The KCNQ gene family encodes potassium channel proteins, which are essential for the transport of potassium ions across the cell membrane. It comprises five genes, and mutations in four of these genes have already been linked to hereditary diseases (cardiac arrhythmias [KCNQ1], epilepsy [KCNQ2 and KCNQ3] and hearing loss [KCNQ4]). KCNQ5 is a highly conserved gene that is primarily expressed in brain. An international group of researchers from Canada, the U.S. and the Netherlands have now discovered that defects of KCNQ5 cause a condition with intellectual disability and/or epileptic encephalopathy. By whole-exome sequencing they identified de novo heterozygous missense mutations in four probands.

Potassium channels act in various functions and physiological processes including propagation of nerve impulses. Kv7.5, the protein encoded by KCNQ5, is a voltage-gated potassium channel. In neurons, it regulates the M-current, a slowly activating and deactivating potassium current that plays an important role in regulating neuronal excitability by inhibiting repeated action-potential firing. By functional analyses in frog oocytes the scientists revealed that the newly identified KCNQ5 variants caused shifts in the voltage dependence of activation and altered activation and deactivation kinetics, with both loss-of-function and gain-of-function mutations leading to pathophysiology.

The study, which has been published in the American Journal of Human Genetics, reveals for the first time a phenotype caused by KCNQ5 mutations.