Van Haute, Lindsey ORCID: 0000-0001-7809-1473, O’Connor, Emily, Díaz-Maldonado, Héctor, Munro, Benjamin, Polavarapu, Kiran ORCID: 0000-0002-8879-6001, Hock, Daniella H ORCID: 0000-0002-6940-4420, Arunachal, Gautham, Athanasiou-Fragkouli, Alkyoni, Bardhan, Mainak ORCID: 0000-0002-4106-409X, Barth, Magalie, Bonneau, Dominique, Brunetti-Pierri, Nicola ORCID: 0000-0002-6895-8819, Cappuccio, Gerarda, Caruana, Nikeisha ORCID: 0000-0002-0817-1686, Dominik, Natalia, Goel, Himanshu, Helman, Guy ORCID: 0000-0002-4784-7423, Houlden, Henry ORCID: 0000-0002-2866-7777, Lenaers, Guy ORCID: 0000-0003-2736-3349, Mention, Karine, Murphy, David, Nandeesh, Bevinahalli, Olimpio, Catarina, Powell, Christopher A, Preethish-Kumar, Veeramani, Procaccio, Vincent, Rius, Rocio ORCID: 0000-0002-9871-3126, Rebelo-Guiomar, Pedro ORCID: 0000-0002-5060-7519, Simons, Cas ORCID: 0000-0003-3147-8042, Vengalil, Seena ORCID: 0000-0002-0629-9221, Zaki, Maha S ORCID: 0000-0001-7840-0002, Ziegler, Alban, Thorburn, David ORCID: 0000-0002-7725-9470, Stroud, David A ORCID: 0000-0002-2048-3383, Maroofian, Reza, Christodoulou, John ORCID: 0000-0002-8431-0641, Gustafsson, Claes ORCID: 0000-0003-3531-8468, Nalini, Atchayaram, Lochmüller, Hanns, Minczuk, Michal ORCID: 0000-0001-8242-1420 and Horvath, Rita ORCID: 0000-0002-9841-170X (2023) TEFM variants impair mitochondrial transcription causing childhood-onset neurological disease. Nature Communications, 14. ISSN 2041-1723

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.

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