RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.

Autor:	Shintaku J; Department of Neurology, H. Houston Merritt Neuromuscular Research Center, Columbia University Irving Medical Center, New York, New York, USA., Pernice WM; Department of Neurology, H. Houston Merritt Neuromuscular Research Center, Columbia University Irving Medical Center, New York, New York, USA., Eyaid W; Genetics Division, Department of Pediatrics, King Saud bin Abdulaziz University for Health Science, King Abdulaziz Medical City, Riyadh, Saudi Arabia., Gc JB; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, USA., Brown ZP; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, USA., Juanola-Falgarona M; Department of Neurology, H. Houston Merritt Neuromuscular Research Center, Columbia University Irving Medical Center, New York, New York, USA., Torres-Torronteras J; Center for Biomedical Network Research on Rare Diseases, Instituto de Salud Carlos III, Madrid, Spain.; Research Group on Neuromuscular and Mitochondrial Diseases, Vall d'Hebron Research Institute, Autonomous University of Barcelona, Barcelona, Spain., Sommerville EW; Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom., Hellebrekers DM; Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, Netherlands., Blakely EL; Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.; NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom., Donaldson A; Clinical Genetics Service, University of Bristol NHS Foundation Trust, Bristol, United Kingdom., van de Laar I; Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands., Leu CS; Mailman School of Public Health and., Marti R; Center for Biomedical Network Research on Rare Diseases, Instituto de Salud Carlos III, Madrid, Spain.; Research Group on Neuromuscular and Mitochondrial Diseases, Vall d'Hebron Research Institute, Autonomous University of Barcelona, Barcelona, Spain., Frank J; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, USA.; Department of Biological Sciences, Columbia University, New York, New York, USA., Tanji K; Department of Neurology, H. Houston Merritt Neuromuscular Research Center, Columbia University Irving Medical Center, New York, New York, USA.; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York, USA., Koolen DA; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands., Rodenburg RJ; Radboud Centre for Mitochondrial Medicine, Department of Pediatrics, Amalia Children's Hospital, Nijmegen, Netherlands.; Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands., Chinnery PF; MRC Mitochondrial Biology Unit and.; Department of Clinical Neuroscience, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom., Smeets HJM; Department of Genetics and Cell Biology, Clinical Genomics Unit, and.; School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands., Gorman GS; Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.; NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom., Bonnen PE; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA., Taylor RW; Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.; NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom., Hirano M; Department of Neurology, H. Houston Merritt Neuromuscular Research Center, Columbia University Irving Medical Center, New York, New York, USA.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2022 Jul 01; Vol. 132 (13).
DOI:	10.1172/JCI145660
Abstrakt:	Mitochondrial DNA (mtDNA) depletion/deletions syndromes (MDDS) encompass a clinically and etiologically heterogenous group of mitochondrial disorders caused by impaired mtDNA maintenance. Among the most frequent causes of MDDS are defects in nucleoside/nucleotide metabolism, which is critical for synthesis and homeostasis of the deoxynucleoside triphosphate (dNTP) substrates of mtDNA replication. A central enzyme for generating dNTPs is ribonucleotide reductase, a critical mediator of de novo nucleotide synthesis composed of catalytic RRM1 subunits in complex with RRM2 or p53R2. Here, we report 5 probands from 4 families who presented with ptosis and ophthalmoplegia as well as other clinical manifestations and multiple mtDNA deletions in muscle. We identified 3 RRM1 loss-of-function variants, including a dominant catalytic site variant (NP_001024.1: p.N427K) and 2 homozygous recessive variants at p.R381, which has evolutionarily conserved interactions with the specificity site. Atomistic molecular dynamics simulations indicate mechanisms by which RRM1 variants affect protein structure. Cultured primary skin fibroblasts of probands manifested mtDNA depletion under cycling conditions, indicating impaired de novo nucleotide synthesis. Fibroblasts also exhibited aberrant nucleoside diphosphate and dNTP pools and mtDNA ribonucleotide incorporation. Our data reveal that primary RRM1 deficiency and, by extension, impaired de novo nucleotide synthesis are causes of MDDS.
Databáze:	MEDLINE
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