TEFM variants impair mitochondrial transcription causing childhood-onset neurological disease

L Van Haute; E O’Connor; H Díaz-Maldonado; B Munro; K Polavarapu; DH Hock; G Arunachal; A Athanasiou-Fragkouli; M Bardhan; M Barth; D Bonneau; N Brunetti-Pierri; G Cappuccio; NJ Caruana; N Dominik; H Goel; G Helman; H Houlden; G Lenaers; K Mention; D Murphy; B Nandeesh; C Olimpio; CA Powell; V Preethish-Kumar; V Procaccio; R Rius; P Rebelo-Guiomar; C Simons; S Vengalil; MS Zaki; A Ziegler; DR Thorburn; DA Stroud; R Maroofian; J Christodoulou; C Gustafsson; A Nalini; H Lochmüller; M Minczuk; R Horvath

Journal article

TEFM variants impair mitochondrial transcription causing childhood-onset neurological disease

L Van Haute, E O’Connor, H Díaz-Maldonado, B Munro, K Polavarapu, DH Hock, G Arunachal, A Athanasiou-Fragkouli, M Bardhan, M Barth, D Bonneau, N Brunetti-Pierri, G Cappuccio, NJ Caruana, N Dominik, H Goel, G Helman, H Houlden, G Lenaers, K Mention Show all

Nature Communications | NATURE PORTFOLIO | Published : 2023

DOI: 10.1038/s41467-023-36277-7

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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, ..

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University of Melbourne Researchers

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Rocio Rius Author

David Thorburn Author

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Funding Acknowledgements

L.V.H, P.R-G., C.A.P and M.M. were supported by Medical Research Council, UK (MC_UU_00015/4). H.L. receives support from the Canadian Institutes of Health Research (Foundation Grant FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C), the Canada Foundation for Innovation (CFI-JELF 38412), and the Canada Research Chairs programme (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279). E.O. is supported by an AFM-Telethon postdoctoral fellowship. CMG receives support from the Swedish Research Council (2017-01257), the Swedish Cancer Foundation (2017-631), the Knut and Alice Wallenberg Foundation, and grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement (ALFGBG-728151). R.H. is a Wellcome Trust Investigator (109915/Z/15/Z), who receives support from the Medical Research Council (UK) (MR/N025431/1 and MR/V009346/1), the European Research Council (309548), the Newton Fund (UK/Turkey, MR/N027302/1), the Addenbrookes Charitable Trust (G100142), Evelyn Trust, Lily Foundation, Stoneygate Fund and an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The study was further supported by the Horizon 2020 research and innovation programme via grant 779257 "Solve-RD". Data were analysed using the RD-Connect Genome-Phenome Analysis Platform developed under FP7/2007-2013 funded project (grant agreement no 305444) and funding from European Joint Programme in Rare Disease (EJP-RD) and INB/ELIXIR-ES. This research was also supported by a New South Wales Office of Health and Medical Research Council Sydney Genomics Collaborative grant (J.C.), NHMRC project grants (1026891 to J.C., 1140906 to D.A.S. and 1164479 to D.R.T, J.C. and D.A.S.), and NHMRC research fellowships (1102896 to D.R.T. and 1140851 to D.A.S.). We are grateful to the Crane and Perkins families for their generous financial support. The research conducted at the Murdoch Children's Research Institute was supported by the Victorian Government's Operational Infrastructure Support Program. We thank the Kinghorn Centre for Clinical Genomics for assistance with production and processing of genome sequencing data. The Chair in Genomic Medicine awarded to J.C. is generously supported by The Royal Children's Hospital Foundation. D.H.H. is supported by the Melbourne Research Scholarship and the Mito Foundation top-up Scholarship. G.H. is supported by the Ochsner MD-PhD Scholarship. We thank the Bio21 Mass Spectrometry and Proteomics Facility (MMSPF) for the provision of instrumentation, training, and technical support, and the Mito Foundation for the provision of instrumentation through the large equipment grant support scheme. This study was supported by Telethon Foundation, Telethon Undiagnosed Diseases Program (TUDP, GSP15001). This study was in part generated within the European Reference Network ITHACA and EURO-NMD. MedGenome Labs Ltd, Bangalore is acknowledged for Sanger sequencing of parental samples.