A Nonsense Mutation in the Inward Rectifier Potassium Channel Gene, Kir6.2, Is Associated With Familial Hyperinsulinism

Abstract

ATP-sensitive potassium (K[ATP]) channels are an essential component of glucose-dependent insulin secretion in pancreatic islet beta-cells. These channels comprise the sulfonylurea receptor (SUR1) and Kir6.2, a member of the inward rectifier K+ channel family. Mutations in the SUR1 subunit are associated with familial hyperinsulinism (HI) (MIM:256450), an inherited disorder characterized by hyperinsulinism in the neonate. Since the Kir6.2 gene maps to human chromosome 11p15.1 (1,2), which also encompasses a locus for HI, we screened the Kir6.2 gene for the presence of mutations in 78 HI probands by single-strand conformation polymorphism (SSCP) and nucleotide sequence analyses. A nonsense mutation, Tyr-->Stop at codon 12 (designated Y12X) was observed in the homozygous state in a single proband. 86Rb+ efflux measurements and single-channel recordings of COS-1 cells co-expressing SUR1 and either wild-type or Y12X mutant Kir6.2 proteins confirmed that K(ATP) channel activity was abolished by this nonsense mutation. The identification of an HI patient homozygous for the Kir6.2/Y12X allele affords an opportunity to observe clinical features associated with mutations resulting in an absence of Kir6.2. These data provide evidence that mutations in the Kir6.2 subunit of the islet beta-cell K(ATP) channel are associated with the HI phenotype and also suggest that the majority of HI cases are not attributable to mutations in the coding region of the Kir6.2 gene.

Loss of Imprinted Genes and Paternal SUR1 Mutations Lead to Focal Form of Congenital Hyperinsulinism

“…The most commonly deleted region of chromosome 11 contained the SUR1 [25]and KIR6.2 [26]genes that code for two subunits of the potassium-ATP channel and are involved in familial recessive PHHI [3, 4, 5, 6, 7]. To understand whether the LOH may also unmask a recessive phenotype responsible for hypersecretion of insulin, we looked for deleterious mutations in the SUR1 gene.…”

“…Treatment of patients with diazoxide and/or somatostatin analogues is not always effective, necessitating an intervention such as pancreatectomy [2]. Rare familial forms may be caused by recessive or dominant defects in four different genes: (1) the sulphonylurea receptor gene (SUR1) [3, 4, 5]; (2) the inward rectifying potassium channel subunit gene (KIR6.2) [6, 7]; (3) the glutamate dehydrogenase gene (GLUD-1) [8], and (4) the glucokinase gene (GK) [9]. …”

?-Endosulfine, a new entity in the control of insulin secretion

“…In the search for possible involvement of K ATP channel mutations in pathology, a rare genetic disease called persistent hypoglycemic hyperinsulinemia of infancy was shown to be due to a mutation of the SUR1 gene which leads to permanent closure of the channel [27, 28] and a resultant non-regulatable and exaggerated insulin secretion. In one case, a Kir 6.2 mutation appears to be associated with a familial hyperinsulinism [29]. In the multigenic NIDDM disorder, it was observed that certain mutations of SUR1 occur slightly more frequently in NIDDM patients than in control subjects [30] leading, in some patients, to a decreased sensitivity to sulfonylureas [31].…”

The molecular basis of persistent hyperinsulinemic hypoglycemia of infancy and its pathologic substrates

“…More recently, however, physiological and morphological studies have made it clear that PHHI is a hyperfunctional disorder of the beta cells associated with heterogeneous pathologic changes [3,14,26]. Recently, molecular studies have revealed that PHHI results from at least three basic genetic defects: first, loss-of-function mutations on chromosome locus 11p15.1 affecting the genes of the two subunits SUR1 and KIR6.2 [11,24,34], which form the ATP-dependent potassium channel that is an integral part of the stimulus-secretion coupling apparatus of insulin release; second, gain-of function mutations of genes for enzymes (glucokinase, glutamate dehydrogenase) that regulate the rate of insulin secretion; and third, a two-hit loss-of-heterozygosity (LOH) mechanism in a group of beta cells [9,10], with a specific loss of maternal alleles of the imprinted chromosome region 11p15.1 unmasking a paternally inherited recessive SUR1 or KIR6.2 mutation (for further review cf. [23]).…”