Figure: Protein structure of the potassium ion channel. This cartoon shows the location of sites in the biomolecule that are affected by the genetic changes (green) they found in children with intellectual disability and epilepsy. These sites are in key functional areas of the protein structure, including the ion conducting pore region (red), voltage sensing domain (blue) and intracellular regulatory domain (purple).

Intellectual disability and epilepsy in children: one culprit – potassium ion channel mutations – offers a new potential drug target

The motivation Intellectual disability and epilepsy are often caused by faulty genes; many different genes have been implicated. One affected group of genes encodes specialized structures known as potassium ion channels. These protein structures form pores in cell membranes that selectively allow the flow of charged potassium ions across the membrane, thereby generating electrical current. In particular, the opening and closing of these channels controls the flow of potassium ions out of brain cells, which in turn controls the excitability and firing of these nerve cells. Without coordinated opening and closing of potassium channels, brain cells cannot form the new networks necessary for learning. Uncoordinated brain cell firing can also cause seizures. An international team of neurologists and geneticists – led by Simon Fraser University’s Tom Claydon – discovered genetic changes in a brain potassium channel in children with intellectual disability or epilepsy. These scientists sought to understand whether these genetic mutations could be responsible for the health issues of the children.

The discovery – The normal role of this potassium channel is not well understood; indeed, before this study no neurological diseases had been linked with changes to the gene. The team used a simple model cell system to determine how the gene changes affect the function of the potassium channels. Using this approach, they discovered that some of the gene changes caused a reduced function of the channels, while others enhanced the channel function.

Its significance – Interestingly, the changes in channel function correlated with the symptoms found in the affected individuals, suggesting that the gene changes are a causative factor in the disease. These researchers propose that dysfunction of this potassium channel affects important brain cell networks and that drugs that target these channels in the brain are of potential use in the treatment of these and other affected individuals.

Read the paper“Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy” by Lehman A, Thouta S, Mancini GMS, Naidu S, van Slegtenhorst M, McWalter K, Person R, Mwenifumbo J, Salvarinova R; CAUSES Study; EPGEN Study, Guella I, McKenzie MB, Datta A, Connolly MB, Kalkhoran SM, Poburko D, Friedman JM6, Farrer MJ, Demos M, Desai S, Claydon T. American Journal of Human Genetics 101(1):65-74 (2017). DOI: 10.1016/j.ajhg.2017.05.016

Website article compiled by Jacqueline Watson with Theresa Kitos