@article{10.1172/JCI145660, author = {Jonathan Shintaku AND Wolfgang M. Pernice AND Wafaa Eyaid AND Jeevan B. GC AND Zuben P. Brown AND Marti Juanola-Falgarona AND Javier Torres-Torronteras AND Ewen W. Sommerville AND Debby M.E.I. Hellebrekers AND Emma L. Blakely AND Alan Donaldson AND Ingrid van de Laar AND Cheng-Shiun Leu AND Ramon Marti AND Joachim Frank AND Kurenai Tanji AND David A. Koolen AND Richard J. Rodenburg AND Patrick F. Chinnery AND H.J.M. Smeets AND GrĂ¡inne S. Gorman AND Penelope E. Bonnen AND Robert W. Taylor AND Michio Hirano}, journal = {The Journal of Clinical Investigation}, publisher = {The American Society for Clinical Investigation}, title = {RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis}, year = {2022}, month = {7}, volume = {132}, url = {https://www.jci.org/articles/view/145660}, 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.}, number = {13}, doi = {10.1172/JCI145660}, url = {https://doi.org/10.1172/JCI145660}, }