This report describes a fly model of epilepsies that are SLC12A5-related. The human gene implicated in these diseases is SLC12A5, which encodes an integral membrane potassium-chloride transporter. SLC12A5 is implicated in two forms of epilepsy; see MIM:616645 and MIM:616685. There is a single fly ortholog, Dmel\kcc, for which classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\kcc is also orthologous to other potassium-chloride cotransporter genes in human (SLC12A4, SLC12A6, and SLC12A7); only SLC12A5 is implicated in epilepsy in humans.
A UAS construct driving the wild-type human gene, Hsap\SLC12A5, has been introduced into flies. Heterologous rescue (functional complementation) of the seizure phenotype of a hypomorphic allele of Dmel\kcc has been observed.
Reduced function of kcc results in seizure sensitivity, including a lowered threshold to evoked electrophysiologically recorded seizure-like activity and "bang-sensitive" phenotypes. Seizure sensitivity is observed in animals with kcc loss-of-function effected by targeted RNAi in either glia or neurons. Amorphic alleles of kcc are lethal. Genetic and physical interactions have been described; see below and in the gene report for kcc.
[updated June 2016 by FlyBase; FBrf0222196]
(Note: The following description is for one of the two forms of epilepsy for which SLC12A5 is implicated as a causative gene.)
Early infantile epileptic encephalopathy-34 (EIEE34) is an autosomal recessive severe neurologic disorder characterized by onset of refractory migrating focal seizures in infancy. Affected children show developmental regression and are severely impaired globally (summary by Stodberg et al., 2015; pubmed:26333769). [from MIM:616645; 2016.06.03]
EIEE34 is inherited as an autosomal recessive; EIG14 (classified as a susceptibility locus) exhibits autosomal dominant inheritance with incomplete penetrance. [from MIM:616645; MIM:616685; 2016.06.03]
The protein encoded by SLC12A5 is an integral membrane K-Cl cotransporter that can function in either a net efflux or influx pathway, depending on the chemical concentration gradients of potassium and chloride. The encoded protein can act as a homomultimer, or as a heteromultimer with other K-Cl cotransporters, to maintain chloride homeostasis in neurons. [from Gene Cards, SLC12A5; 2016.06.03]
Many to one: 4 human to 1 Drosophila; the fly gene kcc is orthologous to SLC12A4, SLC12A5, SLC12A6, and SLC12A7 in human.
High-scoring ortholog of human gene SLC12A4; moderate-scoring ortholog of SLC12A5, SLC12A6, SLC12A7 (1 Drosophila to 4 human). Dmel\kcc shares 51-57% identity and 68-74% similarity with the human genes.
