Year: 2021
Type: article
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.
Source: Acta Neuropathologica
Authors: 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’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
Institutions: Maastricht University Medical Centre, Maastricht University, Radboud University Nijmegen, Radboud University Medical Center, Máxima Medisch Centrum, Amsterdam UMC Location Vrije Universiteit Amsterdam, Swedish University of Agricultural Sciences, University of Sussex, National Institutes of Health, National Human Genome Research Institute, Donders Institute for Brain, Cognition and Behaviour, National Research Centre
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,480
Awards: G1149677164, G3736429804
OpenAlex ID: W4200138245