent Procaccio, Rocio Rius, Pedro Rebelo-Guiomar, Cas Simons, Seena Vengalil, Maha S. Zaki, Alban Ziegler, David R. Thorburn, David A. Stroud, Reza Maroofian, John Christodoulou, Claes Gustafsson, Atchayaram Nalini, Hanns Lochmüller, Michal Minczuk, Rita Horvath, Van Haute, Lindsey [0000-0001-7809-1473], Polavarapu, Kiran [0000-0002-8879-6001], Hock, Daniella H [0000-0002-6940-4420], Bardhan, Mainak [0000-0002-4106-409X], Brunetti-Pierri, Nicola [0000-0002-6895-8819], Caruana, Nikeisha J [0000-0002-0817-1686], Helman, Guy [0000-0002-4784-7423], Houlden, Henry [0000-0002-2866-7777], Lenaers, Guy [0000-0003-2736-3349], Rius, Rocio [0000-0002-9871-3126], Rebelo-Guiomar, Pedro [0000-0002-5060-7519], Simons, Cas [0000-0003-3147-8042], Vengalil, Seena [0000-0002-0629-9221], Zaki, Maha S [0000-0001-7840-0002], Thorburn, David R [0000-0002-7725-9470], Stroud, David A [0000-0002-2048-3383], Christodoulou, John [0000-0002-8431-0641], Gustafsson, Claes [0000-0003-3531-8468], Minczuk, Michal [0000-0001-8242-1420], Horvath, Rita [0000-0002-9841-170X], Apollo - University of Cambridge Repository, Van Haute, Lindsey, O'Connor, Emily, Díaz-Maldonado, Héctor, Munro, Benjamin, Polavarapu, Kiran, Hock, Daniella H, Arunachal, Gautham, Athanasiou-Fragkouli, Alkyoni, Bardhan, Mainak, Barth, Magalie, Bonneau, Dominique, Brunetti-Pierri, Nicola, Cappuccio, Gerarda, Caruana, Nikeisha J, Dominik, Natalia, Goel, Himanshu, Helman, Guy, Houlden, Henry, Lenaers, Guy, Mention, Karine, Murphy, David, Nandeesh, Bevinahalli, Olimpio, Catarina, Powell, Christopher A, Preethish-Kumar, Veeramani, Procaccio, Vincent, Rius, Rocio, Rebelo-Guiomar, Pedro, Simons, Ca, Vengalil, Seena, Zaki, Maha S, Ziegler, Alban, Thorburn, David R, Stroud, David A, Maroofian, Reza, Christodoulou, John, Gustafsson, Clae, Nalini, Atchayaram, Lochmüller, Hann, Minczuk, Michal, and Horvath, Rita
- Subjects
Transcription, Genetic ,RNA, Mitochondrial ,General Physics and Astronomy ,38/90 ,13/106 ,692/1807/1693 ,14 ,DNA, Mitochondrial ,General Biochemistry, Genetics and Molecular Biology ,38 ,38/91 ,82/80 ,Mitochondrial Proteins ,38/1 ,692/420/2489/144 ,692/617/375/374 ,38/23 ,38/22 ,Animals ,Humans ,Child ,Zebrafish ,64 ,Multidisciplinary ,64/116 ,692/308/2056 ,article ,General Chemistry ,13/51 ,Mutation ,38/77 ,692/700/139/422 ,Transcription Factors - Abstract
Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): 309548, Funder: Lily Mae Foundation; doi: https://doi.org/10.13039/100012336, Mutations in the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA biology. The TEFM gene encodes the mitochondrial transcription elongation factor responsible for enhancing the processivity of mitochondrial RNA polymerase, POLRMT. We report for the first time that TEFM variants are associated with mitochondrial respiratory chain deficiency and a wide range of clinical presentations including mitochondrial myopathy with a treatable neuromuscular transmission defect. Mechanistically, we show muscle and primary fibroblasts from the affected individuals have reduced levels of promoter distal mitochondrial RNA transcripts. Finally, tefm knockdown in zebrafish embryos resulted in neuromuscular junction abnormalities and abnormal mitochondrial function, strengthening the genotype-phenotype correlation. Our study highlights that TEFM regulates mitochondrial transcription elongation and its defect results in variable, tissue-specific neurological and neuromuscular symptoms.
- Published
- 2023
- Full Text
- View/download PDF