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POLRMT mutations impair mitochondrial transcription causing neurological disease
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SYSNO ASEP 0541626 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title POLRMT mutations impair mitochondrial transcription causing neurological disease Author(s) Oláhová, M. (GB)
Peter, B. (SE)
Szilagyi, Z. (SE)
Diaz-Maldonado, H. (SE)
Singh, M. (SE)
Sommerville, E. W. (GB)
Blakely, E. L. (GB)
Collier, J. J. (GB)
Hoberg, E. (SE)
Stránecký, V. (CZ)
Hartmannová, H. (CZ)
Bleyer, A. J. (CZ)
McBride, K. L. (US)
Bowden, S. A. (US)
Korandová, Zuzana (FGU-C) ORCID, RID
Pecinová, Alena (FGU-C) RID, ORCID, SAI
Ropers, H.-H. (DE)
Kahrizi, K. (IR)
Najmabadi, H. (IR)
Tarnopolsky, M. A. (CA)
Brady, L. I. (CA)
Weaver, K. N. (US)
Prada, C. E. (US)
Ounap, K. (EE)
Wojcik, M. H. (US)
Pajusalu, S. (EE)
Syeda, S. B. (US)
Pais, L. (US)
Estrella, E. A. (US)
Bruels, Ch. C. (US)
Kunkel, L. M. (US)
Kang, P. B. (US)
Bonnen, P. E. (US)
Mráček, Tomáš (FGU-C) RID, ORCID
Kmoch, S. (CZ)
Gorman, G. S. (GB)
Falkenberg, M. (SE)
Gustafsson, C. M. (SE)
Taylor, R. W. (GB)Article number 1135 Source Title Nature Communications. - : Nature Publishing Group
Roč. 12, č. 1 (2021)Number of pages 13 s. Language eng - English Country GB - United Kingdom Keywords POLRMT ; mitochondrial RNA polymerase ; mitochondrial transcription ; neurological disease Subject RIV CE - Biochemistry OECD category Biochemistry and molecular biology R&D Projects NV19-07-00149 GA MZd - Ministry of Health (MZ) LQ1604 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Research Infrastructure NCMG II - 90132 - Univerzita Karlova Method of publishing Open access Institutional support FGU-C - RVO:67985823 UT WOS 000621426600002 EID SCOPUS 85100963543 DOI 10.1038/s41467-021-21279-0 Annotation While >300 disease-causing variants have been identified in the mitochondrial DNA (mtDNA) polymerase gamma, no mitochondrial phenotypes have been associated with POLRMT, the RNA polymerase responsible for transcription of the mitochondrial genome. Here, we characterise the clinical and molecular nature of POLRMT variants in eight individuals from seven unrelated families. Patients present with global developmental delay, hypotonia, short stature, and speech/intellectual disability in childhood, one subject displayed an indolent progressive external ophthalmoplegia phenotype. Massive parallel sequencing of all subjects identifies recessive and dominant variants in the POLRMT gene. Patient fibroblasts have a defect in mitochondrial mRNA synthesis, but no mtDNA deletions or copy number abnormalities. The in vitro characterisation of the recombinant POLRMT mutants reveals variable, but deleterious effects on mitochondrial transcription. Together, our in vivo and in vitro functional studies of POLRMT variants establish defective mitochondrial transcription as an important disease mechanism. POLRMT is key for transcription of the mitochondrial genome, yet has not been implicated in mitochondrial disease to date. Here, the authors identify mutations in POLRMT in individuals with mitochondrial disease-related phenotypes and characterise underlying defects in mitochondrial transcription. Workplace Institute of Physiology Contact Lucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400 Year of Publishing 2022 Electronic address https://www.nature.com/articles/s41467-021-21279-0
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