Epilepsy is a complex neurological disorder characterized by unprovoked seizures. The etiology is heterogeneous with both
genetic and environmental causes. Genes that regulate neurotransmitters and ion channels in the central nervous system have
been associated with epilepsy. However, a recent screening in human epilepsy patients identified mutations in the PRICKLE1 (PK1) locus, highlighting a potentially novel mechanism underlying seizures. PK1 is a core component of the Planar Cell Polarity
network that regulates tissue polarity. Zebrafish studies have shown that Pk1 coordinates cell movement, neuronal migration
and axonal outgrowth during embryonic development. Yet how dysfunction of Pk1 relates to epilepsy is unknown. To address
the mechanism underlying epileptogenesis, we use zebrafish to characterize Pk1a function and epilepsy-related mutant forms.
We show that knockdown of pk1a activity sensitizes zebrafish larva to a convulsant drug. To model defects in the central nervous system, we use the retina
and find that pk1a knockdown induces neurite outgrowth defects; yet visual function is maintained. Furthermore, we characterized the functional
and biochemical properties of the PK1 mutant forms identified in human patients. Functional analyses demonstrate that the
wild-type Pk1a partially suppresses the gene knockdown retinal defects but not the mutant forms. Biochemical analysis reveals
increased ubiquitination of one mutant form and decreased translational efficiency of another mutant form compared to the
wild-type Pk1a. Taken together, our results indicate that mutation of human PK1 may lead to defects in neurodevelopment and
signal processing providing insight into seizure predisposition in these patients.