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

Lookup NU author(s): Ewen Sommerville, Professor Patrick Chinnery, Professor Grainne Gorman, Professor Robert Taylor



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Copyright: © 2022, Shintaku et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. 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.

Publication metadata

Author(s): Shintaku J, Pernice WM, Eyaid W, Jeevan BGC, Brown ZP, Juanola-Falgarona M, Torres-Torronteras J, Sommerville EW, Hellebrekers DMEI, Blakely EL, Donaldson A, van de Laar I, Leu C-S, Marti R, Frank J, Tanji K, Koolen DA, Rodenburg RJ, Chinnery PF, Smeets HJM, Gorman GS, Bonnen PE, Taylor RW, Hirano M

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Investigation

Year: 2022

Volume: 132

Issue: 13

Print publication date: 01/07/2022

Online publication date: 26/05/2022

Acceptance date: 19/05/2022

Date deposited: 28/07/2022

ISSN (print): 0021-9738

ISSN (electronic): 1558-8238

Publisher: American Society for Clinical Investigation


DOI: 10.1172/JCI145660

PubMed id: 35617047


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Funder referenceFunder name
203105/Z/16/ZWellcome Trust
Lily Foundation
MR/S005021/1Medical Research Council (MRC)
UK National Health Service Highly Specialised Service for Rare Mitochondrial Disorders
UK NIHR Biomedical Research Centre in Age and Age Related Diseases award to the Newcastle upon Tyne Hospitals NHS Foundation