Compound heterozygous mutations in the SUR1 (ABCC 8) subunit of pancreatic KATP channels cause neonatal diabetes by perturbing the coupling between Kir6.2 and SUR1 subunits

 Abstract

KATP channels regulate insulin secretion by coupling β-cell metabolism to membrane excitability. These channels are comprised of a pore-forming Kir6.2 tetramer which is enveloped by four regulatory SUR1 subunits. ATP acts on Kir6.2 to stabilize the channel closed state while ADP (coordinated with Mg2+) activates channels via the SUR1 domains. Aberrations in nucleotide-binding or in coupling binding to gating can lead to hyperinsulinism or diabetes. Here, we report a case of diabetes in a 7-mo old child with compound heterozygous mutations in ABCC8 (SUR1[A30V] and SUR1[G296R]). In unison, these mutations lead to a gain of KATP channel function, which will attenuate the β-cell response to increased metabolism and will thereby decrease insulin secretion. 86Rb+ flux assays on COSm6 cells coexpressing the mutant subunits (to recapitulate the compound heterozygous state) show a 2-fold increase in basal rate of 86Rb+ efflux relative to WT channels. Experiments on excised inside-out patches also reveal a slight increase in activity, manifested as an enhancement in stimulation by MgADP in channels expressing the compound heterozygous mutations or homozygous G296R mutation. In addition, the IC50 for ATP inhibition of homomeric A30V channels was increased ~6-fold, and was increased ~3-fold for both heteromeric A30V+WT channels or compound heterozygous (A30V +G296R) channels. Thus, each mutation makes a mechanistically distinct contribution to the channel gain-of-function that results in neonatal diabetes, and which we predict may contribute to diabetes in related carrier individuals.

Full Text Options
Article
Metrics
 Share
 Full Text
 Info
Pages
133 - 138
doi
10.4161/chan.19980
Type
Research Paper
 Metrics
 Cite This Article
 Permissions
 Permissions
 Reprints
Compound heterozygous mutations in the SUR1 (ABCC 8) subunit of pancreatic KATP channels cause neonatal diabetes by perturbing the coupling between Kir6.2 and SUR1 subunits