Two studies have identified mutations in a sodium-gated potassium channel gene, KCNT1, as a cause of two forms of early-onset epileptic disorders.

...the spectrum of epilepsies caused by mutations in KCNT1 may be wider than we thought...

Sam Berkovic and colleagues focused on autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). The group had previously found mutations in the nicotinic acetylcholine receptor in patients with this disorder, but only in about 10% of cases. “Using the new technology of whole-exome capture and sequencing, we identified involvement of a new gene, KCNT1, in a family with severe ADNFLE involving more-refractory seizures and psychiatric features,” says Berkovic. Mutations in this gene occurred in a region encoding the highly conserved C-terminal domain of KCNT1, and showed complete cosegregation with disease. These findings were then confirmed in two further families with ADNFLE and in a sporadic case.

The other study involved patients with malignant migrating partial seizures of infancy—a rare epileptic encephalopathy characterized by drug-resistant seizures and developmental delay. Using exome sequencing, Rima Nabbout and colleagues identified de novo mutations in the C-terminal domain of KCNT1 in six of 12 patients tested. “This is the first study using trios and exome sequencing in homogeneous sporadic cases of epilepsy,” says Nabbout.

Next, the researchers performed functional studies in Xenopus laevis oocytes transfected with rat mutant Kcnt1 constructs. They found that the mutation enhanced potassium currents through the channel, in a manner that mimicked the physiological response to phosphorylation of the channel by protein kinase C.

In addition to ion conductance, KCNT1 has nonconducting function in developmental signalling pathways. “Mutations in KCNT1 might, therefore, be linked not only to epileptic activity in these severe epilepsies, but also to the brain development protein cascade,” explains Nabbout.

“Together, the two studies suggest that the spectrum of epilepsies caused by mutations in KCNT1 may be wider than we thought,” says Berkovic.