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DTYMK is essential for genome integrity and neuronal survival
Jo M Vanoevelen1,2, Jörgen Bierau3, Janine C Grashorn3
1Department of Clinical Genetics, Maastricht University Medical Centre+, 6229 ER, Maastricht, The Netherlands. j.vanoevelen@maastrichtuniversity.nl.
Acta Neuropathologica
|December 17, 2021
Summary
Impaired dTTP synthesis due to DTYMK gene variants causes severe neurodegeneration. This highlights the critical role of nucleotide metabolism in DNA stability and brain development.
Area of Science:
- Biochemistry
- Genetics
- Neuroscience
Background:
- Nucleotide metabolism is vital for DNA synthesis, repair, and cell proliferation.
- dTTP is a crucial building block for DNA synthesis.
Observation:
- Two unrelated children with bi-allelic DTYMK variants presented with severe microcephaly, growth retardation, and minimal neurodevelopment.
- Brain imaging showed cerebral atrophy and basal ganglia disappearance in affected children.
- dtymk mutant zebrafish models exhibited microcephaly, neuronal cell death, and early lethality.
Findings:
- Loss-of-function variants in DTYMK, encoding dTMPK, severely impair dTTP biosynthesis.
- Affected individuals and zebrafish showed minimal dTMPK activity, impaired DNA replication, and increased ribonucleotide incorporation into the genome.
- dtymk mutants displayed impaired DNA damage response.
Implications:
- DTYMK deficiency causes a severe postnatal neurodegenerative disease, challenging the notion of viability with a blocked essential DNA precursor pathway.
- This study underscores the essential role of dTTP synthesis in maintaining genome stability and neuronal survival.
- Identifies DTYMK as a key gene in neurodevelopment and genome integrity.
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