Cantu syndrome-associated SUR2[H60Y] mutation confers selective gain of function on Kir6.1 ATP-sensitive potassium...

Gain-of-function (GOF) mutations in either Kir6.1 (encoded by KCNJ8) or SUR2 (encoded by ABCC9) are causally associated with Cantu syndrome (CS), characterized by coarse facial appearance, hypertrichosis, and multiple cardiovascular abnormalities. To date, all SUR2 mutations identified in association with CS have demonstrated GOF because of reduced ATP sensitivity using patch-clamp analysis, with the notable exception of SUR2[H60Y], which showed WT behavior in Kir6.2-SUR2A channels. We readdressed the effect of SUR2[H60Y] on channel function of the relevant Kir6.1-SUR2B channels, in intact cells, in a more physiologically relevant condition using DiBAC4(3) membrane potential measurements. The H60Y mutation uniquely causes a GOF of Kir6.1-SUR2B channels but does not cause GOF in Kir6.2-SUR2B channels. By a chimeric approach, we identify regions of both the very N and C termini of Kir6.1 that are responsible for this effect and further identify a specific residue, valine 334, in Kir6.1, which is necessary for the isoform specificity.