TY - JOUR
T1 - DTYMK is essential for genome integrity and neuronal survival
AU - Vanoevelen, Jo M.
AU - Bierau, J. rgen
AU - Grashorn, Janine C.
AU - Lambrichs, Ellen
AU - Kamsteeg, Erik-Jan
AU - Bok, Levinus A.
AU - Wevers, Ron A.
AU - van der Knaap, Marjo S.
AU - Bugiani, Marianna
AU - Frisk, Junmei Hu
AU - Colnaghi, Rita
AU - O’Driscoll, Mark
AU - Hellebrekers, Debby M. E. I.
AU - Rodenburg, Richard
AU - Ferreira, Carlos R.
AU - Brunner, Han G.
AU - van den Wijngaard, Arthur
AU - Abdel-Salam, Ghada M. H.
AU - Wang, Liya
AU - Stumpel, Constance T. R. M.
N1 - Funding Information: We thank the families involved for their extensive collaboration. Rick Kamps is acknowledged for expert help in histology and Yvette E.G. Barrois for additional genotyping. We thank Alexandra Hendrickx for providing mtDNA diagnostics and Martin Reijns and Andrew Jackson (University of Edinburgh) for kindly providing Rnaseh2 ?/? cells. This project was funded by Metakids grant number 2018-081 (Metakids.nl), awarded to JV. Funding Information: We thank the families involved for their extensive collaboration. Rick Kamps is acknowledged for expert help in histology and Yvette E.G. Barrois for additional genotyping. We thank Alexandra Hendrickx for providing mtDNA diagnostics and Martin Reijns and Andrew Jackson (University of Edinburgh) for kindly providing Rnaseh2 –/– cells. This project was funded by Metakids grant number 2018-081 (Metakids.nl), awarded to JV. Publisher Copyright: © 2021, The Author(s).
PY - 2022/2
Y1 - 2022/2
N2 - 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.
AB - 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.
KW - DTYMK
KW - Genome instability
KW - Nucleotide metabolism
KW - Zebrafish
KW - dTMPK
UR - http://www.scopus.com/inward/record.url?scp=85121139055&partnerID=8YFLogxK
U2 - https://doi.org/10.1007/s00401-021-02394-0
DO - https://doi.org/10.1007/s00401-021-02394-0
M3 - Article
C2 - 34918187
SN - 0001-6322
VL - 143
SP - 245
EP - 262
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 2
ER -