Science Topics – 101

De novo Kv2.1 mutants causing infantile generalized seizures and psychomotor developmental delay inhibit repetitive firing of pyramidal neurons
Tenpei Akita1, Hirotomo Saitsu2

Various mutants of voltage-gated potassium channels (Kv) are known to be associated with infantile epileptic seizures and psychomotor developmental delay. However, their pathophysiological mechanisms are not fully understood. By searching whole exome sequencing data of a total of 437 patients with infantile epilepsy, we recently found two novel de novo heterozygous missense mutations in KCNB1, encoding the major delayed rectifier Kv2.1 in cortical and hippocampal pyramidal neurons, in two patients. Both patients exhibited a delay in motor development after birth, and 1-1.5 years after birth they developed severe generalized seizures with diffuse high-amplitude spike-and-wave electroencephalogram discharges. The patients now have intellectual disabilities. One mutation occurred at one of positively charged arginine residues (p.R306C) in the S4 voltage sensor domain of Kv2.1. This mutation strongly disrupted sensitivity and cooperativity of the sensor. Another mutation occurred at the ‘gating hinge’ of the glycine residue (p.G401R) in the S6 pore domain. This nullified the channel function and also had a dominant-negative effect on endogenous Kv2. When individual Kv2.1 mutants were expressed in cultured cortical pyramidal neurons, repetitive firing of action potentials was greatly suppressed, especially in R306C mutant-expressing neurons. Thus our results suggest that insufficient firing of pyramidal neurons disturbs not only the development but also the stability of neuronal circuits, resulting in the disease phenotypes.

Saitsu H*, Akita T* et al. De novo KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing. Scientific Reports 5:15199, doi: 10.1038/srep15199 (2015).
*equal contribution & corresponding authors

  1. Department of Neurophysiology, Hamamatsu University School of Medicine.
  2. Department of Human Genetics, Yokohama City University Graduate School of Medicine.