Differential mechanisms of Cantú syndrome-associated gain of function mutations in the ABCC9 (SUR2) subunit of the KATP channel

J Gen Physiol. 2015 Dec;146(6):527-40. doi: 10.1085/jgp.201511495.


Cantú syndrome (CS) is a rare disease characterized by congenital hypertrichosis, distinct facial features, osteochondrodysplasia, and cardiac defects. Recent genetic analysis has revealed that the majority of CS patients carry a missense mutation in ABCC9, which codes for the sulfonylurea receptor SUR2. SUR2 subunits couple with Kir6.x, inwardly rectifying potassium pore-forming subunits, to form adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channels, which link cell metabolism to membrane excitability in a variety of tissues including vascular smooth muscle, skeletal muscle, and the heart. The functional consequences of multiple uncharacterized CS mutations remain unclear. Here, we have focused on determining the functional consequences of three documented human CS-associated ABCC9 mutations: human P432L, A478V, and C1043Y. The mutations were engineered in the equivalent position in rat SUR2A (P429L, A475V, and C1039Y), and each was coexpressed with mouse Kir6.2. Using macroscopic rubidium ((86)Rb(+)) efflux assays, we show that K(ATP) channels formed with P429L, A475V, or C1039Y mutants enhance K(ATP) activity compared with wild-type (WT) channels. We used inside-out patch-clamp electrophysiology to measure channel sensitivity to ATP inhibition and to MgADP activation. For P429L and A475V mutants, sensitivity to ATP inhibition was comparable to WT channels, but activation by MgADP was significantly greater. C1039Y-dependent channels were significantly less sensitive to inhibition by ATP or by glibenclamide, but MgADP activation was comparable to WT. The results indicate that these three CS mutations all lead to overactive K(ATP) channels, but at least two mechanisms underlie the observed gain of function: decreased ATP inhibition and enhanced MgADP activation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Action Potentials
  • Adenosine Triphosphate / metabolism
  • Amino Acid Sequence
  • Animals
  • COS Cells
  • Cardiomegaly / genetics*
  • Cardiomegaly / metabolism
  • Chlorocebus aethiops
  • Humans
  • Hypertrichosis / genetics*
  • Hypertrichosis / metabolism
  • Mice
  • Molecular Sequence Data
  • Mutation, Missense*
  • Osteochondrodysplasias / genetics*
  • Osteochondrodysplasias / metabolism
  • Potassium Channels, Inwardly Rectifying / metabolism
  • Sulfonylurea Receptors / chemistry
  • Sulfonylurea Receptors / genetics
  • Sulfonylurea Receptors / metabolism*


  • ABCC9 protein, human
  • Kir6.2 channel
  • Potassium Channels, Inwardly Rectifying
  • Sulfonylurea Receptors
  • Adenosine Triphosphate

Supplementary concepts

  • Cantu syndrome