POLRMT mutations impair mitochondrial transcription causing neurological disease

Monika Oláhová, Bradley Peter, Zsolt Szilagyi, Hector Diaz-Maldonado, Meenakshi Singh, Ewen W. Sommerville, Emma L. Blakely, Jack J. Collier, Emily Hoberg, Viktor Stránecký, Hana Hartmannová, Anthony J. Bleyer, Kim L. McBride, Sasigarn A. Bowden, Zuzana Korandová, Alena Pecinová, Hans-Hilger Ropers, Kimia Kahrizi, Hossein Najmabadi, Mark A. Tarnopolsky, Lauren I. Brady, K. Nicole Weaver, Carlos E. Prada, Katrin Õunap, Monica H. Wojcik, Sander Pajusalu, Safoora B. Syeda, Lynn Pais, Elicia A. Estrella, Christine C. Bruels, Louis M. Kunkel, Peter B. Kang, Penelope E. Bonnen, Tomáš Mráček, Stanislav Kmoch, Gráinne S. Gorman, Maria Falkenberg, Claes M. Gustafsson () and Robert W. Taylor ()
Additional contact information
Monika Oláhová: Newcastle University
Bradley Peter: University of Gothenburg
Zsolt Szilagyi: University of Gothenburg
Hector Diaz-Maldonado: University of Gothenburg
Meenakshi Singh: University of Gothenburg
Ewen W. Sommerville: Newcastle University
Emma L. Blakely: Newcastle University
Jack J. Collier: Newcastle University
Emily Hoberg: University of Gothenburg
Viktor Stránecký: Charles University
Hana Hartmannová: Charles University
Anthony J. Bleyer: Charles University
Kim L. McBride: The Ohio State University College of Medicine
Sasigarn A. Bowden: The Ohio State University College of Medicine
Zuzana Korandová: Charles University
Alena Pecinová: Institute of Physiology of the Czech Academy of Sciences
Hans-Hilger Ropers: Max Planck Institute for Molecular Genetics
Kimia Kahrizi: University of Social Welfare and Rehabilitation Sciences
Hossein Najmabadi: University of Social Welfare and Rehabilitation Sciences
Mark A. Tarnopolsky: McMaster University Children’s Hospital
Lauren I. Brady: McMaster University Children’s Hospital
K. Nicole Weaver: Division of Human Genetics, Cincinnati Children’s Hospital Medical Center
Carlos E. Prada: Division of Human Genetics, Cincinnati Children’s Hospital Medical Center
Katrin Õunap: Tartu University Hospital
Monica H. Wojcik: Broad Institute of MIT and Harvard
Sander Pajusalu: Tartu University Hospital
Safoora B. Syeda: University of Florida College of Medicine
Lynn Pais: Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Elicia A. Estrella: Division of Genetics & Genomics, Boston Children’s Hospital and Harvard Medical School
Christine C. Bruels: University of Florida College of Medicine
Louis M. Kunkel: Division of Genetics & Genomics, Boston Children’s Hospital and Harvard Medical School
Peter B. Kang: University of Florida College of Medicine
Penelope E. Bonnen: Baylor College of Medicine
Tomáš Mráček: Institute of Physiology of the Czech Academy of Sciences
Stanislav Kmoch: Charles University
Gráinne S. Gorman: Newcastle University
Maria Falkenberg: University of Gothenburg
Claes M. Gustafsson: University of Gothenburg
Robert W. Taylor: Newcastle University

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-21279-0

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