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

## TL;DR

A specific mutation in the SUR2 gene causes a gain of function in potassium channels linked to Cantu syndrome, but only when paired with the Kir6.1 protein.

## Contribution

The study reveals that the SUR2[H60Y] mutation selectively affects Kir6.1–SUR2B channels, identifying key regions and a specific residue responsible for this isoform specificity.

## Key findings

- The SUR2[H60Y] mutation causes a gain of function in Kir6.1–SUR2B channels but not in Kir6.2–SUR2B channels.
- Regions in the N and C termini of Kir6.1 are responsible for the isoform-specific effect of the mutation.
- Valine 334 in Kir6.1 is a critical residue for the mutation's selective gain of function.

## Abstract

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.