dc.contributor | Vall d'Hebron Barcelona Hospital Campus |
dc.contributor.author | Shintaku, Jonathan |
dc.contributor.author | Pernice, Wolfgang Maximilian Anton |
dc.contributor.author | Eyaid, Wafaa |
dc.contributor.author | GC, Jeevan |
dc.contributor.author | Brown, Zuben P. |
dc.contributor.author | Juanola-Falgarona, Martí |
dc.contributor.author | Torres Torronteras, Javier |
dc.contributor.author | Martí Seves, Ramón |
dc.date.accessioned | 2022-09-09T07:32:25Z |
dc.date.available | 2022-09-09T07:32:25Z |
dc.date.issued | 2022-07-01 |
dc.identifier.citation | Shintaku J, Pernice WM, Eyaid W, GC JB, Brown ZP, Juanola-Falgarona M, et al. RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis. J Clin Invest. 2022 Jul 1;132(13):e145660. |
dc.identifier.issn | 1558-8238 |
dc.identifier.uri | https://hdl.handle.net/11351/8087 |
dc.description | Genetic diseases; Mitochondria; Molecular pathology |
dc.description.abstract | 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. |
dc.language.iso | eng |
dc.publisher | American Society for Clinical Investigation |
dc.relation.ispartofseries | The Journal of Clinical Investigation;132(13) |
dc.rights | Attribution 4.0 International |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ |
dc.source | Scientia |
dc.subject | Mitocondris - Malalties - Aspectes genètics |
dc.subject | ADN mitocondrial |
dc.subject.mesh | DNA, Mitochondrial |
dc.subject.mesh | Mitochondrial Diseases |
dc.subject.mesh | /genetics |
dc.title | RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis |
dc.type | info:eu-repo/semantics/article |
dc.identifier.doi | 10.1172/JCI145660 |
dc.subject.decs | ADN mitocondrial |
dc.subject.decs | enfermedades mitocondriales |
dc.subject.decs | /genética |
dc.relation.publishversion | https://doi.org/10.1172/JCI145660 |
dc.type.version | info:eu-repo/semantics/publishedVersion |
dc.audience | Professionals |
dc.contributor.organismes | Institut Català de la Salut |
dc.contributor.authoraffiliation | [Shintaku J, Pernice WM, Juanola-Falgarona M] 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, Brown ZP] Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, USA. [Torres-Torronteras J, Marti R] Center for Biomedical Network Research on Rare Diseases, Instituto de Salud Carlos III, Madrid, Spain. Grups de Recerca en Malalties Neuromusculars i Mitocondrials, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain |
dc.identifier.pmid | 35617047 |
dc.identifier.wos | 000829089900004 |
dc.rights.accessrights | info:eu-repo/semantics/openAccess |