POLRMT mutations impair mitochondrial transcription causing neurological disease.

Autor: Oláhová M; Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK., Peter B; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden., Szilagyi Z; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden., Diaz-Maldonado H; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden., Singh M; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden., Sommerville EW; Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK., Blakely EL; Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK., Collier JJ; Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK., Hoberg E; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden., Stránecký V; Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, 120 00, Czech Republic., Hartmannová H; Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, 120 00, Czech Republic., Bleyer AJ; Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, 120 00, Czech Republic.; Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, USA., McBride KL; Center for Cardiovascular and Pulmonary Research, Department of Pediatrics, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, USA., Bowden SA; Division of Endocrinology, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, USA., Korandová Z; Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, 120 00, Czech Republic.; Department of Bioenergetics, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic., Pecinová A; Department of Bioenergetics, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic., Ropers HH; Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.; Institute of Human Genetics, University Medical Center of the Johannes Gutenberg University, Mainz, Germany., Kahrizi K; Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran., Najmabadi H; Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran., Tarnopolsky MA; Department of Pediatric and Medicines, Division of Neuromuscular and Neurometabolic Diseases, McMaster University Children's Hospital, Hamilton, Canada., Brady LI; Department of Pediatric and Medicines, Division of Neuromuscular and Neurometabolic Diseases, McMaster University Children's Hospital, Hamilton, Canada., Weaver KN; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA., Prada CE; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.; Department of Pediatrics, Cardiovascular Foundation of Colombia, Floridablanca, Colombia., Õunap K; Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia.; Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Wojcik MH; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Divisions of Newborn Medicine and Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA., Pajusalu S; Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia.; Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA., Syeda SB; Division of Pediatric Neurology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA., Pais L; Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA., Estrella EA; Division of Genetics & Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA., Bruels CC; Division of Pediatric Neurology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA., Kunkel LM; Division of Genetics & Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA., Kang PB; Division of Pediatric Neurology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA.; Department of Molecular Genetics & Microbiology, and Department of Neurology, University of Florida College of Medicine, Gainesville, FL, USA.; Genetics Institute and Myology Institute, University of Florida, Gainesville, FL, USA., Bonnen PE; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Mráček T; Department of Bioenergetics, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic., Kmoch S; Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, 120 00, Czech Republic., Gorman GS; Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK., Falkenberg M; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden., Gustafsson CM; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden. claes.gustafsson@medkem.gu.se., Taylor RW; Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK. robert.taylor@ncl.ac.uk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Feb 18; Vol. 12 (1), pp. 1135. Date of Electronic Publication: 2021 Feb 18.
DOI: 10.1038/s41467-021-21279-0
Abstrakt: 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.
Databáze: MEDLINE
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