Researchers identify genetic defects that cripple DNA repair, causing severe brain damage in children
Scientists have pinpointed mutations in a DNA repair gene that leave children unable to fix broken strands in their genetic code, leading to microcephaly and seizures. The findings could open pathways for early genetic screening and point toward therapies targeting faulty DNA maintenance systems—a growing focus for biotech firms developing treatments for rare genetic disorders.
Originaltitel: Novel PNKP mutations associated with reduced DNA single-strand break repair and severe microcephaly, seizures, and developmental delay
<p>Background: Microcephaly with early-onset seizures (MCSZ) is a neurodevelopmental disorder caused by pathogenic variants in the DNA strand break repair protein, polynucleotide kinase 3 '-phosphatase (PNKP).</p><p>Methods: We have used whole genome sequencing and Sanger sequencing to identify disease-causing variants, followed by a minigene assay, Western blotting, alkaline comet assay, gamma H2AX, and ADP-ribose immunofluorescence.</p><p>Results: Here, we describe a patient with compound heterozygous variants in PNKP, including a missense variant in the DNA phosphatase domain (T323M) and a novel splice acceptor site variant within the DNA kinase domain that we show leads to exon skipping. We show that primary fibroblasts derived from the patient exhibit greatly reduced levels of PNKP protein and reduced rates of DNA single-strand break repair, confirming that the mutated PNKP alleles are dysfunctional.</p><p>Conclusion: The data presented show that the detected compound heterozygous variants result in reduced levels of PNKP protein, which affect the repair of both oxidative and TOP1-induced single-strand breaks, and most likely causes MCSZ in this patient.</p>