POLRMT mutations impair mitochondrial transcription causing neurological disease PMID: 33602924

ADC Targets in Oncology

2026-04-10

POLRMT mutations impair mitochondrial transcription causing neurological disease

Nat Commun. 2021 Feb 18;12(1):1135. doi: 10.1038/s41467-021-21279-0.

Monika Oláhová ^# ¹ , Bradley Peter ^# ² , Zsolt Szilagyi ² , Hector Diaz-Maldonado ² , Meenakshi Singh ² , Ewen W Sommerville ¹ , Emma L Blakely ¹ , Jack J Collier ¹ , Emily Hoberg ² , Viktor Stránecký ³ , Hana Hartmannová ³ , Anthony J Bleyer ³ ⁴ , Kim L McBride ⁵ , Sasigarn A Bowden ⁶ , Zuzana Korandová ³ ⁷ , Alena Pecinová ⁷ , Hans-Hilger Ropers ⁸ ⁹ , Kimia Kahrizi ¹⁰ , Hossein Najmabadi ¹⁰ , Mark A Tarnopolsky ¹¹ , Lauren I Brady ¹¹ , K Nicole Weaver ¹² ¹³ , Carlos E Prada ¹² ¹³ ¹⁴ , Katrin Õunap ¹⁵ ¹⁶ ¹⁷ , Monica H Wojcik ¹⁷ ¹⁸ , Sander Pajusalu ¹⁵ ¹⁶ ¹⁹ , Safoora B Syeda ²⁰ , Lynn Pais ²¹ , Elicia A Estrella ²² , Christine C Bruels ²⁰ , Louis M Kunkel ²² , Peter B Kang ²⁰ ²³ ²⁴ , Penelope E Bonnen ²⁵ , Tomáš Mráček ⁷ , Stanislav Kmoch ³ , Gráinne S Gorman ¹ , Maria Falkenberg ² , Claes M Gustafsson ²⁶ , Robert W Taylor ²⁷

Affiliations

1. Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
2. Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden.
3. Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, 120 00, Czech Republic.
4. Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, USA.
5. Center for Cardiovascular and Pulmonary Research, Department of Pediatrics, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, USA.
6. Division of Endocrinology, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, USA.
7. Department of Bioenergetics, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
8. Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
9. Institute of Human Genetics, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
10. Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
11. Department of Pediatric and Medicines, Division of Neuromuscular and Neurometabolic Diseases, McMaster University Children's Hospital, Hamilton, Canada.
12. Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
13. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
14. Department of Pediatrics, Cardiovascular Foundation of Colombia, Floridablanca, Colombia.
15. Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia.
16. Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
17. Broad Institute of MIT and Harvard, Cambridge, MA, USA.
18. Divisions of Newborn Medicine and Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.
19. Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
20. Division of Pediatric Neurology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA.
21. Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
22. Division of Genetics & Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
23. Department of Molecular Genetics & Microbiology, and Department of Neurology, University of Florida College of Medicine, Gainesville, FL, USA.
24. Genetics Institute and Myology Institute, University of Florida, Gainesville, FL, USA.
25. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
26. Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden. [email protected].
27. Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK. [email protected].
# Contributed equally.

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.