Activating Mutations in theABCC8Gene in Neonatal Diabetes Mellitus

Details

Serval ID
serval:BIB_D0AFB006775F
Type
Article: article from journal or magazin.
Collection
Publications
Title
Activating Mutations in theABCC8Gene in Neonatal Diabetes Mellitus
Journal
New England Journal of Medicine
Author(s)
Babenko Andrey P., Polak Michel, Cavé Hélène, Busiah Kanetee, Czernichow Paul, Scharfmann Raphael, Bryan Joseph, Aguilar-Bryan Lydia, Vaxillaire Martine, Froguel Philippe
ISSN
0028-4793
1533-4406
Publication state
Published
Issued date
03/08/2006
Volume
355
Number
5
Pages
456-466
Language
english
Abstract
BACKGROUND:
The ATP-sensitive potassium (K(ATP)) channel, composed of the beta-cell proteins sulfonylurea receptor (SUR1) and inward-rectifying potassium channel subunit Kir6.2, is a key regulator of insulin release. It is inhibited by the binding of adenine nucleotides to subunit Kir6.2, which closes the channel, and activated by nucleotide binding or hydrolysis on SUR1, which opens the channel. The balance of these opposing actions determines the low open-channel probability, P(O), which controls the excitability of pancreatic beta cells. We hypothesized that activating mutations in ABCC8, which encodes SUR1, cause neonatal diabetes.
METHODS:
We screened the 39 exons of ABCC8 in 34 patients with permanent or transient neonatal diabetes of unknown origin. We assayed the electrophysiologic activity of mutant and wild-type K(ATP) channels.
RESULTS:
We identified seven missense mutations in nine patients. Four mutations were familial and showed vertical transmission with neonatal and adult-onset diabetes; the remaining mutations were not transmitted and not found in more than 300 patients without diabetes or with early-onset diabetes of similar genetic background. Mutant channels in intact cells and in physiologic concentrations of magnesium ATP had a markedly higher P(O) than did wild-type channels. These overactive channels remained sensitive to sulfonylurea, and treatment with sulfonylureas resulted in euglycemia.
CONCLUSIONS:
Dominant mutations in ABCC8 accounted for 12 percent of cases of neonatal diabetes in the study group. Diabetes results from a newly discovered mechanism whereby the basal magnesium-nucleotide-dependent stimulatory action of SUR1 on the Kir pore is elevated and blockade by sulfonylureas is preserved.
Pubmed
Web of science
Create date
25/03/2020 23:13
Last modification date
26/03/2020 7:26
Usage data