Activating mutations in the ABCC8 gene in neonatal diabetes mellitus

Andrey P. Babenko (1) , Michel Polak (1) , Hélène Cavé (1) , Kanetee Busiah (1) , Paul Czernichow (1) , Raphael Scharfmann (1) , Joseph Bryan (1) , Lydia Aguilar-Bryan (1) , Martine Vaxillaire (1) , Philippe Froguel (1)

1 GMM - Génétique des maladies multifactorielles

BACKGROUND : The ATP-sensitive potassium (KATP) channel, composed of the beta-cell proteins sul-fonylurea 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 nucle-otides to subunit Kir6.2, which closes the channel, and activated by nucleotide bind-ing or hydrolysis on SUR1, which opens the channel. The balance of these opposing actions determines the low open-channel probability, PO, which controls the excit-ability 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 neo-natal diabetes of unknown origin. We assayed the electrophysiologic activity of mu-tant and wild-type KATP channels. RESULTSWe identified seven missense mutations in nine patients. Four mutations were famil-ial and showed vertical transmission with neonatal and adult-onset diabetes; the re-maining 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 PO than did wild-type channels. These overactive channels remained sensitive to sulfonylurea, and treatment with sulfonylureas resulted in euglycemia. CONCLUSIONSDominant 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.

Domaines: Génétique humaine

Andrey P. Babenko, Michel Polak, Hélène Cavé, Kanetee Busiah, Paul Czernichow, et al.. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. New England Journal of Medicine, 2006, 355, pp.456-66. ⟨hal-00094668⟩