Deficiency of pnkp in zebrafish causes microcephaly, seizures and developmental delay through mitochondrial dysfunction

Despite its clinical impact, the underlying pathological mechanisms remain unclear. In this work, we utilized CRISPR/Cas9 technology to generate a zebrafish model with a pnkp knockout (pnkp-/-), overcoming limitations seen in prior mouse models that suffered from postpartum death.

This zebrafish model faithfully recapitulated phenotypic traits observed in human PNKP deficiency, facilitating an in-depth exploration of the molecular mechanisms involved. The study revealed that pnkp deficiency disrupts mitochondria function, leading to mitochondrial apoptosis and inhibition of autophagy. Notably, the anti-seizure drug lamotrigine (LTG) demonstrated particularly promising efficacy in rescuing the hyperactive behavior.