DTYMK is essential for genome integrity and neuronal survival.
Jo M VanoevelenJörgen BierauJanine C GrashornEllen LambrichsErik-Jan KamsteegLevinus A BokRon A WeversMarjo S van der KnaapMarianna BugianiJunmei Hu FriskRita ColnaghiMark O'DriscollDebby M E I HellebrekersRichard RodenburgCarlos R FerreiraHan G BrunnerArthur van den WijngaardGhada M H Abdel-SalamLiya WangConstance T R M StumpelPublished in: Acta neuropathologica (2021)
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.
Keyphrases
- early onset
- dna repair
- dna damage
- nucleic acid
- late onset
- cell death
- zika virus
- cerebral ischemia
- genome wide
- young adults
- oxidative stress
- intellectual disability
- circulating tumor
- cell cycle arrest
- single molecule
- subarachnoid hemorrhage
- induced apoptosis
- cell free
- preterm infants
- high resolution
- copy number
- drug induced
- dna damage response
- cell proliferation
- resting state
- functional connectivity
- pi k akt
- wild type