Research article - Peer-reviewed, 2022
DTYMK is essential for genome integrity and neuronal survival
Vanoevelen, Jo M.; Bierau, Jorgen; Grashorn, Janine C.; Lambrichs, Ellen; Kamsteeg, Erik-Jan; Bok, Levinus A.; Wevers, Ron A.; van der Knaap, Marjo S.; Bugiani, Marianna; Frisk, Junmei Hu; Colnaghi, Rita; O'Driscoll, Mark; Hellebrekers, Debby M. E., I; Rodenburg, Richard; Ferreira, Carlos R.; Brunner, Han G.; van den Wijngaard, Arthur; Abdel-Salam, Ghada M. H.; Wang, Liya; Stumpel, Constance T. R. M.Abstract
Nucleotide metabolism is a complex pathway regulating crucial cellular processes such as nucleic acid synthesis, DNA repair and proliferation. This study shows that impairment of the biosynthesis of one of the building blocks of DNA, dTTP, causes a severe, early-onset neurodegenerative disease. Here, we describe two unrelated children with bi-allelic variants in DTYMK, encoding dTMPK, which catalyzes the penultimate step in dTTP biosynthesis. The affected children show severe microcephaly and growth retardation with minimal neurodevelopment. Brain imaging revealed severe cerebral atrophy and disappearance of the basal ganglia. In cells of affected individuals, dTMPK enzyme activity was minimal, along with impaired DNA replication. In addition, we generated dtymk mutant zebrafish that replicate this phenotype of microcephaly, neuronal cell death and early lethality. An increase of ribonucleotide incorporation in the genome as well as impaired responses to DNA damage were observed in dtymk mutant zebrafish, providing novel pathophysiological insights. It is highly remarkable that this deficiency is viable as an essential component for DNA cannot be generated, since the metabolic pathway for dTTP synthesis is completely blocked. In summary, by combining genetic and biochemical approaches in multiple models we identified loss-of-function of DTYMK as the cause of a severe postnatal neurodegenerative disease and highlight the essential nature of dTTP synthesis in the maintenance of genome stability and neuronal survival.Keywords
DTYMK; dTMPK; Nucleotide metabolism; Zebrafish; Genome instabilityPublished in
Acta Neuropathologica2022, volume: 143, number: 2, pages: 245-262
Publisher: SPRINGER
Authors' information
Vanoevelen, Jo M.
Maastricht University
Bierau, Jorgen
Maastricht University
Grashorn, Janine C.
Maastricht University
Lambrichs, Ellen
Maastricht University
Kamsteeg, Erik-Jan
Radboud University Nijmegen
Bok, Levinus A.
Maxima Medical Center
Wevers, Ron A.
Radboud University Nijmegen
van der Knaap, Marjo S.
Vrije Universiteit Amsterdam
Bugiani, Marianna
Vrije Universiteit Amsterdam
Frisk, Jun Mei Hu
Swedish University of Agricultural Sciences, Department of Anatomy, Physiology and Biochemistry (AFB)
Colnaghi, Rita
University of Sussex
O'Driscoll, Mark
University of Sussex
Hellebrekers, Debby M. E.
Maastricht University
Rodenburg, Richard
Radboud University Nijmegen
Ferreira, Carlos R.
National Institutes of Health (NIH) - USA
Brunner, Han G.
Maastricht University
Brunner, Han G.
Radboud University Nijmegen
van den Wijngaard, Arthur
Maastricht University
Abdel-Salam, Ghada M. H.
National Research Centre (NRC)
Swedish University of Agricultural Sciences, Department of Anatomy, Physiology and Biochemistry (AFB)
UKÄ Subject classification
Neurology
Medical Genetics
Publication Identifiers
DOI: https://doi.org/10.1007/s00401-021-02394-0
URI (permanent link to this page)
https://res.slu.se/id/publ/115054