Journal Article

TEFM variants impair mitochondrial transcription causing childhood-onset neurological disease

Rebelo-Guiomar, Pedro, Vengalil, Seena, Gustafsson, Claes, Caruana, Nikeisha J., Stroud, David A., Van Haute, Lindsey, Minczuk, Michal, Brunetti-Pierri, Nicola, Olimpio, Catarina, Hock, Daniella H., Horvath, Rita, Murphy, David, Dominik, Natalia, Christodoulou, John, Barth, Magalie, Procaccio, Vincent, Athanasiou-Fragkouli, Alkyoni, Arunachal, Gautham, O’Connor, Emily, Lenaers, Guy, Maroofian, Reza, Powell, Christopher A., Cappuccio, Gerarda, Preethish-Kumar, Veeramani, Díaz-Maldonado, Héctor, Thorburn, David R., Ziegler, Alban, Nalini, Atchayaram, Bonneau, Dominique, Rius, Rocio, Munro, Benjamin, Polavarapu, Kiran, Nandeesh, Bevinahalli, Helman, Guy, Houlden, Henry, Goel, Himanshu, Simons, Cas, Mention, Karine, Lochmüller, Hanns, Bardhan, Mainak, Zaki, Maha S.

2023

Overview

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. Van Haute et al describe autosomal recessive TEFM variants that impair mitochondrial transcription elongation and reduce the levels of promoter distal mitochondrial RNA transcripts, leading to heterogeneous mitochondrial diseases with a treatable neuromuscular transmission defect.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 13/51 / 14 / 38 / 38/1 / 38/22 / 38/23 / 38/77 / 38/90 / 38/91 / 64 / 64/116 / 692/1807/1693 / 692/308/2056 / 692/420/2489/144 / 692/617/375/374 / 692/700/139/422 / 82/80 / Abnormalities / Animals / Cell Biology / Cellbiologi / Child / Childhood / Children / Defects / DNA, Mitochondrial - genetics / DNA-directed RNA polymerase / Electron transport / Elongation / Embryos / Fibroblasts / gene / genome / Genomes / Genotypes / Humanities and Social Sciences / Humans / identification / initiation / Life Sciences / Mitochondria / Mitochondrial Proteins - genetics / Mitochondrial Proteins - metabolism / multidisciplinary / Muscles / Mutation / mutations / Myopathy / Neurological diseases / Neuromuscular junctions / Neuromuscular transmission / Phenotypes / platform / Ribonucleic acid / RNA / RNA polymerase / RNA, Mitochondrial / Science / Science & Technology - Other Topics / Science (multidisciplinary) / sequence / Signs and symptoms / site / termination / Transcription Factors - genetics / Transcription, Genetic / Zebrafish / Zebrafish - genetics / Zebrafish - metabolism