ClinVar

In 3 unrelated patients (patients 2, 3, and 4) of French origin with developmental and epileptic encephalopathy-14 (DEE14; 614959) manifest clinically as malignant migrating partial seizures of infancy (MMPSI), Barcia et al. (2012) identified a de novo heterozygous 1283G-A transition in exon 13 of the KCNT1 gene, resulting in an arg428-to-gln (R428Q) substitution at a highly conserved residue in the cytoplasmic C-terminal domain. The mutation was initially identified by exome sequencing and confirmed by Sanger sequencing in 1 patient; analysis of this gene in subsequent patients identified the same mutation in 2 other individuals with the same disorder. The mutation was not found in 200 controls or in several large control databases. Expression of the corresponding rat mutation, R409Q, in Xenopus oocytes resulted in Kcnt1-generated currents that resembled wildtype in terms of voltage dependence and kinetic behavior but had 2- to 3-fold higher amplitude compared to wildtype, consistent with a gain of function. The mutation was shown to cause constitutive activation of the Kcnt1 channel, mimicking the effects of phosphorylation of the C-terminal domain by protein kinase C (see, e.g., PRKCA, 176960) activation. The patients had onset of seizures at 2 hours, 17 hours, and 2 months of age, respectively.