Drosophilaas a Model for Intractable Epilepsy:GilgameshSuppresses Seizures inparabss1Heterozygote Flies

Abstract

Intractable epilepsies, that is, seizure disorders that do not respond to currently available therapies, are difficult, often tragic, neurological disorders. Na+ channelopathies have been implicated in some intractable epilepsies, including Dravet syndrome (Dravet 1978), but little progress has been forthcoming in therapeutics. Here we examine a Drosophila model for intractable epilepsy, the Na+ channel gain-of-function mutant parabss1 that resembles Dravet syndrome in some aspects (parker et al. 2011a). In particular, we identify second-site mutations that interact with parabss1, seizure enhancers, and seizure suppressors. We describe one seizure-enhancer mutation named charlatan (chn). The chn gene normally encodes an Neuron-Restrictive Silencer Factor/RE1-Silencing Transcription factor transcriptional repressor of neuronal-specific genes. We identify a second-site seizure-suppressor mutation, gilgamesh (gish), that reduces the severity of several seizure-like phenotypes of parabss1/+ heterozygotes. The gish gene normally encodes the Drosophila ortholog of casein kinase CK1g3, a member of the CK1 family of serine-threonine kinases. We suggest that CK1g3 is an unexpected but promising new target for seizure therapeutics.

Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis

“…Intriguingly, the Drosophila homolog of CSNK1G3 was found to suppress seizures in the Na + -channel gain-of-function mutant para bss1 (62). Also, a mutation in PRICKLE1 , which encodes a regulator of the Dishevelled proteins that are intracellular transducers of Wnt signals (63), has been reported to cause progressive myoclonic epilepsy (61).…”

Seizure suppression through manipulating splicing of a voltage-gated sodium channel

“…For example, topoisomerase 1 ( top1 JS ) and gilgamesh mutant flies, as well as the topoisomerase 1 inhibitor, camptothecin, reduce the severity of bss 1 seizure behaviour (Song et al , 2007; Howlett et al , 2013). In this study, the candidates of our screen are seizure suppressor genes which regulate a common downstream gene transcript, DmNa v .…”

Pathway-driven discovery of epilepsy genes

“…There has been a small but steady push to uncover suppressor genes using classical mapping 87–89 and combinatorial approaches 83,90 in experimental models. Now that changes in these genes can be routinely detected in human exome studies, incorporating them in a diagnostic variant profile analysis will be critical to accurately define risk.…”