Show simple item record

 
dc.contributorVall d'Hebron Barcelona Hospital Campus
dc.contributor.authorShintaku, Jonathan
dc.contributor.authorPernice, Wolfgang Maximilian Anton
dc.contributor.authorEyaid, Wafaa
dc.contributor.authorGC, Jeevan
dc.contributor.authorBrown, Zuben P.
dc.contributor.authorJuanola-Falgarona, Martí
dc.contributor.authorTorres Torronteras, Javier
dc.contributor.authorMartí Seves, Ramón
dc.date.accessioned2022-09-09T07:32:25Z
dc.date.available2022-09-09T07:32:25Z
dc.date.issued2022-07-01
dc.identifier.citationShintaku 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.issn1558-8238
dc.identifier.urihttp://hdl.handle.net/11351/8087
dc.descriptionGenetic diseases; Mitochondria; Molecular pathology
dc.description.abstractMitochondrial 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.isoeng
dc.publisherAmerican Society for Clinical Investigation
dc.relation.ispartofseriesThe Journal of Clinical Investigation;132(13)
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceScientia
dc.subjectMitocondris - Malalties - Aspectes genètics
dc.subjectADN mitocondrial
dc.subject.meshDNA, Mitochondrial
dc.subject.meshMitochondrial Diseases
dc.subject.mesh/genetics
dc.titleRRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis
dc.typeinfo:eu-repo/semantics/article
dc.identifier.doi10.1172/JCI145660
dc.subject.decsADN mitocondrial
dc.subject.decsenfermedades mitocondriales
dc.subject.decs/genética
dc.relation.publishversionhttps://doi.org/10.1172/JCI145660
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dc.audienceProfessionals
dc.contributor.organismesInstitut 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.pmid35617047
dc.identifier.wos000829089900004
dc.rights.accessrightsinfo:eu-repo/semantics/openAccess


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record