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Lookup NU author(s): Dr Monika Olahova, Dr Ewen Sommerville, Dr Jack Collier, Professor Grainne Gorman, Professor Robert Taylor
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2021, The Author(s).While >300 disease-causing variants have been identified in the mitochondrial DNA (mtDNA) polymerase γ, 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.
Author(s): Olahova M, Peter B, Szilagyi Z, Diaz-Maldonado H, Singh M, Sommerville EW, Blakely EL, Collier JJ, Hoberg E, Stranecky V, Hartmannova H, Bleyer AJ, McBride KL, Bowden SA, Korandova Z, Pecinova A, Ropers H-H, Kahrizi K, Najmabadi H, Tarnopolsky MA, Brady LI, Weaver KN, Prada CE, Ounap K, Wojcik MH, Pajusalu S, Syeda SB, Pais L, Estrella EA, Bruels CC, Kunkel LM, Kang PB, Bonnen PE, Mracek T, Kmoch S, Gorman GS, Falkenberg M, Gustafsson CM, Taylor RW
Publication type: Article
Publication status: Published
Journal: Nature Communications
Year: 2021
Volume: 12
Issue: 1
Print publication date: 01/12/2021
Online publication date: 18/02/2021
Acceptance date: 18/12/2020
Date deposited: 07/04/2021
ISSN (electronic): 2041-1723
Publisher: Nature Research
URL: https://doi.org/10.1038/s41467-021-21279-0
DOI: 10.1038/s41467-021-21279-0
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