RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis
Shintaku, Jonathan (Columbia University Irving Medical Center)
Pernice, Wolfgang M. (Columbia University Irving Medical Center)
Eyaid, Wafaa (King Saud bin Abdulaziz University for Health Science)
GC, Jeevan B. (Columbia University)
Brown, Zuben P. (Columbia University)
Juanola-Falgarona, Marti (Columbia University Irving Medical Center)
Torres-Torronteras, Javier (Vall d'Hebron Institut de Recerca (VHIR))
Sommerville, Ewen W. (Newcastle University)
Hellebrekers, Debby M.E.I. (Maastricht University Medical Center)
Blakely, Emma L. (Newcastle Upon Tyne Hospitals NHS Trust (Newcastle, Regne Unit))
Donaldson, Alan (University of Bristol NHS Foundation Trust)
van de Laar, Ingrid (University Medical Center Rotterdam)
Leu, Cheng-Shiun (Mailman School of Public Health)
Martí, Ramon A. (Vall d'Hebron Institut de Recerca (VHIR))
Frank, Joachim (Columbia University)
Tanji, Kurenai (Columbia University Irving Medical Center)
Koolen, David A. (Radboud University Medical Center)
Rodenburg, Richard J. (Radboud University Medical Center)
Chinnery, Patrick F. (University of Cambridge)
Smeets, H.J.M. (Maastricht University)
Gorman, Gráinne S. (Newcastle Upon Tyne Hospitals NHS Trust (Newcastle, Regne Unit))
Bonnen, Penelope E. (Baylor College of Medicine (Houston, Estats Units d'Amèrica))
Taylor, Robert W. (Newcastle Upon Tyne Hospitals NHS Trust (Newcastle, Regne Unit))
Hirano, Michio (Columbia University Irving Medical Center)
Universitat Autònoma de Barcelona

Data:	2022
Resum:	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.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Genetics ; Genetic diseases ; Mitochondria ; Molecular pathology
Publicat a:	The journal of clinical investigation, Vol. 132 (july 2022) , ISSN 1558-8238

DOI: 10.1172/JCI145660
PMID: 35617047

7 p, 5.5 MB

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