• epilepsy

This report describes a fly model of epilepsy using alleles of the fly gene para, which encodes a sodium voltage-gated channel alpha subunit. Human voltage-gated sodium channel alpha subunits are encoded by ten different genes, including several associated with forms of epilepsy (SCN1A, SCN2A, SCN8A, SCN9A); these forms of epilepsy exhibit autosomal dominant inheritance. The Dmel\para gene has been extensively characterized; classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.

UAS constructs of the human genes Hsap\SCN2A and Hsap\SCN5A have been introduced into flies, but have not been characterized in the context of this disease model. None of the other human genes orthologous to Dmel\para has been introduced into flies.

Mutational lesions of Dmel\para analogous to those found in specific forms of epilepsy have been studied; see "epilepsy, generalized, with febrile seizures plus, type 2" (GEFSP2, FBhh0000309) and "early infantile epileptic encephalopathy 6" (EIEE6, FBhh0000306). Variant(s) implicated in human disease tested (as analogous mutation in fly gene): the endogenous para gene was modified, thus affecting multiple isoforms (corresponds to K1270T in the human SCN1A gene, designated para^GEFS+, implicated in GEFSP2); the endogenous para gene was modified, thus affecting multiple isoforms (corresponds to S1231R in the human SCN1A gene, designated para^DS.S1231R, implicated in EIEE6).

Amorphic alleles of Dmel\para are lethal, usually during larval stages; larvae exhibit neurophysiological defects. Animals carrying homozygous or trans-heterozygous loss-of-function mutations can survive to adulthood; many exhibit heat-sensitive paralysis. Two "bang-sensitive" alleles of this gene (para^bss1 and para^bss2) are atypical gain-of-function mutations, and were found to have identical mutational lesions. During initial characterization of the disease model, feeding bang-sensitive animals a known anticonvulsant was observed to reduce the intensity and duration of the induced seizures and paralysis significantly; additional pharmaceutical interventions have been tested subsequently. The bang-sensitive phenotype has been used to characterize genetic interactions; see the FlyBase gene report for para.

Several recent studies have shown that different dietary mediums can significantly impact the severity of the para seizure-sensitive phenotypes.

[updated Apr. 2020 by FlyBase; FBrf0222196]