POLRMT mutations impair mitochondrial transcription causing neurological disease

0541626 - FGÚ 2022 RIV GB eng J - Journal Article
Oláhová, M. - Peter, B. - Szilagyi, Z. - Diaz-Maldonado, H. - Singh, M. - Sommerville, E. W. - Blakely, E. L. - Collier, J. J. - Hoberg, E. - Stránecký, V. - Hartmannová, H. - Bleyer, A. J. - McBride, K. L. - Bowden, S. A. - Korandová, Zuzana - Pecinová, Alena - Ropers, H.-H. - Kahrizi, K. - Najmabadi, H. - Tarnopolsky, M. A. - Brady, L. I. - Weaver, K. N. - Prada, C. E. - Ounap, K. - Wojcik, M. H. - Pajusalu, S. - Syeda, S. B. - Pais, L. - Estrella, E. A. - Bruels, Ch. C. - Kunkel, L. M. - Kang, P. B. - Bonnen, P. E. - Mráček, Tomáš - Kmoch, S. - Gorman, G. S. - Falkenberg, M. - Gustafsson, C. M. - Taylor, R. W.
POLRMT mutations impair mitochondrial transcription causing neurological disease.
Nature Communications. Roč. 12, č. 1 (2021), č. článku 1135. E-ISSN 2041-1723
R&D Projects: GA MZd(CZ) NV19-07-00149; GA MŠMT(CZ) LQ1604
Research Infrastructure: NCMG II - 90132
Institutional support: RVO:67985823
Keywords : POLRMT * mitochondrial RNA polymerase * mitochondrial transcription * neurological disease
OECD category: Biochemistry and molecular biology
Impact factor: 17.694, year: 2021
Method of publishing: Open access
https://www.nature.com/articles/s41467-021-21279-0

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.
Permanent Link: http://hdl.handle.net/11104/0319159