Mutations in the genes encoding the pancreatic β-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) in diabetes mellitus and hyperinsulinism

Diabetes Research Laboratories, Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom.
Human Mutation (Impact Factor: 5.14). 03/2006; 27(3):220-31. DOI: 10.1002/humu.20292
Source: PubMed


The beta-cell ATP-sensitive potassium channel is a key component of stimulus-secretion coupling in the pancreatic beta-cell. The channel couples metabolism to membrane electrical events, bringing about insulin secretion. Given the critical role of this channel in glucose homeostasis, it is not surprising that mutations in the genes encoding for the two essential subunits of the channel can result in both hypo- and hyperglycemia. The channel consists of four subunits of the inwardly rectifying potassium channel Kir6.2 and four subunits of the sulfonylurea receptor 1. It has been known for some time that loss of function mutations in KCNJ11, which encodes for Kir6.2, and ABCC8, which encodes for SUR1, can cause oversecretion of insulin and result in hyperinsulinemia (HI) of infancy; however, heterozygous activating mutations in KCNJ11 that result in the opposite phenotype of diabetes have recently been described. This review focuses on reported mutations in both genes, the spectrum of phenotypes, and the implications for treatment when patients are diagnosed with mutations in these genes.

Full-text preview

Available from:
  • Source
    • "This has indeed been reported for mutations of SUR2 that compromise MgADP responsiveness and increase susceptibility to cardiac diseases (Bienengraeber et al., 2004; Olson et al., 2007). In the case of the pancreatic isoform SUR1, mutations that interfere with ADP activation cause mild forms of hyperinsulinism in homozygous carriers (Dunne et al., 2004; Gloyn et al., 2006). Except for rare cases (Huopio et al., 2000; Thornton et al., 2003), heterozygous subjects are not obviously affected although detailed studies on this point are lacking apart from one mutation, V287D (Huopio et al., 2002) that affects channel subunit assembly and trafficking rather than MgADP "
    [Show abstract] [Hide abstract]
    ABSTRACT: KATP channels, oligomers of 4 pore-forming Kir6.2 proteins and 4 sulfonylurea receptors (SUR), sense metabolism by monitoring both cytosolic ATP, which closes the channel by interacting with Kir6.2, and ADP, which opens it via SUR. SUR mutations that alter activation by ADP are a major cause of KATP channelopathies. We examined the mechanism of ADP activation by analysis of single-channel and macropatch recordings from Xenopus oocytes expressing various mixtures of wild-type SUR2A and an ADP-activation-defective mutant. Evaluation of the data by a binomial distribution model suggests that wild-type and mutant SURs freely co-assemble and that channel activation results from interaction of ADP with only 2 of 4 SURs. This finding explains the heterozygous nature of most KATP channelopathies linked to mutations altering ADP activation. It also suggests that the channel deviates from circular symmetry and could function as a dimer-of-dimers.
    Full-text · Article · Jan 2014 · Frontiers in Physiology
  • Source
    • "The unusual finding of a severe, autosomal-dominant ABCC8 mutation causing CHI in only 50% of the carriers suggested that variable mutant allele expression may determine the disease phenotype. Mutations in the ABCC8 gene are responsible for 40–50% of CHI cases, focal or diffuse (4,14,15). Previous studies of dominant SUR1 mutations show that mutant channels were expressed on the cell surface, but their response to MgADP was defective; in the heterozygous state, channels had intermediate responses to MgADP (16–18). The mutated protein found in our family, with its predicted two amino acid insertion, is expressed on the cell surface, but the channel does not open in response to MgADP or diazoxide even in the heterozygous state. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Congenital hyperinsulinism (CHI) is most commonly caused by mutations in the β-cell ATP-sensitive K(+) (K(ATP)) channel genes. Severe CHI was diagnosed in a 1-day-old girl; the mother's cousin and sister had a similar phenotype. ABCC8 gene sequencing (leukocyte DNA) revealed a heterozygous, exon 37, six-base pair in-frame insertion mutation in the affected patient and aunt but also in her unaffected mother and grandfather. In expression studies using transfected COSm6 cells, mutant sulfonylurea receptor 1 (SUR1) protein was expressed on the cell surface but failed to respond to MgADP even in the heterozygous state. mRNA expression in lymphocytes determined by sequencing cDNA clones and quantifying 6FAM-labeled PCR products found that although the healthy mother predominantly expressed the normal transcript, her affected daughter, carrying the same mutant allele, primarily transcribed the mutant. The methylation pattern of the imprinting control region of chromosome 11p15.5 and ABCC8 promoter was similar for all family members. In conclusion, differences in transcript expression may determine the clinical phenotype of CHI in this maternally inherited dominant mutation. The use of peripheral lymphocytes as a peripheral window to the β-cell transcription profile can serve in resolving β-cell phenotypes. The severe, dominant-negative nature of the 1508insAS mutation suggests that it affects the functional stoichiometry of SUR1-regulated gating of K(ATP) channels.
    Full-text · Article · Nov 2011 · Diabetes
  • Source
    • "Recent GWAS have uncovered a number of loci affecting risk of T2D (Voight et al. 2010). While some of these loci include genes known to play a role in glucose metabolism and diabetes pathogenesis (PPARG, KCNJ11) (Willson et al. 2001; Gloyn et al. 2006), others represent genomic regions with unknown functional roles in disease etiology. Among these, a set of single nucleotide polymorphisms (SNPs) on chromosome 10q25.2 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Genome-wide association studies (GWAS) have consistently implicated noncoding variation within the TCF7L2 locus with type 2 diabetes (T2D) risk. While this locus represents the strongest genetic determinant for T2D risk in humans, it remains unclear how these noncoding variants affect disease etiology. To test the hypothesis that the T2D-associated interval harbors cis-regulatory elements controlling TCF7L2 expression, we conducted in vivo transgenic reporter assays to characterize the TCF7L2 regulatory landscape. We found that the 92-kb genomic interval associated with T2D harbors long-range enhancers regulating various aspects of the spatial-temporal expression patterns of TCF7L2, including expression in tissues involved in the control of glucose homeostasis. By selectively deleting this interval, we establish a critical role for these enhancers in robust TCF7L2 expression. To further determine whether variation in Tcf7l2 expression may lead to diabetes, we developed a Tcf7l2 copy-number allelic series in mice. We show that a null Tcf7l2 allele leads, in a dose-dependent manner, to lower glycemic profiles. Tcf7l2 null mice also display enhanced glucose tolerance coupled to significantly lowered insulin levels, suggesting that these mice are protected against T2D. Confirming these observations, transgenic mice harboring multiple Tcf7l2 copies and overexpressing this gene display reciprocal phenotypes, including glucose intolerance. These results directly demonstrate that Tcf7l2 plays a role in regulating glucose tolerance, suggesting that overexpression of this gene is associated with increased risk of T2D. These data highlight the role of enhancer elements as mediators of T2D risk in humans, strengthening the evidence that variation in cis-regulatory elements may be a paradigm for genetic predispositions to common disease.
    Full-text · Article · Jun 2011 · Genome Research
Show more