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

Yorifuji, Tohru; Nagashima, Kazuaki; Kurokawa, Keiji; Kawai, Masahiko; Oishi, Mariko; Akazawa, Yoshiharu; Hosokawa, Munetaka; Yamada, Yoshio; Inagaki, Nobuya; Nakahata, Tatsutoshi

doi:10.1210/jc.2005-0096

Cited by 109 publications

(99 citation statements)

References 16 publications

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“…A cut-off point at 6 months is consistent with previous work looking at autoantibodies and HLA suggesting that type 1 diabetes is rare in those aged below 6 months [22]. Our study would not support testing for KCNJ11 mutations in patients diagnosed after 6 months, although relatives of probands with transient neonatal diabetes have been diagnosed at 3, 5, 22 and 26 years [2,3]. The detection rate of 26% in our series was lower than the 34-64% previously reported [1,4,6,10], although the 95% confidence limits of all series overlap.…”

Section: Discussionsupporting

confidence: 67%

“…The channel consists of two types of essential subunit: the pore-forming subunit Kir6.2 and the regulatory subunit sulfonylurea receptor 1 (SUR1), which is the target for sulfonylureas. Heterozygous activating mutations in KCNJ11, the gene for the Kir6.2 subunit, can cause both permanent and transient neonatal diabetes, which-in a minority of cases-have neurological features such as developmental delay and epilepsy [1][2][3][4][5]. The identification of a KCNJ11 mutation can have a major impact on a patient's treatment.…”

Section: Introductionmentioning

confidence: 99%

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Mutations in KCNJ11, which encodes Kir6.2, are a common cause of diabetes diagnosed in the first 6 months of life, with the phenotype determined by genotype

et al. 2006

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Section: Discussionsupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Mutations in KCNJ11, which encodes Kir6.2, are a common cause of diabetes diagnosed in the first 6 months of life, with the phenotype determined by genotype

et al. 2006

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“…This adds to accumulating evidence that KCNJ11 mutations that cause neonatal diabetes do so by affecting K ATP channel ATP sensitivity, either directly or indirectly [8,9,13,14,[26][27][28][29][30].…”

Section: Discussionmentioning

confidence: 99%

“…The commonest cause of permanent neonatal diabetes (PNDM) are heterozygous activating mutations in the KCNJ11, the gene encoding Kir6.2, which constitutes the pore-forming subunit of the K ATP channel in the pancreatic beta cell [7][8][9]. KCNJ11 mutations account for around 50% of cases of PNDM [7][8][9][10][11][12][13]. Some of these mutations lead to a more severe syndrome in which developmental delay and epilepsy accompany neonatal diabetes, a condition known as DEND syndrome [9].…”

Section: Introductionmentioning

confidence: 99%

Functional analysis of six Kir6.2 (KCNJ11) mutations causing neonatal diabetes

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Shimomura

Proks

et al. 2006

Pflugers Arch - Eur J Physiol

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ATP-sensitive potassium (K ATP ) channels, composed of pore-forming Kir6.2 and regulatory sulphonylurea receptor (SUR) subunits, play an essential role in insulin secretion from pancreatic beta cells. Binding of ATP to Kir6.2 inhibits, whereas interaction of Mg-nucleotides with SUR, activates the channel. Heterozygous activating mutations in Kir6.2 (KCNJ11) are a common cause of neonatal diabetes (ND). We assessed the functional effects of six novel Kir6.2 mutations associated with ND: H46Y, N48D, E227K, E229K, E292G, and V252A. K ATP channels were expressed in Xenopus oocytes and the heterozygous state was simulated by coexpression of wild-type and mutant Kir6.2 with SUR1 (the beta cell type of SUR). All mutations reduced the sensitivity of the K ATP channel to inhibition by MgATP, and enhanced whole-cell K ATP currents. Two mutations (E227K, E229K) also enhanced the intrinsic open probability of the channel, thereby indirectly reducing the channel ATP sensitivity. The other four mutations lie close to the predicted ATP-binding site and thus may affect ATP binding. In pancreatic beta cells, an increase in the K ATP current is expected to reduce insulin secretion and thereby cause diabetes. None of the mutations substantially affected the sensitivity of the channel to inhibition by the sulphonylurea tolbutamide, suggesting patients carrying these mutations may respond to these drugs.

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“…pproximately 50% of cases of permanent neonatal diabetes (PNDM) result from heterozygous mutations in KCNJ11, the gene encoding Kir6.2, which constitutes the pore-forming subunit of the ATP-sensitive K ϩ channel (K ATP channel) (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). Some of these mutations also give rise to muscle weakness and developmental delay (intermediate DEND syndrome) or to a severe condition in which neonatal diabetes is associated with developmental delay, muscle weakness, and epilepsy (DEND syndrome) (2).…”

mentioning

confidence: 99%

Mutations at the Same Residue (R50) of Kir6.2 (KCNJ11) That Cause Neonatal Diabetes Produce Different Functional Effects

et al. 2006

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Heterozygous mutations in the human Kir6.2 gene (KCNJ11), the pore-forming subunit of the ATP-sensitive K ؉ channel (K ATP channel), are a common cause of neonatal diabetes. We identified a novel KCNJ11 mutation, R50Q, that causes permanent neonatal diabetes (PNDM) without neurological problems. We investigated the functional effects this mutation and another at the same residue (R50P) that led to PNDM in association with developmental delay. Wild-type or mutant Kir6.2/SUR1 channels were examined by heterologous expression in Xenopus oocytes. Both mutations increased resting wholecell currents through homomeric and heterozygous K ATP channels by reducing channel inhibition by ATP, an effect that was larger in the presence of Mg 2؉ . However the magnitude of the reduction in ATP sensitivity (and the increase in the whole-cell current) was substantially larger for the R50P mutation. This is consistent with the more severe phenotype. Single-R50P channel kinetics (in the absence of ATP) did not differ from wild type, indicating that the mutation primarily affects ATP binding and/or transduction. This supports the idea that R50 lies in the ATP-binding site of Kir6.2. The sulfonylurea tolbutamide blocked heterozygous R50Q (89%) and R50P (84%) channels only slightly less than wild-type channels (98%), suggesting that sulfonylurea therapy may be of benefit for patients with either mutation. Diabetes 55: [1705][1706][1707][1708][1709][1710][1711][1712] 2006 A pproximately 50% of cases of permanent neonatal diabetes (PNDM) result from heterozygous mutations in KCNJ11, the gene encoding Kir6.2, which constitutes the pore-forming subunit of the ATP-sensitive K ϩ channel (K ATP channel) (1-11). Some of these mutations also give rise to muscle weakness and developmental delay (intermediate DEND syndrome) or to a severe condition in which neonatal diabetes is associated with developmental delay, muscle weakness, and epilepsy (DEND syndrome) (2).Kir6.2 serves as the pore-forming subunit of the K ATP channel in multiple tissues (12,13), with four Kir6.2 subunits coming together to form a tetrameric pore through which K ϩ ions move (14). Each Kir6.2 subunit is coupled to a regulatory sulfonylurea receptor (SUR) subunit. There are several isoforms of SUR: SUR1 is found in pancreatic ␤-cells and brain (15), SUR2A in cardiac and skeletal muscle (16), and SUR2B in vascular smooth muscle (17).K ATP channels couple-cell metabolism to membrane electrical activity by regulating K ϩ fluxes across the plasma membrane. They are involved in multiple physiological processes, including glucose homeostasis, protection against ischemic stress in heart and brain, regulation of neuronal electrical activity, and control of vascular tone (18). In general, opening of K ATP channels inhibits electrical activity and leads to cell quiescence, whereas closing of K ATP channels stimulates electrical activity and cellular responses. For example, in pancreatic ␤-cells, K ATP channels are open at substimulatory glucose concentrations (18 -20). As a resul...

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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

Abstract: These results broaden the spectrum of diabetes phenotypes caused by mutations of KCNJ11 and suggest that mutations in this gene should be taken into consideration for not only permanent neonatal diabetes but also other forms of diabetes with milder phenotypes and later onset.

Cited by 109 publications

References 16 publications

Mutations in KCNJ11, which encodes Kir6.2, are a common cause of diabetes diagnosed in the first 6 months of life, with the phenotype determined by genotype

Mutations in KCNJ11, which encodes Kir6.2, are a common cause of diabetes diagnosed in the first 6 months of life, with the phenotype determined by genotype

Functional analysis of six Kir6.2 (KCNJ11) mutations causing neonatal diabetes

Mutations at the Same Residue (R50) of Kir6.2 (KCNJ11) That Cause Neonatal Diabetes Produce Different Functional Effects

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