DTYMK is essential for genome integrity and neuronal survival

Acta Neuropathol. 2022 Feb;143(2):245-262. doi: 10.1007/s00401-021-02394-0.

Jo M Vanoevelen ^# ¹ ², Jörgen Bierau ^# ³, Janine C Grashorn ³, Ellen Lambrichs ³, Erik-Jan Kamsteeg ⁴, Levinus A Bok ⁵, Ron A Wevers ⁶, Marjo S van der Knaap ⁷, Marianna Bugiani ⁸, Junmei Hu Frisk ⁹, Rita Colnaghi ¹⁰, Mark O'Driscoll ¹⁰, Debby M E I Hellebrekers ³, Richard Rodenburg ⁶, Carlos R Ferreira ¹¹, Han G Brunner ³ ⁴ ¹² ¹³ ¹⁴, Arthur van den Wijngaard ³, Ghada M H Abdel-Salam ¹⁵, Liya Wang ⁹, Constance T R M Stumpel ¹⁶

Affiliations

1 Department of Clinical Genetics, Maastricht University Medical Centre+, 6229 ER, Maastricht, The Netherlands. j.vanoevelen@maastrichtuniversity.nl.
2 GROW-School for Oncology and Developmental Biology, 6229 ER, Maastricht, The Netherlands. j.vanoevelen@maastrichtuniversity.nl.
3 Department of Clinical Genetics, Maastricht University Medical Centre+, 6229 ER, Maastricht, The Netherlands.
4 Department of Human Genetics, Radboud UMC, 6525 GA, Nijmegen, The Netherlands.
5 Department of Pediatrics, Màxima Medical Center, 5504 DB, Veldhoven, The Netherlands.
6 Translational Metabolic Laboratory, Radboud UMC, 6525 GA, Nijmegen, The Netherlands.
7 Department of Child Neurology, VUMC, 1105 AZ, Amsterdam, The Netherlands.
8 Department of Neuropathology, VUMC, 1105 AZ, Amsterdam, The Netherlands.
9 Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, 75007, Uppsala, Sweden.
10 Genome Damage and Stability Centre, University of Sussex, Brighton, BN1 9RH, UK.
11 National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
12 GROW-School for Oncology and Developmental Biology, 6229 ER, Maastricht, The Netherlands.
13 MHENS School of Neuroscience, 6229 ER, Maastricht, The Netherlands.
14 Donders Institute of Neuroscience, Radboud UMC, 6525 GA, Nijmegen, The Netherlands.
15 Department of Clinical Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo, 12311, Egypt.
16 Department of Clinical Genetics, Maastricht University Medical Centre+, 6229 ER, Maastricht, The Netherlands. c.stumpel@mumc.nl.
# Contributed equally.

PMID: 34918187 DOI: 10.1007/s00401-021-02394-0

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.

Keywords

DTYMK; Genome instability; Nucleotide metabolism; Zebrafish; dTMPK.

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