POLRMT mutations impair mitochondrial transcription causing neurological disease.

TitlePOLRMT mutations impair mitochondrial transcription causing neurological disease.
Publication TypeJournal Article
Year of Publication2021
AuthorsOláhová, M, Peter, B, Szilagyi, Z, Diaz-Maldonado, H, Singh, M, Sommerville, EW, Blakely, EL, Collier, JJ, Hoberg, E, Stránecký, V, Hartmannová, H, Bleyer, AJ, McBride, KL, Bowden, SA, Korandová, Z, Pecinová, A, Ropers, H-H, Kahrizi, K, Najmabadi, H, Tarnopolsky, MA, Brady, LI, K Weaver, N, Prada, CE, Õunap, K, Wojcik, MH, Pajusalu, S, Syeda, SB, Pais, L, Estrella, EA, Bruels, CC, Kunkel, LM, Kang, PB, Bonnen, PE, Mráček, T, Kmoch, S, Gorman, GS, Falkenberg, M, Gustafsson, CM, Taylor, RW
JournalNat Commun
Date Published2021 02 18
KeywordsAdolescent, Adult, Child, DNA, Mitochondrial, DNA-Directed RNA Polymerases, Female, Fibroblasts, Humans, Infant, Male, Mitochondria, Mutation, Nervous System Diseases, Oxidative Phosphorylation, Pedigree, Protein Domains, Protein Subunits, RNA, Messenger, Transcription, Genetic, Young Adult

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.

Alternate JournalNat Commun
PubMed ID33602924
PubMed Central IDPMC7893070
Grant ListUM1 HG008900 / HG / NHGRI NIH HHS / United States
203105/Z/16/Z / WT / Wellcome Trust / United Kingdom
G0800674 / MR / Medical Research Council / United Kingdom
T32 GM007748 / GM / NIGMS NIH HHS / United States
/ DH / Department of Health / United Kingdom
R01 NS080929 / NS / NINDS NIH HHS / United States