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Neonatal diabetes caused by a homozygous KCNJ11 mutation demonstrates that tiny changes in ATP sensitivity markedly affect diabetes risk.
Vedovato N
,
Cliff E
,
Proks P
,
Poovazhagi V
,
Flanagan SE
,
Ellard S
,
Hattersley AT
,
Ashcroft FM
.
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AIMS/HYPOTHESIS: The pancreatic ATP-sensitive potassium (KATP) channel plays a pivotal role in linking beta cell metabolism to insulin secretion. Mutations in KATP channel genes can result in hypo- or hypersecretion of insulin, as in neonatal diabetes mellitus and congenital hyperinsulinism, respectively. To date, all patients affected by neonatal diabetes due to a mutation in the pore-forming subunit of the channel (Kir6.2, KCNJ11) are heterozygous for the mutation. Here, we report the first clinical case of neonatal diabetes caused by a homozygous KCNJ11 mutation.
METHODS: A male patient was diagnosed with diabetes shortly after birth. At 5 months of age, genetic testing revealed he carried a homozygous KCNJ11 mutation, G324R, (Kir6.2-G324R) and he was successfully transferred to sulfonylurea therapy (0.2 mg kg(-1) day(-1)). Neither heterozygous parent was affected. Functional properties of wild-type, heterozygous and homozygous mutant KATP channels were examined after heterologous expression in Xenopus oocytes.
RESULTS: Functional studies indicated that the Kir6.2-G324R mutation reduces the channel ATP sensitivity but that the difference in ATP inhibition between homozygous and heterozygous channels is remarkably small. Nevertheless, the homozygous patient developed neonatal diabetes, whereas the heterozygous parents were, and remain, unaffected. Kir6.2-G324R channels were fully shut by the sulfonylurea tolbutamide, which explains why the patient's diabetes was well controlled by sulfonylurea therapy.
CONCLUSIONS/INTERPRETATION: The data demonstrate that tiny changes in KATP channel activity can alter beta cell electrical activity and insulin secretion sufficiently to cause diabetes. They also aid our understanding of how the Kir6.2-E23K variant predisposes to type 2 diabetes.
Fig. 1. Metabolic activation of WT and mutant KATP channels. (a) Representative whole-cell currents recorded from oocytes expressing WT or homG324R channels in response to 500 ms voltage steps of ±20 mV from a holding potential of −10 mV. Sodium azide (azide, 3 mmol/l) and tolbutamide (tolb., 0.5 mmol/l) were added as indicated. (b) Current in control solution for WT (n = 13), hetG324R (het; n = 9) and homG324R (hom; n = 10) expressed as a percentage of that in the presence of 3 mmol/l sodium azide (per cent maximal current). (c) Mean tolbutamide block for WT (98.2 ± 0.2%, n = 7), hetG324R (het; 97.9 ± 0.3%, n = 6) and homG324R (hom; 98.1 ± 0.4%, n = 7) channels (measured in the presence of sodium azide)
Fig. 2. MgATP inhibition of KATP channels is reduced by the Kir6.2-G324R mutation. (a) Representative currents recorded at −60 mV from inside-out patches excised from oocytes expressing WT or mutant KATP channels. The dashed line indicates the zero current level. MgATP (10 μmol/l) was applied as indicated. (b, c) Relationship between KATP current and MgATP concentration for WT (black squares), homG324R (grey filled squares; b) and hetG324R (grey empty squares; c) channels. Current in the presence of nucleotide (I) is expressed as a fraction of that in its absence (IC). The curves are the best fit to the Hill equation. ***p < 0.001 compared with WT (t test)
Fig. 3. Comparison of ATP sensitivities. (a) IC50 for MgATP inhibition and (b) fraction of unblocked current at 3 mmol/l MgATP for the indicated channels: WT (n = 13), homE23K (n = 5), hetG324R (n = 6), homG324R (n = 8), hetE227L (n = 7). Mean values for TNDM (white hatched bars), PNDM (grey hatched bars) and DEND/iDEND (grey bars) channels are given for comparison (for references, see ESM Fig. 1). Data are mean ± SEM. **p < 0.01 compared with WT (t test)
Fig. 4. Molecular model of the Kir6.2 tetramer [19]. (a) Top view from the extracellular side, showing the position of G324 (red), D323 (yellow) and R325 (cyan). ATP (orange sticks) is shown docked into its putative binding site. (b) Detail of two adjacent Kir6.2 subunits (one green, one grey). The first 32 amino acids are not included in the model so N-term denotes residue 32
Antcliff,
Functional analysis of a structural model of the ATP-binding site of the KATP channel Kir6.2 subunit.
2005, Pubmed
Antcliff,
Functional analysis of a structural model of the ATP-binding site of the KATP channel Kir6.2 subunit.
2005,
Pubmed
Ashcroft,
The Walter B. Cannon Physiology in Perspective Lecture, 2007. ATP-sensitive K+ channels and disease: from molecule to malady.
2007,
Pubmed
Ashcroft,
Type 2 diabetes mellitus: not quite exciting enough?
2004,
Pubmed
Cook,
Intracellular ATP directly blocks K+ channels in pancreatic B-cells.
,
Pubmed
D'Amato,
Variable phenotypic spectrum of diabetes mellitus in a family carrying a novel KCNJ11 gene mutation.
2008,
Pubmed
Fatehi,
The ATP-sensitive K(+) channel ABCC8 S1369A type 2 diabetes risk variant increases MgATPase activity.
2012,
Pubmed
Flanagan,
Update of mutations in the genes encoding the pancreatic beta-cell K(ATP) channel subunits Kir6.2 (KCNJ11) and sulfonylurea receptor 1 (ABCC8) in diabetes mellitus and hyperinsulinism.
2009,
Pubmed
Florez,
Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region.
2004,
Pubmed
Gloyn,
Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.
2004,
Pubmed
,
Xenbase
Gloyn,
Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes.
2003,
Pubmed
Gribble,
Properties of cloned ATP-sensitive K+ currents expressed in Xenopus oocytes.
1997,
Pubmed
,
Xenbase
Hamming,
Coexpression of the type 2 diabetes susceptibility gene variants KCNJ11 E23K and ABCC8 S1369A alter the ATP and sulfonylurea sensitivities of the ATP-sensitive K(+) channel.
2009,
Pubmed
Hattersley,
Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy.
2005,
Pubmed
Liu,
Mutations in KCNJ11 are associated with the development of autosomal dominant, early-onset type 2 diabetes.
2013,
Pubmed
Lodwick,
Sulfonylurea receptors regulate the channel pore in ATP-sensitive potassium channels via an intersubunit salt bridge.
2014,
Pubmed
Nichols,
Adenosine diphosphate as an intracellular regulator of insulin secretion.
1996,
Pubmed
Proks,
Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features.
2004,
Pubmed
,
Xenbase
Riedel,
Current status of the E23K Kir6.2 polymorphism: implications for type-2 diabetes.
2005,
Pubmed
Riedel,
Kir6.2 polymorphisms sensitize beta-cell ATP-sensitive potassium channels to activation by acyl CoAs: a possible cellular mechanism for increased susceptibility to type 2 diabetes?
2003,
Pubmed
Sakura,
Sequence variations in the human Kir6.2 gene, a subunit of the beta-cell ATP-sensitive K-channel: no association with NIDDM in while Caucasian subjects or evidence of abnormal function when expressed in vitro.
1996,
Pubmed
,
Xenbase
Schwanstecher,
K(IR)6.2 polymorphism predisposes to type 2 diabetes by inducing overactivity of pancreatic beta-cell ATP-sensitive K(+) channels.
2002,
Pubmed
Schwanstecher,
The common single nucleotide polymorphism E23K in K(IR)6.2 sensitizes pancreatic beta-cell ATP-sensitive potassium channels toward activation through nucleoside diphosphates.
2002,
Pubmed
Tarasov,
Functional analysis of two Kir6.2 (KCNJ11) mutations, K170T and E322K, causing neonatal diabetes.
2007,
Pubmed
,
Xenbase
Tarasov,
A Kir6.2 mutation causing neonatal diabetes impairs electrical activity and insulin secretion from INS-1 beta-cells.
2006,
Pubmed
Tucker,
Truncation of Kir6.2 produces ATP-sensitive K+ channels in the absence of the sulphonylurea receptor.
1997,
Pubmed
,
Xenbase
Villareal,
Kir6.2 variant E23K increases ATP-sensitive K+ channel activity and is associated with impaired insulin release and enhanced insulin sensitivity in adults with normal glucose tolerance.
2009,
Pubmed
Yorifuji,
The C42R mutation in the Kir6.2 (KCNJ11) gene as a cause of transient neonatal diabetes, childhood diabetes, or later-onset, apparently type 2 diabetes mellitus.
2005,
Pubmed
