TEFM variants impair mitochondrial transcription causing childhood-onset neurological disease
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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Item type | Article |
URI | https://vuir.vu.edu.au/id/eprint/47445 |
DOI | 10.1038/s41467-023-36277-7 |
Official URL | https://www.nature.com/articles/s41467-023-36277-7 |
Subjects | Current > FOR (2020) Classification > 3101 Biochemistry and cell biology Current > FOR (2020) Classification > 3205 Medical biochemistry and metabolomics Current > Division/Research > Institute for Health and Sport |
Keywords | TEFM; mitochondrial respiratory chain deficiency; mitochondrial myopathy; mitochondrial transcription elongation; Zebrafish |
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