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

Channels
Yu-Wen LinDiva D De León

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 Mg(2+)) 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. (86)Rb(+) flux assays on COSm6 cells coexpressing the mutant subunits (to recapitulate the compound heterozygous state) show a 2-fold increase in basal rate of (86)Rb(+) 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 IC 50 for ATP inhibition of homomeric...Continue Reading

References

Jan 1, 1997·Annual Review of Physiology·C G Nichols, A N Lopatin
Aug 28, 2003·The Journal of Biological Chemistry·Andrey P Babenko, Joseph Bryan
Dec 8, 2004·Human Mutation·Ornella MassaUNKNOWN Early Onset Diabetes Study Group of the Italian Society of Pediatric Endocrinology and Diabetology
Dec 8, 2004·Proceedings of the National Academy of Sciences of the United States of America·Peter ProksFrances M Ashcroft
Aug 3, 2005·The Journal of Clinical Investigation·Frances M Ashcroft
Aug 4, 2006·The New England Journal of Medicine·Andrey P BabenkoPhilippe Froguel
Aug 4, 2006·The New England Journal of Medicine·Ewan R PearsonUNKNOWN Neonatal Diabetes International Collaborative Group
Apr 9, 2009·The Journal of Clinical Endocrinology and Metabolism·Tim J CraigFrances M Ashcroft
Oct 6, 2010·Reviews in Endocrine & Metabolic Disorders·Emma L EdghillSian Ellard

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Citations

Jun 29, 2013·Diabetes & Metabolism Journal·Peter Proks
Aug 22, 2017·Internal Medicine·Kenju Shimomura, Yuko Maejima
May 8, 2020·Nature Reviews. Endocrinology·Tanadet PipatpolkaiFrances M Ashcroft

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