TEFM variants impair mitochondrial transcription causing childhood-onset neurological disease

Lindsey 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 () and Rita Horvath ()
Additional contact information
Lindsey Haute: University of Cambridge
Emily O’Connor: University of Ottawa
Héctor Díaz-Maldonado: University of Gothenburg
Benjamin Munro: University of Cambridge
Kiran Polavarapu: University of Ottawa
Daniella H. Hock: University of Melbourne
Gautham Arunachal: National Institute of Mental Health and Neurosciences
Alkyoni Athanasiou-Fragkouli: University College London
Mainak Bardhan: National Institute of Mental Health and Neurosciences
Magalie Barth: Mitovasc INSERM 1083, CNRS 6015, University Hospital of Angers
Dominique Bonneau: Mitovasc INSERM 1083, CNRS 6015, University Hospital of Angers
Nicola Brunetti-Pierri: University of Naples Federico II
Gerarda Cappuccio: University of Naples Federico II
Nikeisha J. Caruana: University of Melbourne
Natalia Dominik: University College London
Himanshu Goel: University of Newcastle
Guy Helman: Murdoch Children’s Research Institute
Henry Houlden: University College London
Guy Lenaers: Mitovasc INSERM 1083, CNRS 6015, University Hospital of Angers
Karine Mention: Hôpital Jeanne de Flandre
David Murphy: University College London
Bevinahalli Nandeesh: National Institute of Mental Health and Neurosciences
Catarina Olimpio: University of Cambridge
Christopher A. Powell: University of Cambridge
Veeramani Preethish-Kumar: National Institute of Mental Health and Neurosciences
Vincent Procaccio: Mitovasc INSERM 1083, CNRS 6015, University Hospital of Angers
Rocio Rius: Murdoch Children’s Research Institute
Pedro Rebelo-Guiomar: University of Cambridge
Cas Simons: Murdoch Children’s Research Institute
Seena Vengalil: National Institute of Mental Health and Neurosciences
Maha S. Zaki: National Research Centre
Alban Ziegler: Mitovasc INSERM 1083, CNRS 6015, University Hospital of Angers
David R. Thorburn: Murdoch Children’s Research Institute
David A. Stroud: University of Melbourne
Reza Maroofian: University College London
John Christodoulou: Murdoch Children’s Research Institute
Claes Gustafsson: University of Gothenburg
Atchayaram Nalini: National Institute of Mental Health and Neurosciences
Hanns Lochmüller: University of Ottawa
Michal Minczuk: University of Cambridge
Rita Horvath: University of Cambridge

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-36277-7

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