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Acta Neurologica. DTYMK 2021.pdf (7.24 MB)

DTYMK is essential for genome integrity and neuronal survival

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posted on 2023-06-10, 02:13 authored by Jo M Vanoevelen, Jörgen Bierau, Janine C Grashorn, Ellen Lambrichs, Erik-Jan Kamsteeg, Levinus A Bok, Ron A Wevers, Marjo S van der Knaap, Marianna Bugiani, Junmei Hu Frisk, Rita Colnaghi, Mark O'DriscollMark O'Driscoll, Debby M E I Hellebrekers, Richard Rodenburg, Carlos R Ferreira, Han G Brunner, Arthur van den Wijngaard, Ghada M H Abdel-Salam, Liya Wang, Constance T R M Stumpel
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.

Funding

Determining the role of the prolyl cis-trans isomerase Cyclophilin A in DNA Repair at stalled DNA replication forks.; G3052; MRC-MEDICAL RESEARCH COUNCIL; MRC – Ref: MR/T

History

Publication status

  • Published

File Version

  • Published version

Journal

Acta Neuropathologica

ISSN

0001-6322

Publisher

Springer

Page range

245-262

Article number

a143

Event location

Germany

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2022-01-10

First Open Access (FOA) Date

2022-01-10

First Compliant Deposit (FCD) Date

2022-01-07

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