A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes

Abstract

Neonatal diabetes is a genetically heterogeneous disorder with nine different genetic aetiologies reported to date. Heterozygous activating mutations in the KCNJ11 gene encoding Kir6.2, the pore-forming subunit of the ATP-sensitive potassium (K(ATP)) channel, are the most common cause of permanent neonatal diabetes. The sulphonylurea receptor (SUR) SUR1 serves as the regulatory subunit of the K(ATP) channel in pancreatic beta cells. We therefore hypothesized that activating mutations in the ABCC8 gene, which encodes SUR1, might cause neonatal diabetes. We identified a novel heterozygous mutation, F132L, in the ABCC8 gene of a patient with severe developmental delay, epilepsy and neonatal diabetes (DEND syndrome). This mutation had arisen de novo and was not present in 150 control chromosomes. Residue F132 shows evolutionary conservation across species and is located in the first set of transmembrane helices (TMD0) of SUR1, which is proposed to interact with Kir6.2. Functional studies of recombinant K(ATP) channels demonstrated that F132L markedly reduces the sensitivity of the K(ATP) channel to inhibition by MgATP and this increases the whole-cell K(ATP) current. The functional consequence of this ABCC8 mutation mirrors that of KCNJ11 mutations causing neonatal diabetes and provides new insights into the interaction of Kir6.2 and SUR1. As SUR1 is expressed in neurones as well as in beta cells, this mutation can account for both neonatal diabetes and the neurological phenotype. Our results demonstrate that SUR1 mutations constitute a new genetic aetiology for neonatal diabetes and that they act by reducing the K(ATP) channel's ATP sensitivity.

New ABCC8 Mutations in Relapsing Neonatal Diabetes and Clinical Features

“…IGT, impaired glucose tolerance; N, normal; NA, not available. and in one patient previously reported with a SUR1 mutation (F132L) and severe DEND (developmental delay, epilepsy, and neonatal diabetes) syndrome (21). Indeed, in our cohort, we note that KCNJ11 mutations are mainly associated with PND (17 of 18), whereas the majority of ABCC8 mutations are linked to TND cases when considering the present cohort (6 of 7) and our published work (7 of 9) (13).…”

SUR1: a unique ATP-binding cassette protein that functions as an ion channel regulator

“…Currents of larger magnitude are considered to hyperpolarize other cells in which Kir6.2 is expressed, such as muscle and brain, accounting for the DEND phenotype. Consistent with this idea, the single SUR1 mutation that is associated with neurological problems results in a greater K ATP current than those that cause only neonatal diabetes (Proks et al 2006a(Proks et al , 2007 figure 4a). In general, the increase in the current produced by SUR1 mutations is smaller than that caused by Kir6.2 mutations, reflecting the smaller number of severe phenotypes and the relatively higher incidence of relapsing-remitting (transient) diabetes (TNDM) than permanent neonatal diabetes (PNDM) or DEND syndrome (figure 4b).…”

Amino acid properties may be useful in predicting clinical outcome in patients with Kir6.2 neonatal diabetes

“…Activating mutations in the KCNJ11 and ABCC8 genes, which encode the Kir6.2 and SUR1 subunits of the pancreatic b-cell ATP-sensitive potassium (K ATP ) channel, are the most common cause of NDM accounting for w50% of all cases (2,3,4,5,6,7). In the pancreatic b-cell, glucose metabolism results in an increase in the concentration of intracellular ATP.…”

“…ATP binds to the Kir6.2 subunit of the K ATP channel initiating channel closure, membrane depolarization and ultimately insulin secretion. Activating mutations in KCNJ11 and ABCC8 cause NDM by reducing the sensitivity of the K ATP channel to ATP (2,3).…”