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POLRMT mutations impair mitochondrial transcription causing neurological disease

M. Oláhová, B. Peter, Z. Szilagyi, H. Diaz-Maldonado, M. Singh, EW. Sommerville, EL. Blakely, JJ. Collier, E. Hoberg, V. Stránecký, H. Hartmannová, AJ. Bleyer, KL. McBride, SA. Bowden, Z. Korandová, A. Pecinová, HH. Ropers, K. Kahrizi, H....

. 2021 ; 12 (1) : 1135. [pub] 20210218

Jazyk angličtina Země Velká Británie

Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc21019220

Grantová podpora
UM1 HG008900 NHGRI NIH HHS - United States
203105/Z/16/Z Wellcome Trust - United Kingdom
G0800674 Medical Research Council - United Kingdom
T32 GM007748 NIGMS NIH HHS - United States
Department of Health - United Kingdom
R01 NS080929 NINDS NIH HHS - United States

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.

Broad Institute of MIT and Harvard Cambridge MA USA

Center for Cardiovascular and Pulmonary Research Department of Pediatrics Nationwide Children's Hospital The Ohio State University College of Medicine Columbus USA

Center for Mendelian Genomics Broad Institute of MIT and Harvard Cambridge Massachusetts USA

Department of Bioenergetics Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic

Department of Clinical Genetics Institute of Clinical Medicine University of Tartu Tartu Estonia

Department of Clinical Genetics United Laboratories Tartu University Hospital Tartu Estonia

Department of Genetics Yale University School of Medicine New Haven CT USA

Department of Human Molecular Genetics Max Planck Institute for Molecular Genetics Berlin Germany

Department of Medical Biochemistry and Cell Biology University of Gothenburg Gothenburg Sweden

Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA

Department of Molecular Genetics and Microbiology and Department of Neurology University of Florida College of Medicine Gainesville FL USA

Department of Pediatric and Medicines Division of Neuromuscular and Neurometabolic Diseases McMaster University Children's Hospital Hamilton Canada

Department of Pediatrics Cardiovascular Foundation of Colombia Floridablanca Colombia

Department of Pediatrics University of Cincinnati College of Medicine Cincinnati OH USA

Division of Endocrinology Nationwide Children's Hospital The Ohio State University College of Medicine Columbus USA

Division of Genetics and Genomics Boston Children's Hospital and Harvard Medical School Boston MA USA

Division of Human Genetics Cincinnati Children's Hospital Medical Center Cincinnati OH USA

Division of Pediatric Neurology Department of Pediatrics University of Florida College of Medicine Gainesville FL USA

Divisions of Newborn Medicine and Genetics and Genomics Department of Pediatrics Boston Children's Hospital Boston MA USA

Genetics Institute and Myology Institute University of Florida Gainesville FL USA

Genetics Research Center University of Social Welfare and Rehabilitation Sciences Tehran Iran

Institute of Human Genetics University Medical Center of the Johannes Gutenberg University Mainz Germany

Research Unit for Rare Diseases Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine Charles University Prague 120 00 Czech Republic

Section on Nephrology Wake Forest School of Medicine Winston Salem USA

Wellcome Centre for Mitochondrial Research Translational and Clinical Research Institute The Medical School Newcastle University Newcastle upon Tyne NE2 4HH UK

Citace poskytuje Crossref.org

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