HUMAN MUTATION 27(3),220^231,2006
Mutations in the Genes Encoding the Pancreatic
Beta-Cell KATPChannel Subunits Kir6.2
(KCNJ11) and SUR1 (ABCC8) in Diabetes
Mellitus and Hyperinsulinism
Anna L. Gloyn,1?Juveria Siddiqui,1and Sian Ellard2
1Diabetes Research Laboratories, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom;
2Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, United Kingdom
Communicated by Michel J. Goossens
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. Hum Mutat 27(3), 220–231, 2006.
rrrr2006 Wiley-Liss, Inc.
KEY WORDS: permanent neonatal diabetes; transient neonatal diabetes; hyperinsulinemia of infancy; potassium
channel; sulfonylurea receptor; inwardly rectifying potassium channel; KCNJ11; Kir6.2; ABCC8; SUR1
ATP-sensitive potassium (KATP) channels regulate the flux of K1
ions across cell membranes and thereby link cell metabolism to
electrical activity. Metabolic inhibition opens KATPchannels, and
the resulting efflux of K1ions causes membrane hyperpolarization
and the suppression of electrical activity. Conversely, increased
metabolism closes the KATP channels, resulting in membrane
depolarization that stimulates electrical activity. This electrical
activity can then trigger muscle contraction and the release of
hormones or neurotransmitters. The importance of KATPchannels
in insulin secretion was established over 20 years ago [Ashcroft
et al., 1984]. These channels couple glucose metabolism to
membrane electrical activity and insulin release in pancreatic beta-
cells. When blood glucose levels rise, the resulting increase in
glucose metabolism results in a change in the ratio of cytosolic
nucleotides (ADP/ATP), which causes closure of the KATP
channel and leads to membrane depolarization. This subsequently
activates voltage-dependent calcium channels, leading to an influx
of calcium. This increase in intracellular calcium [Ca21]iis then
the trigger for insulin granule exocytosis (Fig. 1). The beta-cell
KATPchannel can be pharmacologically regulated by sulfonylurea
drugs, which work by binding to and closing the KATPchannel,
and are widely used to treat type 2 diabetes (T2DM). Conversely,
a second class of drugs, such as diazoxide, work by opening the
channel (K channel openers).
The beta-cell KATPchannel consists of two essential subunits: 1)
Kir6.2, which is the pore-forming unit and belongs to the inwardly
rectifying potassium channel family, and 2) sulfonylurea receptor 1
(SUR1), which belongs to the ATP-binding cassette (ABC)
transporter family. The channel is a octameric complex of 4 Kir6.2
and 4 SUR1 subunits [Clement et al., 1997; Inagaki et al., 1997].
The binding of ATP to Kir6.2 results in KATPchannel closure, while
sulfonylurea drugs, potassium channel openers, and magnesium
nucleotides bind to SUR1 via its two cytosolic nucleotide binding
domains. Given the central role of the KATPchannel in insulin
secretion, it is not surprising that mutations in the genes that encode
the subunits of this channel can result in both hypo- and
hyperglycemia [Gloyn et al., 2004a; Thomas et al., 1995a, 1996a].
The human SUR1 cDNA contains a single open reading frame
that encodes for 1,581 amino acids with a molecular weight of 177
KDa (GenBank NM_000352.2). The gene (ABCC8; MIM]
Published online 13 January 2006 in Wiley InterScience (www.
The Supplementary Material referred to in this article can be
accessed at http://www.interscience.wiley.com/jpages/1059-7794/
Received 22 August 2005; accepted revised manuscript 11
tories, Oxford Centre for Diabetes, Endocrinology and Metabolism,
Churchill Hospital,Old Road, Headington,Oxford,UnitedKingdom.
Grant sponsor: DiabetesUK;Grant sponsor:WellcomeTrust.
rrrr2006 WILEY-LISS, INC.
600509) consists of 39 exons and spans more than 100 kb of
genomic DNA [Aguilar-Bryan et al., 1995]. ABCC8 has an
alternatively spliced exon 17, which incorporates an additional
amino acid (GenBank L78208, L78224). Homology analysis has
shown that SUR1 is a member of the ABC superfamily, which
includes cystic fibrosis transconductance regulators (CFTRs) and
multidrug-resistance proteins (MDPs). Membrane topology has
shown that the SUR1 consists of two nucleotide binding domains
(NBDs) that control channel activity through their interaction
with cytocyolic nucleotides [Tusnady et al., 1997]. Both NBDs
contain two amino acid sequence motifs (termed ‘‘Walker A’’ and
‘‘Walker B’’), which are phosphate binding loops that form
intimate contact with the phosphates of the nucleotide tripho-
sphates that bind to the NBDs. NBDs are also found in other
members of the ABC superfamily.
Kir6.2 was cloned the same year as SUR1, and the gene
(KCNJ11; MIM] 600937) consists of a single exon encoding a
390-amino acid protein (GenBank NM_000525.2) [Inagaki et al.,
1995]. Interestingly, it is only 4.5 Kb from the ABCC8 gene on
chromosome 11p15.1. Kir6.2 consists of two transmembrane
regions and a pore-forming subunit [Tusnady et al., 1997].
HYPERINSULINEMIA (HI) OF INFANCY
Hyperinsulinemia of infancy (HI; MIM] 256450), also known as
persistent hyperinsulinemic hypoglycemia of infancy (PHHI;
MIM] 601820) or congenital hyperinsulinism (CHI), is character-
ized by inappropriate oversecretion of insulin despite hypoglyce-
mia. This is a serious condition because in the absence of
treatment it can result in irreversible brain damage. Most cases of
HI are sporadic. Familial forms are rarer but well documented.
Sporadic HI has an estimated incidence of one in 27,000 live
births in Ireland, and one in 50,000 live births in Finland [Glaser
et al., 2000], compared to one in 20,000 in Kuwait [Ramadan
et al., 1999]. However, in some isolated communities the disease
incidence is much higher (e.g., one in 3,200 in the central area
of Finland, and one in 2,500 in the Arabian peninsula) [Glaser
et al., 2000].
HI is a heterogeneous disorder with mutations reported in the
beta-cell potassium ATP (KATP) channel genes ABCC8 (also
SUR1; MIM] 600509) and KCNJ11 (also Kir6.2; MIM] 600937),
the mitochondrial enzymes glutamate dehydrogenase (GLUD1;
MIM] 602485), and short-chain L-3-hydroxyacyl-CoA dehydro-
genase (SCHAD; MIM] 601609) and the key glycolytic enzyme
glucokinase (GCK; MIM] 606762). There is also one case of
autosomal-dominant hyperinsulinemic hypoglycemia due to a
mutation in the insulin receptor (INSR) [Hojlund et al., 2004]. HI
is not only genetically heterogeneous, but also histologically
heterogeneous as there is diversity in the pancreatic histopathology.
Both diffuse and focal forms of HI have been described. The diffuse
histology affects all of the beta-cells within the islets of Langerhans,
while in the focal form only an isolated lesion of the pancreatic
beta-cells is affected and the surrounding tissue is normal.
HI has a variable clinical phenotype, but usually presents during
the neonatal period or infancy (although cases with GCK mutations
have been diagnosed in adulthood [Gloyn et al., 2003a]) with
seizures, coma, and often high birth weight (due to high levels of
insulin in utero). The mode of inheritance depends on the genetic
etiology. GCK and GLUD1 mutations are inherited in an autosomal-
dominant manner, while the majority of cases of HI due to ABCC8,
KCNJ11, and SCHAD mutations are autosomal-recessive.
SUR1 (ABCC8) MUTATIONS IN HI
Mutations in SUR1 (ABCC8) are the most common cause of
HI, and were the first to be described. The SUR1 gene was an
excellent candidate located within a region on chromosome
11p15.1 reported to be linked to HI [Thomas et al., 1995b].
Almost 20 years after the first mutation was first discovered, close
to 100 mutations distributed throughout the gene have been
described (Table 1). These mutations can be divided into two
functional classes: those that result in a protein that is not present
at the surface of the membrane (class I), and those in which the
channel is present but always closed (class II) [Ashcroft, 2005].
Class I mutations lead to reduced surface expression of KATP
channels, either by a total loss of protein or by defective trafficking
[Taschenberger et al., 2002]. Class II mutations impair the ability
of MgADP to stimulate channel activity, and hence prevent
channel activation in response to metabolic inhibition [Huopio
et al., 2002a]. The majority of class II mutations are located in the
NBDs of SUR1. In general, class I mutations produce a more
severe phenotype, whereas some class II mutations result in a
milder phenotype due to a partial response to MgADP . There have
been two reports of autosomal-dominantly inherited ABCC8
mutations [Huopio et al., 2000; Thornton et al., 2003], and,
interestingly, in one of these families the mutation was also
reported to lead to diabetes in adulthood [Huopio et al., 2003].
KIR6.2 (KCNJ11) MUTATIONS IN HI
Relatively few mutations (n512) have been reported in
KCNJ11 (Kir6.2; Table 2). This is perhaps not surprising given
the fact that the gene is much smaller than the ABCC8 gene.
Mutations in KCNJ11 cause HI by either reducing or completely
abolishing KATP channel activity in the surface membrane
FIGURE 1. Schematic representation of the pancreatic beta-cell,
illustrating the current model for insulin secretion. Glucose
the cell glucose is metabolized and the resulting increase in ATP
and decrease in MgADP inhibit the beta-cell ATP-sensitive
potassiumchannel (KATP), leading tochannelclosureandmem-
brane depolarization. This subsequently activates voltage-
calcium, which is the trigger for insulin release. Sulfonylureas
anddiazoxide bind theKATPchannel via the SUR1subunit.
HUMAN MUTATION 27(3),220^231,2006221
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