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Vanoevelen, Jo M.; Bierau, Jörgen; 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.

DTYMK is essential for genome integrity and neuronal survival

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  • Media type: E-Article
  • Title: DTYMK is essential for genome integrity and neuronal survival
  • Contributor: Vanoevelen, Jo M.; Bierau, Jörgen; 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.
  • Published: Springer Science and Business Media LLC, 2022
  • Published in: Acta Neuropathologica, 143 (2022) 2, Seite 245-262
  • Language: English
  • DOI: 10.1007/s00401-021-02394-0
  • ISSN: 0001-6322; 1432-0533
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:p>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 <jats:italic>DTYMK,</jats:italic> 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 <jats:italic>dtymk</jats:italic> 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 <jats:italic>dtymk</jats:italic> 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 <jats:italic>DTYMK</jats:italic> 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.</jats:p>