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DTYMK is essential for genome integrity and neuronal survival

Vanoevelen, Jo M. and Bierau, Jorgen and Grashorn, Janine C. and Lambrichs, Ellen and Kamsteeg, Erik-Jan and Bok, Levinus A. and Wevers, Ron A. and van der Knaap, Marjo S. and Bugiani, Marianna and Frisk, Junmei Hu and Colnaghi, Rita and O'Driscoll, Mark and Hellebrekers, Debby M. E. and Rodenburg, Richard and Ferreira, Carlos R. and Brunner, Han G. and van den Wijngaard, Arthur and Abdel-Salam, Ghada M. H. and Wang, Liya and Stumpel, Constance T. R. M. (2022). DTYMK is essential for genome integrity and neuronal survival. Acta Neuropathologica. 143 :2 , 245-262
[Research article]

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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.

Authors/Creators:Vanoevelen, Jo M. and Bierau, Jorgen and Grashorn, Janine C. and Lambrichs, Ellen and Kamsteeg, Erik-Jan and Bok, Levinus A. and Wevers, Ron A. and van der Knaap, Marjo S. and Bugiani, Marianna and Frisk, Junmei Hu and Colnaghi, Rita and O'Driscoll, Mark and Hellebrekers, Debby M. E. and Rodenburg, Richard and Ferreira, Carlos R. and Brunner, Han G. and van den Wijngaard, Arthur and Abdel-Salam, Ghada M. H. and Wang, Liya and Stumpel, Constance T. R. M.
Title:DTYMK is essential for genome integrity and neuronal survival
Series Name/Journal:Acta Neuropathologica
Year of publishing :2022
Volume:143
Number:2
Page range:245-262
Number of Pages:18
Publisher:SPRINGER
ISSN:0001-6322
Language:English
Publication Type:Research article
Article category:Scientific peer reviewed
Version:Published version
Copyright:Creative Commons: Attribution 4.0
Full Text Status:Public
Subjects:(A) Swedish standard research categories 2011 > 3 Medical and Health Sciences > 301 Basic Medicine > Medical Genetics
(A) Swedish standard research categories 2011 > 3 Medical and Health Sciences > 302 Clinical Medicine > Neurology
Keywords:DTYMK, dTMPK, Nucleotide metabolism, Zebrafish, Genome instability
URN:NBN:urn:nbn:se:slu:epsilon-p-115054
Permanent URL:
http://urn.kb.se/resolve?urn=urn:nbn:se:slu:epsilon-p-115054
Additional ID:
Type of IDID
DOI10.1007/s00401-021-02394-0
Web of Science (WoS)000730882900001
ID Code:27077
Faculty:VH - Faculty of Veterinary Medicine and Animal Science
Department:(VH) > Dept. of Anatomy, Physiology and Biochemistry
Deposited By: SLUpub Connector
Deposited On:14 Feb 2022 10:25
Metadata Last Modified:14 Feb 2022 10:31

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