KCNQ1 – A long underestimated potassium channel in the brain?

KCNQ1 is the pore-forming alpha subunit of a voltage-dependent potassium channel complex. It is predominantly expressed in the heart and in the inner ear, however, it is also present in the brain. Genetic variants in KCNQ1 have been linked to several disorders, like Romano-Ward syndrome, Jervell and Lange Nielson syndrome and diabetes mellitus type 2. Moreover, KCNQ1 is also discussed to contribute to the pathogenesis of Alzheimer´s disease and neurodevelopmental disorders, even though it´s function in the human brain remains unknown. In this study we aim to elucidate the function of KCNQ1 in human neuronal cells. We generated homozygous and heterozygous KCNQ1 knockout (KO) iPSC lines which were differentiated into neuronal stem cells (NSCs) and into cortical neurons. iPSC-derived NSCs with loss of KCNQ1 show reduced neurite outgrowth compared to the isogenic controls, indicating a role of KCNQ1 already during early neuronal differentiation. This is in line with results from the expression analysis focusing on different neuronal marker genes in cortical neurons. Cortical neurons with loss of KCNQ1 reveal impairments in neuronal differentiation, with reduced expression of genes encoding for pre- and postsynaptic proteins and an increased expression of cortical layer 1 marker Reelin. In summary, we obtained first evidence for an important role of KCNQ1 during neuronal differentiation which we will follow-up with functional and “omics” analysis.