ABCMdb

ABCC8 p.Glu1506Lys

Predicted by SNAP2:	A: D (91%), C: D (91%), D: D (91%), F: D (91%), G: D (95%), H: D (91%), I: D (91%), K: D (95%), L: D (91%), M: D (91%), N: D (91%), P: D (85%), Q: D (85%), R: D (95%), S: D (91%), T: D (91%), V: D (91%), W: D (95%), Y: D (91%),
Predicted by PROVEAN:	A: D, C: D, D: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Novel de novo mutation in sulfonylurea receptor 1 ... Diabetes. 2008 Jul;57(7):1935-40. Epub 2008 Apr 4. Abdulhadi-Atwan M, Bushman J, Tornovsky-Babaey S, Perry A, Abu-Libdeh A, Glaser B, Shyng SL, Zangen DH
Novel de novo mutation in sulfonylurea receptor 1 presenting as hyperinsulinism in infancy followed by overt diabetes in early adolescence.
Diabetes. 2008 Jul;57(7):1935-40. Epub 2008 Apr 4., [PMID:18390792]

Abstract [show]
OBJECTIVE: Congenital hyperinsulinism, usually associated with severe neonatal hypoglycemia, may progress to diabetes, typically during the 4th decade of life in nonpancreatectomized patients. We aimed to genotype the ATP-sensitive K(+) channel in a 10.5-year-old girl presenting with overt diabetes following hyperinsulinism in infancy. RESEARCH DESIGN AND METHODS: A female aged 10.5 years presented with new-onset, antibody-negative diabetes (A1C 10.6%). She was born large for gestational age (5 kg) to a nondiabetic mother and developed frequent hypoglycemic episodes, which persisted until age 3 years and responded initially to intravenous glucose and later to oral sweets. Currently, she is fully pubertal and obese (BMI 30.2 kg/m(2)), with a partially controlled convulsive disorder (since age 1 year) and poor school performance. Glucose levels were >11.1 mmol/l throughout 72 h of continuous glucose monitoring, with low insulin secretion during intravenous glucose tolerance testing. KCNJ11 and ABCC8 mutation analysis was performed, and the mutation identified was characterized in COSm6 cells. RESULTS: A novel, de novo heterozygous ABCC8 sulfonylurea receptor (SUR)1 mutation (R370S) was identified in the patient's DNA but not in that of either parent. Cotransfection of Kir6.2 and mutant SUR1 demonstrate that the mutated protein is expressed efficiently at the cell surface but fails to respond to MgADP, resulting in minimal channel activity. Interestingly, the heterozygous channel (WT:R370S) responded well to glibenclamide, a finding that lead to the successful initiation of sulfonylurea therapy. CONCLUSIONS: This new ABCC8 mutation is associated with neonatal hyperinsulinism progressing within 10 years to insulinopenic diabetes. Consistent with in vitro findings, the patient responded to sulfonylurea treatment. The mechanism causing the relatively rapid loss in beta-cell function is not clear, but it may involve mutation-induced increased beta-cell apoptosis related to increased metabolic demand.

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152 Huopio and coworkers (11,12) reported a dominant inactivating ABCC8 mutation, E1506K, that caused hyperinsulinemic hypoglycemia followed by hypoinsulinemic diabetes; however, when compared with our patient, nonpancreatectomized E1506K patients in whom overt diabetes presented later, during middle age, had mild neonatal hypoglycemia. Login to comment

[hide] Hyperinsulinemic hypoglycemia evolving to gestatio... Pediatr Diabetes. 2010 Nov;11(7):505-8. doi: 10.1111/j.1399-5448.2009.00626.x. Vieira TC, Bergamin CS, Gurgel LC, Moises RS
Hyperinsulinemic hypoglycemia evolving to gestational diabetes and diabetes mellitus in a family carrying the inactivating ABCC8 E1506K mutation.
Pediatr Diabetes. 2010 Nov;11(7):505-8. doi: 10.1111/j.1399-5448.2009.00626.x., [PMID:20042013]

Abstract [show]
Congenital hyperinsulinism of infancy (CHI) is the most common cause of hypoglycemia in newborns and infants. Several molecular mechanisms are involved in the development of CHI, but the most common genetic defects are inactivating mutations of the ABCC8 or KCNJ11 genes. The classical treatment for CHI has been pancreatectomy that eventually leads to diabetes. More recently, conservative treatment has been attempted in some cases, with encouraging results. Whether or not the patients with heterozygous ABCC8 mutations submitted to conservative treatment may spontaneously develop type 2 diabetes in the long run, is a controversial issue. Here, we report a family carrying the dominant heterozygous germ line E1506K mutation in ABCC8 associated with persistent hypoglycemia in the newborn period and diabetes in adulthood. The mutation occurred as a de novo germ line mutation in the mother of the index patient. Her hypoglycemic symptoms as a child occurred after the fourth year of life and were very mild, but she developed glucose metabolism impairment in adulthood. On the other hand, in her daughter, the clinical manifestations of the disease occurred in the neonatal period and were more severe, leading to episodes of tonic-clonic seizures that were well controlled with octreotide or diazoxide. Our data corroborate the hypothesis that the dominant E1506K ABCC8 mutation, responsible for CHI, predisposes to the development of glucose intolerance and diabetes later in life.

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0 Pediatric Diabetes 2010: 11: 505-508 doi: 10.1111/j.1399-5448.2009.00626.x All rights reserved (c) 2009 John Wiley & Sons A/S Pediatric Diabetes Case Report Hyperinsulinemic hypoglycemia evolving to gestational diabetes and diabetes mellitus in a family carrying the inactivating ABCC8 E1506K mutation Vieira TC, Bergamin CS, Gurgel LC, Mois´es RS. Hyperinsulinemic hypoglycemia evolving to gestational diabetes and diabetes mellitus in a family carrying the inactivating ABCC8 E1506K mutation. Login to comment
7 Here, we report a family carrying the dominant heterozygous germ line E1506K mutation in ABCC8 associated with persistent hypoglycemia in the newborn period and diabetes in adulthood. Login to comment
11 Our data corroborate the hypothesis that the dominant E1506K ABCC8 mutation, responsible for CHI, predisposes to the development of glucose intolerance and diabetes later in life. Login to comment
23 These patients carried the inactivating heterozygous ABCC8 E1506K mutation (8, 9). Login to comment
25 Here, we report a family carrying the E1506K mutation in ABCC8 associated with persistent hypoglycemia in the newborn period and diabetes mellitus in adulthood. Login to comment
37 When the child was one year old, the molecular studies of ABCC8 revealed the E1506K mutation, and octreotide was switched to diazoxide 10 mg/kg/day. Login to comment
52 506 CHI and E1506K SUR1 mutation Fig. 1. Login to comment
54 Solid circles correspond to the affected mother and daughter; (B) Partial sequence chromatogram of exon 37 of ABCC8 gene showing the heterozygous mutation 4516G>A (E1506K) (a) and wild-type sequence (b). Login to comment
57 Results showed that the mother harbors a de novo ABCC8 E1506K mutation that was transmitted to her daughter (Fig. 1). Login to comment
58 Discussion The heterozygous missense mutation E1506K in ABCC8 gene has been previously identified among patients with CHI (8, 12). Login to comment
59 In vitro electrophysiological functional studies of this mutation showed that E1506K mutant KATP channels were insensitive to metabolic inhibition, but were activated by diazoxide (8). Login to comment
60 These findings are consistent with the ability of diazoxide, but not low-blood glucose, to inhibit insulin secretion in E1506K mutation carriers. Login to comment
65 Reports of CHI as a result of the E1506K mutation also describe variable degrees of hypoglycemia in the affected patients, beginning at the neonatal period or later (8, 12). Login to comment
74 Huopio et al. studied a large Finish pedigree carrying the dominant E1506K mutation and found that the patients had hyperinsulinism in infancy but were predisposed to develop gestational diabetes, glucose intolerance, and type 2 diabetes in adulthood. Login to comment
75 Insulin secretion decreased linearly with age in E1506K carriers, Pediatric Diabetes 2010: 11: 505-508 507 independently of their glucose tolerance status (9). Login to comment
80 However, so far, there are no studies showing elevated β cell intracellular calcium concentrations in E1506K carriers. Login to comment
84 In the present report, the fact that the mother of the index patient had hypoglycemia in childhood but developed gestational diabetes, impaired glucose tolerance and diabetes mellitus in adulthood, reinforces the hypothesis that the dominant E1506K ABCC8 mutation may have an important role in the progressive impairment of the β-cell function. Login to comment

[hide] Identification of a functionally important negativ... Diabetes. 2004 Dec;53 Suppl 3:S123-7. Campbell JD, Proks P, Lippiat JD, Sansom MS, Ashcroft FM
Identification of a functionally important negatively charged residue within the second catalytic site of the SUR1 nucleotide-binding domains.
Diabetes. 2004 Dec;53 Suppl 3:S123-7., [PMID:15561899]

Abstract [show]
The ATP-sensitive K+ channel (KATP channel) couples glucose metabolism to insulin secretion in pancreatic beta-cells. It is comprised of sulfonylurea receptor (SUR)-1 and Kir6.2 proteins. Binding of Mg nucleotides to the nucleotide-binding domains (NBDs) of SUR1 stimulates channel opening and leads to membrane hyperpolarization and inhibition of insulin secretion. To elucidate the structural basis of this regulation, we constructed a molecular model of the NBDs of SUR1, based on the crystal structures of mammalian proteins that belong to the same family of ATP-binding cassette transporter proteins. This model is a dimer in which there are two nucleotide-binding sites, each of which contains residues from NBD1 as well as from NBD2. It makes the novel prediction that residue D860 in NBD1 helps coordinate Mg nucleotides at site 2. We tested this prediction experimentally and found that, unlike wild-type channels, channels containing the SUR1-D860A mutation were not activated by MgADP in either the presence or absence of MgATP. Our model should be useful for designing experiments aimed at elucidating the relationship between the structure and function of the KATP channel.

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72 C: Expanded view of site 2 of the SUR1 model showing the proximity of D860 to the ATP ␥-phosphate in Site 2. because its mutation to lysine (E1506K) leads to congenital hyperinsulinism in humans (18). Login to comment

[hide] From congenital hyperinsulinism to diabetes mellit... Pediatr Diabetes. 2005 Jun;6(2):103-13. Hussain K, Cosgrove KE
From congenital hyperinsulinism to diabetes mellitus: the role of pancreatic beta-cell KATP channels.
Pediatr Diabetes. 2005 Jun;6(2):103-13., [PMID:15963039]

Abstract [show]
Pancreatic beta-cell adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channels play a pivotal role in linking glucose metabolism to regulated insulin secretion. K(ATP) channels are hetero-octameric complexes comprising two subunits Kir6.2 and sulfonylurea receptor 1 (SUR1). Changes in the intracellular concentration of nucleotides (ATP) cause alterations in the resting and opening state of the K(ATP) channels. Loss-of-function mutations in the genes encoding the two subunits of K(ATP) channels lead to the most common form of congenital hyperinsulinism (CHI). This causes persistent and severe hypoglycemia in the neonatal and infancy period. CHI can cause mental retardation and epilepsy if not treated properly. On the other hand, now there is evidence of an association between polymorphisms in the Kir6.2 gene and type 2 diabetes mellitus, mutations in the Kir6.2 gene and neonatal diabetes mellitus, and mutations in the SUR1 gene and diabetes mellitus. Interestingly, for reasons that are unclear at present, mice knockout models of K(ATP) channels are different from the human phenotype of CHI. This article is a review focusing on how abnormalities in the pancreatic beta-cell K(ATP) channels can lead to severe hypoglycemia on the one hand and diabetes mellitus on the other.

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132 For example, some SUR1 mutations (such as the E1506K and G1382S mutations) cause CHI by reducing the sensitivity of the channel to stimulation by MgADP, thus demonstrating the critical role of MgADP in activating KATP channels in physiological conditions (54). Login to comment
207 SUR1 mutations as a cause of CHI leading to diabetes mellitus A unique example of how defects in KATP channels can cause CHI and diabetes is illustrated by the dominant heterozygous missense mutation (E1506K) in the SUR ABCC8 gene in a large Finnish family (91). Login to comment
208 In the infancy period, heterozygous E1506K carriers of this mutation have a mild form of CHI due to reduction of KATP channel activity. Login to comment
211 Glucose-induced, first-phase insulin secretion was normal in children younger than 10 yr of age who were heterozygous for the SUR1 E1506K mutation; it fell rapidly after puberty and was almost completely lost in adulthood. Login to comment

[hide] Physiological and pathophysiological roles of ATP-... Prog Biophys Mol Biol. 2003 Feb;81(2):133-76. Seino S, Miki T
Physiological and pathophysiological roles of ATP-sensitive K+ channels.
Prog Biophys Mol Biol. 2003 Feb;81(2):133-76., [PMID:12565699]

Abstract [show]
ATP-sensitive potassium (K(ATP)) channels are present in many tissues, including pancreatic islet cells, heart, skeletal muscle, vascular smooth muscle, and brain, in which they couple the cell metabolic state to its membrane potential, playing a crucial role in various cellular functions. The K(ATP) channel is a hetero-octamer comprising two subunits: the pore-forming subunit Kir6.x (Kir6.1 or Kir6.2) and the regulatory subunit sulfonylurea receptor SUR (SUR1 or SUR2). Kir6.x belongs to the inward rectifier K(+) channel family; SUR belongs to the ATP-binding cassette protein superfamily. Heterologous expression of differing combinations of Kir6.1 or Kir6.2 and SUR1 or SUR2 variant (SUR2A or SUR2B) reconstitute different types of K(ATP) channels with distinct electrophysiological properties and nucleotide and pharmacological sensitivities corresponding to the various K(ATP) channels in native tissues. The physiological and pathophysiological roles of K(ATP) channels have been studied primarily using K(ATP) channel blockers and K(+) channel openers, but there is no direct evidence on the role of the K(ATP) channels in many important cellular responses. In addition to the analyses of naturally occurring mutations of the genes in humans, determination of the phenotypes of mice generated by genetic manipulation has been successful in clarifying the function of various gene products. Recently, various genetically engineered mice, including mice lacking K(ATP) channels (knockout mice) and mice expressing various mutant K(ATP) channels (transgenic mice), have been generated. In this review, we focus on the physiological and pathophysiological roles of K(ATP) channels learned from genetic manipulation of mice and naturally occurring mutations in humans.

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1014 Recently, a mutation of SUR1 (SUR1-E1506K), which causes dominantly inherited PHHI, also has been shown to cause diabetes mellitus in later life (Huopio et al., 2000). Login to comment
1006 Recently, a mutation of SUR1 (SUR1-E1506K), which causes dominantly inherited PHHI, also has been shown to cause diabetes mellitus in later life (Huopio et al., 2000). Login to comment

[hide] Noninvasive diagnosis of focal hyperinsulinism of ... Diabetes. 2006 Jan;55(1):13-8. Otonkoski T, Nanto-Salonen K, Seppanen M, Veijola R, Huopio H, Hussain K, Tapanainen P, Eskola O, Parkkola R, Ekstrom K, Guiot Y, Rahier J, Laakso M, Rintala R, Nuutila P, Minn H
Noninvasive diagnosis of focal hyperinsulinism of infancy with [18F]-DOPA positron emission tomography.
Diabetes. 2006 Jan;55(1):13-8., [PMID:16380471]

Abstract [show]
Congenital hyperinsulinism of infancy (CHI) is characterized by severe hypoglycemia due to dysregulated insulin secretion, associated with either focal or diffuse pathology of the endocrine pancreas. The focal condition is caused by a paternally inherited mutation in one of the genes encoding the subunits of the beta-cell ATP-sensitive potassium channel (SUR1/ABCC8 or Kir6.2/KCNJ11) and somatic loss of maternal 11p15 alleles within the affected area. Until now, preoperative diagnostics have relied on technically demanding and invasive catheterization techniques. We evaluated the utility of fluorine-18 l-3,4-dihydroxyphenylalanine ([(18)F]-DOPA) positron emission tomography (PET) to identify focal pancreatic lesions in 14 CHI patients, 11 of which carried mutations in the ABCC8 gene (age 1-42 months). To reduce bias in PET image interpretation, quantitative means for evaluation of pancreatic [(18)F]-DOPA uptake were established. Five patients had a visually apparent focal accumulation of [(18)F]-DOPA and standardized uptake value (SUV) >50% higher (mean 1.8-fold) than the maximum SUV of the unaffected part of the pancreas. When these patients were operated on, a focus of 4-5 x 5-8 mm matching with the PET scan was found, and all were normoglycemic after resection of the focus. The remaining nine patients had diffuse accumulation of [(18)F]-DOPA in the pancreas (SUV ratio <1.5). Diffuse histology was verified in four of these, and pancreatic catheterization was consistent with diffuse pathology in four cases. In conclusion, [(18)F]-DOPA PET is a promising noninvasive method for the identification and localization of the focal form of CHI.

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83 The two previously detected founder mutations SUR1-V187D (5) and SUR1-E1506K (24) were screened by direct sequencing in all Finnish patients. Login to comment

[hide] K(ATP) channels and insulin secretion disorders. Am J Physiol Endocrinol Metab. 2002 Aug;283(2):E207-16. Huopio H, Shyng SL, Otonkoski T, Nichols CG
K(ATP) channels and insulin secretion disorders.
Am J Physiol Endocrinol Metab. 2002 Aug;283(2):E207-16., [PMID:12110524]

Abstract [show]
ATP-sensitive potassium (K(ATP)) channels are inhibited by intracellular ATP and activated by ADP. Nutrient oxidation in beta-cells leads to a rise in [ATP]-to-[ADP] ratios, which in turn leads to reduced K(ATP) channel activity, depolarization, voltage-dependent Ca(2+) channel activation, Ca(2+) entry, and exocytosis. Persistent hyperinsulinemic hypoglycemia of infancy (HI) is a genetic disorder characterized by dysregulated insulin secretion and, although rare, causes severe mental retardation and epilepsy if left untreated. The last five or six years have seen rapid advance in understanding the molecular basis of K(ATP) channel activity and the molecular genetics of HI. In the majority of cases for which a genotype has been uncovered, causal HI mutations are found in one or the other of the two genes, SUR1 and Kir6.2, that encode the K(ATP) channel. This article will review studies that have defined the link between channel activity and defective insulin release and will consider implications for future understanding of the mechanisms of control of insulin secretion in normal and diseased states.

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76 Reduced sensitivity to stimulation by MgADP is a defect of channels generated by a number of HI-associated SUR1 mutations, including F591L, T1139M, R1215Q, G1382S, and E1506K (25, 59) (Fig. 1B). Login to comment
139 The dominantly inherited mutation SUR1(E1506K) (Fig. 3B) associates with a different phenotype (25). Login to comment
141 This clinical finding is in agreement with the results of coexpression studies of recombinant wild-type (wt)-Kir6.2 and SUR1[E1506K]. Login to comment
143 Despite the dominant nature of SUR1[E1506K] in causing the disease, it does not exert a completely dominant negative effect when expressed EINVITED REVIEW AJP-Endocrinol Metab • VOL 283 • AUGUST 2002 • www.ajpendo.org together with the wild-type gene in Xenopus oocytes. Login to comment
144 Studies of glucose homeostasis in carriers of the SUR1[E1506K] mutation have indicated that this mutation leads to insulin deficiency and to development of diabetes mellitus in later life (25). Login to comment
164 Birthplaces of parents of HI patients with founder mutations SUR1(E1506K) (E) and SUR1(V187D) (F) are indicated (8, 40). Login to comment
165 B: pedigree and haplotype analysis of a large Finnish pedigree carrying the SUR1(E1506K) mutation. Login to comment
168 The haplotype 3-4-4 associates with E1506K in all cases. Login to comment
65 Reduced sensitivity to stimulation by MgADP is a defect of channels generated by a number of HI-associated SUR1 mutations, including F591L, T1139M, R1215Q, G1382S, and E1506K (25, 59) (Fig. 1B). Login to comment
128 The dominantly inherited mutation SUR1(E1506K) (Fig. 3B) associates with a different phenotype (25). Login to comment
130 This clinical finding is in agreement with the results of coexpression studies of recombinant wild-type (wt)-Kir6.2 and SUR1[E1506K]. Login to comment
132 Despite the dominant nature of SUR1[E1506K] in causing the disease, it does not exert a completely dominant negative effect when expressed together with the wild-type gene in Xenopus oocytes. Login to comment
133 Studies of glucose homeostasis in carriers of the SUR1[E1506K] mutation have indicated that this mutation leads to insulin deficiency and to development of diabetes mellitus in later life (25). Login to comment
153 Birthplaces of parents of HI patients with founder mutations SUR1(E1506K) (E) and SUR1(V187D) (F) are indicated (8, 40). Login to comment
154 B: pedigree and haplotype analysis of a large Finnish pedigree carrying the SUR1(E1506K) mutation. Login to comment
157 The haplotype 3-4-4 associates with E1506K in all cases. Login to comment

[hide] Sulphonylurea action revisited: the post-cloning e... Diabetologia. 2003 Jul;46(7):875-91. Epub 2003 Jun 18. Gribble FM, Reimann F
Sulphonylurea action revisited: the post-cloning era.
Diabetologia. 2003 Jul;46(7):875-91. Epub 2003 Jun 18., [PMID:12819907]

Abstract [show]
Hypoglycaemic agents such as sulphonylureas and the newer group of "glinides" stimulate insulin secretion by closing ATP-sensitive potassium (K(ATP)) channels in pancreatic beta cells, but have varying cross-reactivity with related channels in extrapancreatic tissues such as heart, vascular smooth and skeletal muscle. Experiments on the structure-function relationships of recombinant K(ATP) channels and the phenotypes of mice deficient in different K(ATP) channel subunits have provided important insights into the mechanisms underlying sulphonylurea selectivity, and the potential consequences of K(ATP) channel blockade outside the pancreatic beta cell. The different pharmacological properties of K(ATP) channels from beta cells compared with those from cardiac, smooth and skeletal muscle, are accounted for by the expression of alternative types of sulphonylurea receptor, with non-identical drug binding sites. The sulphonylureas and glinides are found to fall into two groups: one exhibiting selectivity for beta cell sulphonylurea receptors (SUR1), and the other blocking cardiovascular and skeletal muscle sulphonylurea receptors (SUR2) with potencies similar to their action on SUR1. In seeking potential side effects of K(ATP) channel inhibitors in humans, it is essential to take these drug differences into account, along with the probability (suggested by the studies on K(ATP) channel knockout mice) that the effects of extrapancreatic K(ATP) channel inhibition might be either subtle or rare. Further studies are still required before a final decision can be made on whether non-selective agents are appropriate for the therapy of Type 2 diabetes.

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69 A mutation in SUR1 (E1506K) that causes mild autosomal dominant CHI in infants, has also been found to cause autosomal dominant Type 2 diabetes in adult life [78, 79]. Login to comment

[hide] Hyperinsulinaemic hypoglycaemia and diabetes melli... Diabetologia. 2011 Oct;54(10):2575-83. Epub 2011 Jun 15. Kapoor RR, Flanagan SE, James CT, McKiernan J, Thomas AM, Harmer SC, Shield JP, Tinker A, Ellard S, Hussain K
Hyperinsulinaemic hypoglycaemia and diabetes mellitus due to dominant ABCC8/KCNJ11 mutations.
Diabetologia. 2011 Oct;54(10):2575-83. Epub 2011 Jun 15., [PMID:21674179]

Abstract [show]
AIMS/HYPOTHESIS: Dominantly acting loss-of-function mutations in the ABCC8/KCNJ11 genes can cause mild medically responsive hyperinsulinaemic hypoglycaemia (HH). As controversy exists over whether these mutations predispose to diabetes in adulthood we investigated the prevalence of diabetes in families with dominantly inherited ATP-sensitive potassium (K(ATP)) channel mutations causing HH in the proband. METHODS: We studied the phenotype of 30 mutation carriers (14 children and 16 adults) from nine families with dominant ABCC8/KCNJ11 mutations. Functional consequences of six novel missense mutations were examined by reconstituting the K(ATP) channel in human embryonic kidney 293 (HEK293) cells and evaluating the effect of drugs and metabolic poisoning on the channels using the (86)Rb flux assay. RESULTS: The mutant channels all showed a lack of (86)Rb efflux on exposure to the channel agonist diazoxide or metabolic inhibition. In the families, dominant ABCC8/KCNJ11 mutations were associated with increased birthweight (median + 1.56 SD score [SDS]). Fourteen children had HH and five adults were reported with HH or hypoglycaemic episodes (63%). Progression from hypoglycaemia to diabetes mellitus occurred in two individuals. Eight adults had a history of gestational diabetes in multiple pregnancies or were diabetic (diagnosed at a median age of 31 years). Within these families, none of the 19 adults who were not carriers of the ABCC8/KCNJ11 mutation was known to be diabetic. CONCLUSIONS/INTERPRETATION: The phenotype associated with dominant ABCC8/KCNJ11 mutations ranges from asymptomatic macrosomia to persistent HH in childhood. In adults, it may also be an important cause of dominantly inherited early-onset diabetes mellitus.

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131 first reported a dominant inactivating ABCC8 mutation, E1506K (E1507K according to reference sequence NM_000352.2), that caused HH progression to hypoinsulinaemic DM during middle age [9, 14]. Login to comment

[hide] A new subtype of autosomal dominant diabetes attri... Lancet. 2003 Jan 25;361(9354):301-7. Huopio H, Otonkoski T, Vauhkonen I, Reimann F, Ashcroft FM, Laakso M
A new subtype of autosomal dominant diabetes attributable to a mutation in the gene for sulfonylurea receptor 1.
Lancet. 2003 Jan 25;361(9354):301-7., [PMID:12559865]

Abstract [show]
BACKGROUND: ATP-sensitive potassium (KATP) channels are major regulators of glucose-induced insulin secretion in pancreatic beta cells. We have described a dominant heterozygous mutation--E1506K--in the sulfonylurea receptor 1 (SUR1) gene (ABCC8) in a Finnish family, which leads to congenital hyperinsulinaemia due to reduction of K(ATP)-channel activity. We aimed to characterise glucose metabolism in adults heterozygous for the E1506K mutation. METHODS: Glucose tolerance was assessed by an oral glucose tolerance test, insulin secretion by the intravenous glucose tolerance test and hyperglycaemic clamp, and insulin sensitivity by hyperinsulinaemic euglycaemic clamp in 11 people heterozygous for the E1506K mutation and 19 controls. FINDINGS: Four people who were heterozygous for the SUR1 E1506K mutation had diabetes, five had impaired glucose tolerance, one had impaired fasting glucose, and one had normal glucose tolerance. Although glucose-induced, first-phase insulin secretion was normal in children younger than 10 years of age who were heterozygous for the SUR1 E1506K mutation (n=2; 66 and 334 pmol/L), it fell rapidly after puberty (n=3; 12-32 pmol/L), and was almost completely lost in adulthood (n=11; 12-32 pmol/L). Furthermore, these heterozygous people had a substantial reduction in maximum glucose-stimulated insulin secretion during hyperglycemic clamp (carriers without diabetes 422 pmol/L; carriers with diabetes 97 pmol/L). By contrast, insulin sensitivity (M/I value) was normal in carriers of the E1506K mutation who did not have diabetes and was reduced by 15% in those who were heterozygous with diabetes (0.07 in those without diabetes and 0.05 in those with the disorder; not significantly different from controls). INTERPRETATION: Heterozygous E1506K substitution in the SUR1 gene causes congenital hyperinsulinism in infancy, loss of insulin secretory capacity in early adulthood, and diabetes in middle-age. This variant represents a new subtype of autosomal dominant diabetes.

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1 We have described a dominant heterozygous mutation-E1506K-in the sulfonylurea receptor 1 (SUR1) gene (ABCC8) in a Finnish family, which leads to congenital hyperinsulinaemia due to reduction of KATP-channel activity. Login to comment
2 We aimed to characterise glucose metabolism in adults heterozygous for the E1506K mutation. Login to comment
3 Methods Glucose tolerance was assessed by an oral glucose tolerance test, insulin secretion by the intravenous glucose tolerance test and hyperglycaemic clamp, and insulin sensitivity by hyperinsulinaemic euglycaemic clamp in 11 people heterozygous for the E1506K mutation and 19 controls. Login to comment
4 Findings Four people who were heterozygous for the SUR1 E1506K mutation had diabetes, five had impaired glucose tolerance, one had impaired fasting glucose, and one had normal glucose tolerance. Login to comment
5 Although glucose-induced, first-phase insulin secretion was normal in children younger than 10 years of age who were heterozygous for the SUR1 E1506K mutation (n=2; 66 and 334 pmol/L), it fell rapidly after puberty (n=3; 12-32 pmol/L), and was almost completely lost in adulthood (n=11; 12-32 pmol/L). Login to comment
7 By contrast, insulin sensitivity (M/I value) was normal in carriers of the E1506K mutation who did not have diabetes and was reduced by 15% in those who were heterozygous with diabetes (0·07 in those without diabetes and 0·05 in those with the disorder; not significantly different from controls). Login to comment
8 Interpretation Heterozygous E1506K substitution in the SUR1 gene causes congenital hyperinsulinism in infancy, loss of insulin secretory capacity in early adulthood, and diabetes in middle-age. This variant represents a new subtype of autosomal dominant diabetes. Login to comment
16 However, congenital hyperinsulinaemia offers a model to investigate the long-term results of constant depolarisation of the beta-cell membrane and amplified concentrations of intracellular calcium on insulin secretion and risk of diabetes.5,6 We have described a dominant mutation in the SUR1 gene (E1506K) in patients with congenital hyperinsulinaemia. Login to comment
17 This mutation leads to a reduction, but not complete loss, of KATP channel activity.7 We aimed to investigate glucose homoeostasis in carriers of the SUR1 E1506K mutation in a large Finnish pedigree. Login to comment
18 Participants and methods Participants Between December, 2000, and May, 2001, we recruited all known relatives of patients who had been diagnosed with congenital hyperinsulinaemia in early infancy7 who were heterozygous for the dominant SUR1 mutation E1506K. Login to comment
35 SULFONYLUREA RECEPTOR 1 Regulates insulin secretion in the pancreatic beta-cells * * * † † † † † * * *** * NN * * N N NN N N NN N N N N NN N NN NN NN N N N N N N N N DM DM CHI CHI CHI CHI CHICHI/DM DM DM DM DM Male Female Died Figure 1: Pedigree of patients with the E1506K mutation in the sulfonylurea receptor 1 gene Heterozygous carriers are shown by half-filled symbols and individuals with normal genotype by N. DM indicates people with diabetes and CHI, congenital hyperinsulinaemia. Login to comment
38 Control People heterozygous for (n=19) the sulfonylurea receptor 1 E1506K mutation No diabetes Diabetes (n=7) (n=4) Sex (male/female) 10/9 3/4 0/4 Age (years, mean [SD]) 41 (6) 45 (15) 50 (15) Systolic blood pressure 128 (14) 130 (16) 128 (32) (mm Hg, mean [SD]) Diastolic blood pressure 86 (9) 83 (10) 76 (9) (mm Hg [SD]) Body-mass index 25·8 (3·8) 24·2 (2·5) 28·8 (3·7) (kg/m2 , mean [SD]) Fasting blood glucose 4·6 (0·4) 5·0 (0·8) 8·3 (2·5) (mmol/L, mean [SD]) Fasting plasma insulin 55·8 (20·2) 34·3 (9·7) 57·5 (21.6) (pmol/L) Fasting C-peptide (pmol/L) 514 (157) 444 (105) 578 (108) Data are mean (SD) or number of participants. Login to comment
39 Table 1: Clinical and biochemical characteristics of participants 303 0 4 2 0 2 50 100 150 200 250 300 350 400 450 4 6 8 10 11 12 Bloodglucose(mmol/L) Incrementalbloodglucosearea underthecurve(mmol/Lperh) Control E1506K carriers, no diabetes E1506K carriers, diabetes 0 0 Incrementalplasmainsulinarea underthecurve(pmol/Lperh) 500 1000 1500 2000 2500 3000 0 18 20 16 14 12 10 8 6 * ‡ † † † ‡ ‡ ‡ ‡ ‡ ‡ * * 50 200 250 100 150 300 350 400 Plasmainsulin(pmol/L)PlasmaC-peptide(pmol/L) Incrementalplasmainsulinarea underthecurve(pmol/Lperh) Minutes 1200 30 60 90 Control E1506K carriers, no diabetes E1506K carriers, diabetes * * * A B C D E F 400 200 0 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 Figure 2: Oral glucose tolerance test in controls and carriers of the E1506K mutation with or without diabetes Concentrations of blood glucose (A), plasma insulin (C), plasma C-peptide (E), and incremental areas under the curve of blood glucose (B), plasma insulin (D), and plasma C-peptide (F). Login to comment
41 Longer error bars in C and E represent SDs of E1506K carriers with no diabetes. Login to comment
51 Results Participants 11 individuals (relatives of patients diagnosed with congenital hyperinsulinaemia7 ) who were heterozygous for the SUR1 E1506K mutation participated in the study (figure 1). Login to comment
59 To ascertain concentrations of plasma insulin and 18 20 16 14 12 10 8 6 4 2 0 0 0 20 40 60 80 100 0 Minutes 100 1000 2000 3000 4000 5000 200 300 400 500 600 700 800 Bloodglucose(mmol/L) Incrementalbloodglucosearea underthecurve(mmol/Lpermin) Incrementalplasmainsulinarea underthecurve(pmol/Lpermin) Plasmainsulin(pmol/L) 100 2 4 6 8 * Control Control E1506K carriers, no diabetes E1506K carriers, diabetes A B C D ‡ ‡ ‡ ‡‡‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ † † E1506K carriers, no diabetes E1506K carriers, diabetes Figure 3: Intravenous glucose tolerance tests in controls and carriers of the E1506K mutation with or without diabetes Concentrations of blood glucose (A) and plasma insulin (C), and incremental blood glucose (B) and plasma insulin (D) areas under the curve. Login to comment
72 Glucose response- when expressed as the incremental glucose area under the curve-was significantly higher in participants heterozygous for the E1506K mutation than in controls (p=0·0010 in those without diabetes, p<0·0001 in those with the disease; figure 2, B). Login to comment
77 Intravenous glucose tolerance test Plasma insulin concentrations at all timepoints measured after intravenous glucose administration, and incremental plasma insulin areas under the curve, were significantly reduced in both groups of individuals with the E1506K mutation (p<0·0001 at 2, 4, 6, 8 min in both groups; p=0·0004 at 10 min in carriers without diabetes; and p=0·0005 in carrier with diabetes; figure 3). Login to comment
78 First-phase insulin secretion was normal or high in the youngest patients with congenital hyperinsulinaemia, but those older than 10 years of age had impaired first-phase insulin secretion.12 Insulin secretion decreased linearly with age in individuals heterozygous for the E1506K mutation, independently of their glucose tolerance status (regression equation: plasma insulin 1 minϩ3 min= 32·1-0·282ϫage; Pearson correlation coefficient -0·591; figure 4). Login to comment
79 All controls had higher insulin secretion than did adults heterozygous for the SUR1 E1506K mutation (p<0·0001). Login to comment
80 Hyperglycaemic and hyperinsulinaemic euglycaemic clamp In the hyperglycaemic clamp, plasma insulin (p=0·0120 and p<0·0001) and C-peptide responses (p=0·0180 and p<0·0001) were strikingly reduced in all individuals with the E1506K mutation (p values given are for those without and with diabetes, respectively; table 2). Login to comment
82 Mean rates of whole-body glucose uptake (M value) did not differ significantly between groups (60·5 [SD 16·5], 64·4 [16·0], and 400 300 200 100 10 20 30 40 50 60 70 80 0 0 E1506K carriers, CHI Controls Plasmainsulinsecretion(pmol/L) Age (years) E1506K carriers, no diabetes E1506K carriers, diabetes Figure 4: Sum of the 1 and 3 min insulin concentrations during intravenous glucose tolerance test in patients with congenital hyperinsulinaemia, controls, and carriers of the E1506K mutation with or without diabetes Line=linear regression line. Login to comment
84 Controls People heterozygous for the sulfonylurea receptor 1 E1506K mutation No diabetes p Diabetes p Maximum insulin response (pmol/L, mean [SD]) 857 (476) 422 (362) 0·0120 97 (40) <0·0001 Maximum C-peptide response (pmol/L, mean [SD]) 3893 (927) 2887 (1097) 0·0180 1138 (288) <0·0001 M/I value (␮mol kg-1 min-1 Ϭpmol/L, mean [SD]) 0·07 (0·02) 0·07 (0·02) 0·975 0·05 (0·04) 0·824 Data are mean (SD). Login to comment
87 However, compared with controls, rate of whole-body glucose uptake was reduced by 15% in individuals heterozygous for the SUR1 E1506K mutation with diabetes. Login to comment
89 Discussion Our results show that the E1506K mutation in the KATP channel subunit (SUR1) had a dominant pattern of inheritance in a large pedigree, leading to development of insulin deficiency and type 2 diabetes. Login to comment
90 Results of electrophysiological studies have shown that sulfonylurea receptor 1 E1506K mutant channels move to the plasma membrane, but these channels are no longer activated by MgADP.7 As a result, they remain shut even at low blood glucose concentrations, producing continuous membrane depolarisation that leads to maintained Ca2+ influx, which in turn causes the persistent insulin secretion that characterises congenital hyperinsulinaemia. Login to comment
91 The severely blunted, first-phase, glucose-stimulated insulin secretion and reduced maximum glucose-stimulated insulin secretory capacity we noted in adults heterozygous for the E1506K mutation suggests that these individuals have a defect in insulin secretion, which developed after puberty (figure 4). Login to comment
93 In most patients with congenital hyperinsulinaemia, and as we saw in all our participants with the E1506K mutation, the clinical course of disease is characterised by slow progressive loss of beta-cell function.13 Results of studies have suggested that this loss may result from beta-cell apoptosis.6 Indeed, patients with congenital hyperinsulinaemia who have had their pancreas removed, and who have mutations in the SUR1 gene, have increased numbers of apoptotic cells in focal lesions.6,14 Although the mechanism has not been completely defined, the concentration of intracellular calcium is likely to be an important determinant of beta-cell apoptosis.15 In transgenic mice with congenital hyperinsulinaemia overexpressing a dominant negative form of KIR6.2 in pancreatic beta-cells, which disrupts KATP channel activity,16 hyperinsulinaemia is evident in the neonatal period, but insulin deficiency, attributed to apoptosis, develops later. Login to comment
94 A similar rise in beta-cell apoptosis could explain the diminished insulin secretory capacity of our study individuals with the SUR1 E1506K mutation. Login to comment
96 Mutations in six different genes are known to cause monogenic maturity-onset diabetes of the young.2 Our results show that the E1506K mutation in the SUR1 gene causes a rare subtype of diabetes that fulfils criteria for this diabetes subtype: the mutation has an autosomal dominant inheritance based on linkage and haplotype analysis,7 and leads to insulin deficiency in early adulthood and to diabetes in middle-age. Login to comment
97 Moreover, seven of eight women heterozygous for the SUR1 E1506K mutation had abnormal glucose tolerance during pregnancy, which is typical in females with monogenic maturity-onset diabetes of the young.17 However, age of onset of diabetes in our patients was not typical of that seen in patients with this diabetes subtype. Login to comment
100 Furthermore, polymorphisms of the SUR1 gene have been linked to low insulin secretory capacity.20,23 We did not find the E1506K mutation in any of the 160 chromosomes of patients with type 2 diabetes.7 Despite their severe insulin deficiency, only four of the 11 individuals with the E1506K mutation fulfilled criteria for diabetes. Login to comment
101 These four people had almost complete loss of first-phase insulin secretion during the intravenous glucose tolerance test, and their insulin secretory capacity did not differ significantly from that of adults with diabetes who were heterozygous for the SUR1 E1506K mutation. Login to comment
102 Our findings are closely similar to those from a study of SUR1 knockout mice, in which mice had a complete absence of first-phase insulin secretion and abnormal glucose tolerance.24 In our study, individuals heterozygous for the SUR1 E1506K mutation with diabetes showed a 15% reduction in insulin sensitivity compared with those without diabetes. Login to comment
108 This pathway for insulin secretion is important, because mice without receptors for the incretins, glucagon-like peptide 1, and gastric inhibitory polypeptide show impaired insulin secretion and abnormal glucose tolerance without insulin resistance.26,27 Incretin-induced insulin secretion in individuals heterozygous for the E1506K mutation in our study could have helped prevent conversion from impaired glucose tolerance to frank diabetes. Login to comment
111 When beta cells are no longer able to compensate, the insulin secretory response becomes progressively impaired, gradually leading to a deficiency in early and late phases of insulin secretion and to abnormal glucose tolerance.28 The E1506K mutation in the SUR1 gene in the family we have studied causes congenital hyperinsulinaemia due to continuous overstimulation of insulin secretion, and leads to insulin deficiency and diabetes in middle-age. This mutation results in an autosomal dominant subtype of diabetes. Login to comment

[hide] Molecular and clinical analysis of Japanese patien... J Clin Endocrinol Metab. 2011 Jan;96(1):E141-5. Epub 2010 Oct 13. Yorifuji T, Kawakita R, Nagai S, Sugimine A, Doi H, Nomura A, Masue M, Nishibori H, Yoshizawa A, Okamoto S, Doi R, Uemoto S, Nagasaka H
Molecular and clinical analysis of Japanese patients with persistent congenital hyperinsulinism: predominance of paternally inherited monoallelic mutations in the KATP channel genes.
J Clin Endocrinol Metab. 2011 Jan;96(1):E141-5. Epub 2010 Oct 13., [PMID:20943781]

Abstract [show]
BACKGROUND: Preoperative identification of the focal form of congenital hyperinsulinism is important for avoiding unnecessary subtotal pancreatectomy. However, neither the incidence nor the histological spectrum of the disease is known for Japanese patients. AIMS: The aim of the study was to elucidate the molecular and histological spectrum of congenital hyperinsulinism in Japan. SUBJECTS: Thirty-six Japanese infants with persistent congenital hyperinsulinism were included in the study. METHODS: All exons of the ATP-sensitive potassium channel (K(ATP) channel) genes (KCNJ11 and ABCC8), the GCK gene, and exons 6 and 7 and 10-12 of the GLUD1 gene were amplified from genomic DNA and directly sequenced. In patients with K(ATP) channel mutations, the parental origin of each mutation was determined, and the results were compared with the histological findings of surgically treated patients. In one of the patients with scattered lesions, islets were sampled by laser capture microdissection for mutational analysis. RESULTS: Mutations were identified in 24 patients (66.7%): five in GLUD1 and 19 in the K(ATP) channel genes. Sixteen had a paternally derived, monoallelic K(ATP) channel mutation predictive of the focal form. In 10 patients who underwent pancreatectomy, the molecular diagnosis correctly predicted the histology, more accurately than [18F]-3,4-dihydroxyphenylalanine positron emission tomography scans. Three patients showed focal lesions that occupied larger areas of the pancreas. Preferential loss of the maternal allele was observed in these islets. CONCLUSION: The majority of the Japanese patients with K(ATP) channel hyperinsulinism (84.2%) demonstrated paternally inherited monoallelic mutations that accurately predicted the presence of the focal form.

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76 Parental origin 1 F 9 months 38 ͓2.1͔ 4.8 ͓33͔ 83 ͓49͔ GLUD1 c.661CϾT p.R221C yes ND F, D 2 M 7 months 30 ͓1.7͔ 3 ͓21͔ 132 ͓77͔ GLUD1 c.797AϾG p.Y266C yes ND F, D 3 F 3 months 29 ͓1.6͔ 4 ͓28͔ 246 ͓144͔ GLUD1 c.1336GϾA p.G446S Yes ND F, D 4 M 10 months Ͻ45 ͓2.5͔ 7.7 ͓53͔ 154 ͓90͔ GLUD1 c.1229AϾG p.N410S No ND F, D 5 M 0 d 10 ͓0.6͔ 10 ͓69͔ 250 ͓147͔ GLUD1 c.1229AϾC p.N410T Yes ND F, D 6a F 2 d 31 ͓1.7͔ 30.2 ͓210͔ 78 ͓46͔ ABCC8 c.382GϾA c.3748CϾT p.E128K p.R1250X Yes, Yes Biparental 7 M 2 d 5 ͓0.3͔ 7.5 ͓52͔ 131 ͓77͔ ABCC8 c.2506CϾT c.4575_4587del13 p.R836X p.M1524Mfs1539X Yes, No Biparental F, O 8 M 0 d Ͻ45 ͓2.5͔ 11 ͓76͔ 58 ͓34͔ ABCC8 c.4516GϾA p.E1506K Yes Mat F, D 9a F 1 month Ͻ20 ͓1.1͔ 42.4 ͓294͔ NA ABCC8 c.2506CϾT p.R836X Yes Pat 10a M 2 d 10 ͓0.56͔ 23.5 ͓163͔ NA ABCC8 c.4412-13GϾA - Yes Pat 11a F 0 d 33 ͓1.8͔ 46.6 ͓324͔ 79 ͓46͔ ABCC8 c.3745GϾT p.V1249F No Pat 12a F 3 months 20 ͓1.1͔ 5.16 ͓36͔ 78 ͓46͔ ABCC8 c.2992CϾT p.R998X Yes Pat 13a F 0 d 23 ͓1.3͔ 101 ͓701͔ 45 ͓24͔ ABCC8 c.4608 ϩ 1GϾA - No Pat 14a M 0 d 22 ͓1.2͔ 22.7 ͓158͔ 75 ͓44͔ ABCC8 c.2992CϾT p.R998X Yes Pat 15a M 5 months 33 ͓1.8͔ 5.42 ͓38͔ NA ABCC8 c.2992CϾT p.R998X Yes Pat 16a M 0 d 28 ͓1.6͔ 38.7 ͓269͔ 66 ͓39͔ ABCC8 c.331GϾA p.G111R Yes Pat 17 F 2 months 15 ͓0.8͔ 9.9 ͓69͔ 90 ͓53͔ ABCC8 c.61_62insG p.V21Gfs88X No Pat F, O 18 M 0 d 19.6 ͓1.1͔ 44 ͓306͔ 79 ͓46͔ ABCC8 c.2506CϾT p.R836X Yes Pat F, O 19 F 7 months 35 ͓1.9͔ 11.2 ͓78͔ 97 ͓57͔ ABCC8 c.2506CϾT p.R836X Yes Pat F, O 20 M 4 months Ͻ45 ͓2.5͔ 7.5 ͓52͔ 84 ͓49͔ ABCC8 c.3928_3929insG p.A1310Gfs1405X No Pat F, O 21 M 2 d 38 ͓2.1͔ 3.4 ͓24͔ 91 ͓53͔ ABCC8 c.4186GϾT p.D1396Y No Pat F 22 F 0 d 9 ͓0.5͔ 22 ͓153͔ NA ABCC8 c.2506CϾT p.R836X Yes Pat F, O 23 M 2 d 0 ͓0͔ 17.3 ͓120͔ 317 ͓186͔ ABCC8 c.4412-13GϾA - Yes Pat F, D 24a M 0 d 33 ͓1.8͔ 21.9 ͓152͔ 75 ͓44͔ KCNJ11 c.637GϾA p.A213T No Pat The clinical data are those at the initial presentation. Login to comment
90 Conflicting results have been reported for the diabeto- genesity of p.E1506K in ABCC8 (12, 14, 15). Login to comment

[hide] Genotypes of the pancreatic beta-cell K-ATP channe... Clin Endocrinol (Oxf). 2005 Apr;62(4):458-65. Ohkubo K, Nagashima M, Naito Y, Taguchi T, Suita S, Okamoto N, Fujinaga H, Tsumura K, Kikuchi K, Ono J
Genotypes of the pancreatic beta-cell K-ATP channel and clinical phenotypes of Japanese patients with persistent hyperinsulinaemic hypoglycaemia of infancy.
Clin Endocrinol (Oxf). 2005 Apr;62(4):458-65., [PMID:15807877]

Abstract [show]
OBJECTIVE: Persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) is a disorder of glucose metabolism that is characterized by dysregulated secretion of insulin from pancreatic beta-cells. This disease has been reported to be associated with mutations of the sulfonylurea receptor SUR1 (ABCC8) or the inward-rectifying potassium channel Kir6.2 (KCNJ11), which are two subunits of the pancreatic beta-cell ATP-sensitive potassium channel. PATIENTS AND METHODS: In 14 Japanese PHHI patients, all exons of SUR1 and Kir6.2 genes were analysed by polymerase chain reaction (PCR) and direct sequencing. Four patients responded to diazoxide, and nine patients underwent a subtotal pancreatectomy. Histologically, seven patients were diagnosed to have a focal form and two a diffuse form of the disease. RESULTS: We found nine novel mutations in the SUR1 gene and two in the Kir6.2 gene. In the SUR1 gene mutations, three were nonsense mutations (Y512X, Y1354X and G1469X), one was a one-base deletion in exon 7, and two were missense mutations in the nucleotide-binding domain 2 (K1385Q, R1487K). The other three mutations occurred in introns 14, 29 and 36, which might cause aberrant splicing of RNA. Two siblings in one family were heterozygotes for a missense mutation, K1385Q, which was maternally inherited. In Kir6.2 gene screening, one patient was found to be a compound heterozygote of a missense mutation (R34H) and a one-base deletion (C344fs/ter). CONCLUSION: The novel mutations reported here could be pathological candidates for PHHI in Japan. They also reveal that SUR1 and Kir6.2 mutations in the Japanese population exhibit heterogeneity and that they occurred at a frequency similar to other genetic populations.

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103 One is a loss of the serine at codon 1387 (delSer1387),7 while others are missense mutations, R1353H8 and E1506K. Login to comment
104 6 The phenotypes in the last mutation are a mild form of congenital hyperinsulinaemic hypoglycaemia in infancy and then gestational or permanent diabetes later.34 The K1385Q mutation may also be inherited autosomal-dominantly and be related to the different phenotypes in insulin secretion in the same manner as E1506K, although the possibility that they are compound heterozygotes of K1385Q with an unknown mutation in either the 5' upstream region or the intronic region of the paternal allele has not yet been ruled out. Login to comment

[hide] Dominantly acting ABCC8 mutations in patients with... Clin Genet. 2011 Jun;79(6):582-7. doi: 10.1111/j.1399-0004.2010.01476.x. Flanagan SE, Kapoor RR, Banerjee I, Hall C, Smith VV, Hussain K, Ellard S
Dominantly acting ABCC8 mutations in patients with medically unresponsive hyperinsulinaemic hypoglycaemia.
Clin Genet. 2011 Jun;79(6):582-7. doi: 10.1111/j.1399-0004.2010.01476.x., [PMID:20573158]

Abstract [show]
Recessive inactivating mutations in the ABCC8 and KCNJ11 genes encoding the adenosine triphosphate-sensitive potassium (K(ATP)) channel subunit sulphonylurea receptor 1 (SUR1) and inwardly rectifying potassium channel subunit (Kir6.2) are the most common cause of hyperinsulinaemic hypoglycaemia (HH). Most of these patients do not respond to treatment with the (K(ATP)) channel agonist diazoxide. Dominant inactivating ABCC8 and KCNJ11 mutations are less frequent, but are usually associated with a milder form of hypoglycaemia that is responsive to diazoxide therapy. We studied five patients from four families with HH who were unresponsive to diazoxide and required a near total pancreatectomy. Mutations in KCNJ11 and ABCC8 were sought by sequencing and dosage analysis. Three novel heterozygous ABCC8 mis-sense mutations (G1485E, D1506E and M1514K) were identified in four probands. All the mutations affect residues located within the Nucleotide Binding Domain 2 of the SUR1 subunit. Testing of family members showed that the mutations had arisen de novo with dominant inheritance in one pedigree. This study extends the clinical phenotype associated with dominant (K(ATP)) channel mutations to include severe congenital HH requiring near total pancreatectomy in addition to a milder form of diazoxide responsive hypoglycaemia. The identification of dominant vs recessive mutations does not predict clinical course but it is important for estimating the risk of HH in future siblings and offspring.

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30 Huopio et al. described the first dominantly inherited ABCC8 mutation, E1507K (described by Huopio et al. as E1506K based on isoform L78207 that excludes the alternatively spliced amino acid in exon 17), that caused HH in early life and predisposes to later insulin deficiency. Login to comment

[hide] Acute insulin response tests for the differential ... J Clin Endocrinol Metab. 2002 Oct;87(10):4502-7. Huopio H, Jaaskelainen J, Komulainen J, Miettinen R, Karkkainen P, Laakso M, Tapanainen P, Voutilainen R, Otonkoski T
Acute insulin response tests for the differential diagnosis of congenital hyperinsulinism.
J Clin Endocrinol Metab. 2002 Oct;87(10):4502-7., [PMID:12364426]

Abstract [show]
Mutations in genes encoding the two subunits of the beta-cell ATP-sensitive potassium channel (K(ATP)) channel (SUR1 and Kir6.2) are the major cause of congenital hyperinsulinism (CHI). In this study, the K(ATP) channel genes were screened in a population-based study that included all verified Finnish CHI patients (n = 43) in a 27-yr period. Seven different mutations were identified, which accounted for 60% of all cases. The functional consequences of the major missense mutations were studied in vivo by determining acute (1-3 min) plasma insulin and C-peptide responses to calcium (n = 18), glucose (n = 12), and tolbutamide (n = 11) in those CHI patients who were able to take part in these studies. C-peptide and insulin responses to calcium were significantly higher in the patients with SUR1-E1506K mutation, compared with patients without K(ATP) channel mutations. The patients with SUR1-V187D mutation showed a reduced response to tolbutamide but unexpectedly did not show any response to calcium stimulation. A compound heterozygous patient with Kir6.2-(-54)/K67N mutations responded to calcium but also to tolbutamide. In conclusion, our results show that a positive response in the calcium test is indicative of a K(ATP) channel mutation, but all mutations cannot be identified with this method. The insulin response to tolbutamide in patients with SUR1 mutations is impaired to different extents, depending on the genotype. The combination of calcium and tolbutamide tests is a useful tool for the detection of CHI patients with K(ATP) channel dysfunction. Our results, however, also demonstrate the complexity of these responses and the difficulties in their interpretation.

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4 C-peptide and insulin responses to calcium were significantly higher in the patients with SUR1-E1506K mutation, compared with patients without KATP channel mutations. Login to comment
20 Indeed, the previously reported SUR1 mutations V187D (3) and E1506K (14) are the cause of most genetically characterized CHI cases. Login to comment
22 In contrast, the dominantly inherited mutation SUR1-E1506K associates with milder diazoxide-responsive form of CHI. Login to comment
37 The third group consisted of six patients (aged 6-27 yr) carrying the dominant SUR1-E1506K mutation. Login to comment
43 All pancreatectomized patients who were included in AIR tests had the diffuse form of CHI as judged by histopathological examination (no KATP channel mutation, n ϭ 1; Kir6.2-(-54)/K67N, n ϭ 1; SUR1-E1506K, n ϭ 1; SUR1-V187D, n ϭ 5). Login to comment
58 Clinical characteristics of the patients Case Sex Age Cause of hyperinsulinism Previous treatment of hyperinsulinism No KATP channel mutation 1 M 2 Unknown Diazoxide 2 F 3 Unknown Octreotide 3 M 5 Unknown Diazoxide 4 M 20 Unknown Diazoxide, subtotal pancreatectomy 5 F 26 Unknown Diazoxide Kir6.2-(-54)/K67N 6 M 8 Paternal Kir6.2-K67N, maternal Kir6.2-(-54) Octreotide, subtotal pancreatectomy SUR1-E1506K 7 F 6 Dominant maternal SUR1-E1506K Diazoxide 8 F 9 Dominant maternal SUR1-E1506K Diazoxide 9 F 15 Dominant maternal SUR1-E1506K Frequent feeds 10 F 16 Dominant maternal SUR1-E1506K Diazoxide 11 F 19 Dominant maternal SUR1-E1506K Frequent feeds 12 M 27 Dominant maternal SUR1-E1506K Diazoxide, subtotal pancreatectomy SUR1-V187D 13 F 1 Paternal SUR1-V187D, maternal genotype pending Octreotide 14 F 6 Maternal SUR1-V187D, paternal genotype pending Subtotal pancreatectomy 15 M 8 Paternal SUR1-V187D, maternal genotype pending Subtotal pancreatectomy 16 F 8 Homozygous SUR1-V187D Subtotal pancreatectomy 17 F 9 Maternal SUR1-V187D, paternal genotype pending Subtotal pancreatectomy 18 F 14 Maternal SUR1-V187D, paternal genotype pending Subtotal pancreatectomy 19 M 11 Paternal SUR1-V187D, maternal SUR1-A1457T Subtotal pancreatectomy 20 F 13 Paternal SUR1-V187D, maternal SUR1-V1550D Subtotal pancreatectomy SUR1-L1551V 21 M 2 Paternal SUR1-L1551V, maternal genotype pending Diazoxide 22 F 0.2 Paternal SUR1-L1551V, maternal genotype pending Diazoxide Diabetic patients are shown in italics. Login to comment
95 in all study groups: 0.19 mmol/liter in CHI patients without KATP mutations, 0.23 mmol/liter in the patient with both Kir6.2 mutations, 0.17 mmol/liter in SUR1-E1506K patients, and 0.23 mmol/liter in SUR1-V187D patients. Login to comment
96 The acute plasma C-peptide response to calcium was significantly increased in patients with SUR1-E1506K (159 Ϯ 28 pmol/liter), compared with either patients without KATP channel mutations (33 Ϯ 25 pmol/liter) (P Ͻ 0.05) or SUR1-V187D carriers (41 Ϯ 15 pmol/liter) (P Ͻ 0.05). Login to comment
101 The plasma insulin and C-peptide responses to tolbutamide appeared to be lower in subjects with SUR-V187D and SUR-E1506K channel mutations, compared with the subjects without KATP channel mutations, but the differences were not statistically significant because of the small number of observations. Login to comment
102 One of four patients with SUR1-E1506K showed a clear response to tolbutamide, but the response was low in all other cases. Login to comment
105 It was clearly subnormal in the prepubertal SUR1-V187D homozygous patient (case 16) and in the postpubertal SUR1-E1506K heterozygotes. Login to comment
108 The two previously reported founder SUR1 mutations, V187D (3) and E1506K (14), account for 88% of the genetically characterized cases. Login to comment
115 Because no other mutations were detected in this family, the possibility remains that this diazoxide-responsive mutation could be inherited dominantly, analogous with the E1506K mutation (14). Login to comment
118 AIRs in nondiabetic patients shown as the means of the increments at 1 and 3 min Case Insulin response to calcium C-peptide response to calcium Insulin response to tolbutamide C-peptide response to tolbutamide Insulin response to glucose No KATP channel mutation 1 37 62 175 727 299 2 0 0 392 1099 607 3 20 49 139 5 38 101 906 1413 1438 Median 29 55 450 1132 453 Kir6.2-(-54)/K67N 6 284 652 491 1136 1083 SUR1-E1506K 7 62 147 127 306 197 8 55 171 476 1148 1001 9 36 77 34 36 105 10 83 265 34 93 75 11 42 200 26 33 74 Median 55 171 34 93 105 SUR1-V187D 13 10 80 166 550 216 16 5 30 1 8 42 Median 8 55 84 279 129 Reference values 1 Ϯ 4a 318 Ϯ 72b 252 Ϯ 54b (-12-25) (158-478) The individual results and median values are shown for each group, expressed as picomoles per liter. Login to comment
143 Consistent with this idea, subjects with SUR1-E1506K and the Kir6.2 mutations showed a significant response to calcium. Login to comment
157 A diminished response to tolbutamide was also seen in the oldest SUR1-E1506K subjects, which may at least partly be explained by the natural course of E1506K- associated CHI. Login to comment
159 According to the recombinant KATP channel studies of the dominant SUR1-E1506K, the mutated channels were partially activated by diazoxide and further blocked by tolbutamide (14). Login to comment
161 However, the high response in our single case with Kir6.2 mutations and the variable response of SUR1-E1506K cases suggest that these patients would not be detected by this test alone. Login to comment

[hide] Potassium channel regulation. EMBO Rep. 2003 Nov;4(11):1038-42. Campbell JD, Sansom MS, Ashcroft FM
Potassium channel regulation.
EMBO Rep. 2003 Nov;4(11):1038-42., [PMID:14593442]

Abstract [show]
The sulphonylurea receptor (SUR) is a member of the ATP-binding cassette (ABC) family of membrane proteins. It functions as the regulatory subunit of the ATP-sensitive potassium (KATP) channel, which comprises SUR and Kir6.x proteins. Here, we review data demonstrating functional differences between the two nucleotide binding domains (NBDs) of SUR1. In addition, to explain the structural basis of these functional differences, we have constructed a molecular model of the NBD dimer of human SUR1. We discuss the experimental data in the context of this model, and show how the model can be used to design experiments aimed at elucidating the relationship between the structure and function of the KATP channel.

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107 Although some of these mutations prevent targeting of the protein to the plasma membrane, others, such as G1381S, R1420C, E1506K and L1551V (Fig. 3) cause CHI by impairing KATP channel activation in response to metabolic inhibition or MgADP (Huopio et al., 2000). Login to comment
117 Site 1 Site 2 NDB1 NDB2 G1381S E1506K L1551V R1402C Fig. 3 | Location of congenital hyperinsulinism mutations in the nucleotide-binding domains of sulphonylurea receptor SUR1. Login to comment

[hide] Dominantly inherited hyperinsulinaemic hypoglycaem... J Inherit Metab Dis. 2005;28(3):267-76. de Lonlay P, Giurgea I, Sempoux C, Touati G, Jaubert F, Rahier J, Ribeiro M, Brunelle F, Nihoul-Fekete C, Robert JJ, Saudubray JM, Stanley C, Bellanne-Chantelot C
Dominantly inherited hyperinsulinaemic hypoglycaemia.
J Inherit Metab Dis. 2005;28(3):267-76., [PMID:15868462]

Abstract [show]
Congenital hyperinsulinism (HI), the most important cause of hypoglycaemia in early infancy, is a heterogeneous disease with two types of histological lesions, focal and diffuse, with major consequences in terms of surgical approaches. In contrast to focal islet-cell hyperplasia, always sporadic to our knowledge, diffuse hyperinsulinism is a heterogeneous disorder involving several genes, various mechanisms of pathogenic mutations and different transmissions: (i) channelopathy involving the genes encoding the sulphonylurea receptor (SUR1) or the inward-rectifying potassium channel (Kir6.2) in recessively inherited HI or more rarely dominantly inherited HI; (ii) metabolic disorders implicating the short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) enzyme inrecessively inherited HI, the glucokinase gene (GK), the glutamate dehydrogenase gene (GLUD1) when hyperammonemia is associated, dominant exercise-induced HI with still-unknown mechanism, and more recently the human insulin receptor gene in dominantly inherited hyperinsulinism. Thus, dominant HI disorders always correspond to diffuse HI, where most hypoglycaemia occur in infancy, and are sensitive to medical treatment. Channel causes could be due to dominant negative mutation with one abnormality in channels composed of four Kir6.2 subunits and four SUR1 subunits, leading to a complete destruction of the channel structure or function, or due to haploinsufficiency with only one functional allele, leading to 50% of functional protein, which is not sufficient to obtain enough opened channels to maintain the membrane depolarized. Metabolic causes are due to a gain of function of enzyme activity (deregulated enzymes), except for physical exercise-induced hyperinsulinaemic hypoglycaemia, of still-unknown cause. Congenital hyperinsulinism (HI) is the most important cause of hypoglycaemia in early infancy (Aynsley-Green et al 2000; Cornblath et al 1990; Pagliara et al 1973; Thomas et al 1977). The inappropriate oversecretion of insulin is responsible for profound hypoglycaemia that requires aggressive treatment to prevent severe and irreversible brain damage (Volpe 1995). HI is a heterogeneous disease associated with several genes, various mechanisms of pathogenic mutations and different transmissions (Dunne et al 2004).

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83 One founder mutation in Finnish HI patients, E1506K, was found in a large pedigree with dominant inheritance. Login to comment

[hide] Familial leucine-sensitive hypoglycemia of infancy... J Clin Endocrinol Metab. 2004 Sep;89(9):4450-6. Magge SN, Shyng SL, MacMullen C, Steinkrauss L, Ganguly A, Katz LE, Stanley CA
Familial leucine-sensitive hypoglycemia of infancy due to a dominant mutation of the beta-cell sulfonylurea receptor.
J Clin Endocrinol Metab. 2004 Sep;89(9):4450-6., [PMID:15356046]

Abstract [show]
Familial leucine-sensitive hypoglycemia of infancy was described in 1956 as a condition in which symptomatic hypoglycemia was provoked by protein meals or the amino acid, leucine. The purpose of this study was to determine the genetic basis for hypoglycemia in a family diagnosed with leucine-sensitive hypoglycemia in 1960. Recently diagnosed family members showed a dominantly transmitted pattern of diazoxide-responsive hyperinsulinism (HI). However, they did not fit the characteristics of HI caused by glutamate dehydrogenase gene mutations, previously felt to explain leucine-sensitive hypoglycemia. Islet function was examined using acute insulin response (AIR) tests to calcium, leucine, glucose, and tolbutamide as well as oral protein tolerance tests. Five of five affected family members showed an abnormal positive calcium AIR, and two of five showed a positive leucine AIR. Protein-induced hypoglycemia was demonstrated in five of six affected subjects. Mutation analysis of four known HI genes (sulfonylurea receptor 1, Kir6.2, glutamate dehydrogenase, and glucokinase) in family members identified an R1353H missense mutation in exon 33 of SUR1. (86)Rb(+) efflux and electrophysiological studies of R1353H SUR1 coexpressed with wild-type Kir6.2 in COSm6 cells demonstrated partially impaired ATP-dependent potassium channel function. Leucine-sensitive hypoglycemia in this family was found to result from a dominantly expressed SUR1 mutation.

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160 There have been two previous descriptions of dominantly inherited SUR1 mutations, E1506K by Huopio et al. (15) and delSer1387 from our institution (16). Login to comment
161 The E1506K mutation caused HI in seven children within a large pedigree. Login to comment
165 Unlike the R1353H and E1506K families, the delSer1387 family members showed only partial diazoxide responsiveness (16). Login to comment
168 In patch-clamp expression studies, E1506K SUR1 formed KATP channels that were sensitive to diazoxide, but not to metabolic inhibition, consistent with partial impairment of function (15). Login to comment
172 Thus, the R1353H mutation appears to cause a partial disruption of SUR1 receptor function similar to E1506K, but less severe than delSer1387. Login to comment
173 The milder impairment of function by R1353H and E1506K compared with delSer1387 correlates with the greater diazoxide responsiveness of patients with these two mutations. Login to comment
220 This was also noted in the family with the dominant E1506K SUR1 mutation described by Huopio et al. (15). Login to comment
222 Based on their observations of subnormal insulin responses to oral and iv glucose and to hyperglycemic clamp studies in adults with the SUR1 E1506K mutations, Huopio et al. (15) suggested that the KATP defect causes diabetes due to beta-cell apoptosis as a result of continuous depolarization and high cytoplasmic calcium concentrations of beta-cells. Login to comment
223 Supporting this hypothesis is their finding that insulin secretion was lower in older compared with younger E1506K heterozygotes (23). Login to comment

[hide] Mutations of the same conserved glutamate residue ... Diabetes. 2011 Jun;60(6):1813-22. Mannikko R, Flanagan SE, Sim X, Segal D, Hussain K, Ellard S, Hattersley AT, Ashcroft FM
Mutations of the same conserved glutamate residue in NBD2 of the sulfonylurea receptor 1 subunit of the KATP channel can result in either hyperinsulinism or neonatal diabetes.
Diabetes. 2011 Jun;60(6):1813-22., [PMID:21617188]

Abstract [show]
OBJECTIVE: Two novel mutations (E1506D, E1506G) in the nucleotide-binding domain 2 (NBD2) of the ATP-sensitive K(+) channel (K(ATP) channel) sulfonylurea receptor 1 (SUR1) subunit were detected heterozygously in patients with neonatal diabetes. A mutation at the same residue (E1506K) was previously shown to cause congenital hyperinsulinemia. We sought to understand why mutations at the same residue can cause either neonatal diabetes or hyperinsulinemia. RESEARCH DESIGN AND METHODS: Neonatal diabetic patients were sequenced for mutations in ABCC8 (SUR1) and KCNJ11 (Kir6.2). Wild-type and mutant K(ATP) channels were expressed in Xenopus laevis oocytes and studied with electrophysiological methods. RESULTS: Oocytes expressing neonatal diabetes mutant channels had larger resting whole-cell K(ATP) currents than wild-type, consistent with the patients' diabetes. Conversely, no E1506K currents were recorded at rest or after metabolic inhibition, as expected for a mutation causing hyperinsulinemia. K(ATP) channels are activated by Mg-nucleotides (via SUR1) and blocked by ATP (via Kir6.2). All mutations decreased channel activation by MgADP but had little effect on MgATP activation, as assessed using an ATP-insensitive Kir6.2 subunit. Importantly, using wild-type Kir6.2, a 30-s preconditioning exposure to physiological MgATP concentrations (>300 micromol/L) caused a marked reduction in the ATP sensitivity of neonatal diabetic channels, a small decrease in that of wild-type channels, and no change for E1506K channels. This difference in MgATP inhibition may explain the difference in resting whole-cell currents found for the neonatal diabetes and hyperinsulinemia mutations. CONCLUSIONS: Mutations in the same residue can cause either hyperinsulinemia or neonatal diabetes. Differentially altered nucleotide regulation by NBD2 of SUR1 can explain the respective clinical phenotypes.

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1 A mutation at the same residue (E1506K) was previously shown to cause congenital hyperinsulinemia. Login to comment
6 Conversely, no E1506K currents were recorded at rest or after metabolic inhibition, as expected for a mutation causing hyperinsulinemia. Login to comment
9 Importantly, using wild-type Kir6.2, a 30-s preconditioning exposure to physiological MgATP concentrations (.300 mmol/L) caused a marked reduction in the ATP sensitivity of neonatal diabetic channels, a small decrease in that of wild-type channels, and no change for E1506K channels. Login to comment
50 Furthermore, the mutation of E1506 to lysine (E1506K) results in reduced channel activation by MgADP and is associated with hyperinsulinism (26,27). Login to comment
98 As previously reported (27), Kir6.2/SUR1-E1506K (homE1506K) currents were minimal in both the absence and presence of azide but were slightly increased by diazoxide. Login to comment
105 Tolbutamide (500 mmol/L) blocked hetE1506D currents by 95 6 1% (n = 8), hetE1506G currents by 95 6 1% (n = 6), and E1506K currents by 91 6 2% (n = 6) compared with 96 6 1% (n = 7) for wild-type channels. Login to comment
137 C: Kir6.2/SUR1-E1506G (n = 10), IC50 = 18.8, h = 0.93. Login to comment
138 D: Kir6.2/SUR1-E1506K (n = 11), IC50 = 11.0, h = 1.14. Login to comment
140 F: Kir6.2/SUR1-E1506G (n = 7), IC50 = 6.9, h = 0.86. Login to comment
141 G: SUR1-E1506K (n = 7), IC50 = 6.4, h = 1.00. stimulation at SUR1 because ATP does not interact with SUR1 in the absence of Mg2+ (34). Login to comment
179 No increase in current was observed for the Kir6.2-G334D/SUR1-E1506D (G334D/E1506D) or Kir6.2-G334D/SUR1-E1506G (G334D/ E1506G) channels; in contrast, the Kir6.2-G334D/SUR1-E1506K (G334D/E1506K) currents increased 1.5-fold on excision. Login to comment
180 This suggests that the G334D/E1506 and G334D/ E1506K channels were partially blocked under resting conditions in the oocyte, whereas the G334D/E1506D and G334D/E1506G channels were fully open. Login to comment
181 Larger amplitudes were found for the G334D/E1506 (8.5 6 1.9 nA, n = 16) and G334D/E1506K (14 6 1.9 nA, n = 9) currents than for the G334D/E1506D (1.0 6 0.2 nA, n = 11) or G334D/ E1506G (0.8 6 0.2 nA, n = 13) currents, again suggesting that the E1506D and E1506G mutations may impair surface expression in the homomeric state. Login to comment
204 The off-rate of MgADP was not significantly different for the G334D/E1506K channels but was slower for the G334D/E1506D and G334D/E1506G channels, with a toff of 10 and 11 s, respectively. Login to comment
205 The off-rate of MgATP was significantly less for all three mutant channels, with a toff of 8.5 s for G334D/E1506K, 16 s for G334D/E1506G, and 67 s for G334D/E1506D. Login to comment
210 Such ATP preconditioning reduced the ATP sensitivity of the two neonatal diabetic mutant channels but had little or no effect on wild-type or E1506K channels, respectively (Table 1). Login to comment
238 In contrast, this effect was very small for wild-type channels and absent for E1506K channels. Login to comment
265 The off-rate of MgADP was much faster than that of MgATP for the E1506D channels, and MgADP had little stimulatory effect, which supports arguments that it cannot be the MgADP-bound state. Login to comment
266 The most striking difference between the E1506K and E1506G/E1506D channels is that shown in Figs. 6 and 7: pre-exposure to millimolar concentrations of MgATP desensitizes the channel to subsequent inhibition by a lower ATP concentration. Login to comment
49 Furthermore, the mutation of E1506 to lysine (E1506K) results in reduced channel activation by MgADP and is associated with hyperinsulinism (26,27). Login to comment
97 As previously reported (27), Kir6.2/SUR1-E1506K (homE1506K) currents were minimal in both the absence and presence of azide but were slightly increased by diazoxide. Login to comment
104 Tolbutamide (500 mmol/L) blocked hetE1506D currents by 95 6 1% (n = 8), hetE1506G currents by 95 6 1% (n = 6), and E1506K currents by 91 6 2% (n = 6) compared with 96 6 1% (n = 7) for wild-type channels. Login to comment
178 No increase in current was observed for the Kir6.2-G334D/SUR1-E1506D (G334D/E1506D) or Kir6.2-G334D/SUR1-E1506G (G334D/ E1506G) channels; in contrast, the Kir6.2-G334D/SUR1-E1506K (G334D/E1506K) currents increased 1.5-fold on excision. Login to comment
203 The off-rate of MgADP was not significantly different for the G334D/E1506K channels but was slower for the G334D/E1506D and G334D/E1506G channels, with a toff of 10 and 11 s, respectively. Login to comment
209 Such ATP preconditioning reduced the ATP sensitivity of the two neonatal diabetic mutant channels but had little or no effect on wild-type or E1506K channels, respectively (Table 1). Login to comment
237 In contrast, this effect was very small for wild-type channels and absent for E1506K channels. Login to comment

[hide] Characterisation of new KATP-channel mutations ass... Diabetologia. 2003 Feb;46(2):241-9. Epub 2003 Jan 9. Reimann F, Huopio H, Dabrowski M, Proks P, Gribble FM, Laakso M, Otonkoski T, Ashcroft FM
Characterisation of new KATP-channel mutations associated with congenital hyperinsulinism in the Finnish population.
Diabetologia. 2003 Feb;46(2):241-9. Epub 2003 Jan 9., [PMID:12627323]

Abstract [show]
AIMS/HYPOTHESIS: ATP-sensitive potassium (K(ATP)) channels are crucial for the regulation of insulin secretion from pancreatic beta cells and mutations in either the Kir6.2 or SUR1 subunit of this channel can cause congenital hyperinsulinism (CHI). The aim of this study was to analyse the functional consequences of four CHI mutations (A1457T, V1550D and L1551V in SUR1, and K67N in Kir6.2) recently identified in the Finnish population. METHODS: Wild type or mutant Kir6.2 and SUR1 subunits were coexpressed in Xenopus oocytes. The functional properties of the channels were examined by measuring currents in intact oocytes or giant inside-out membrane patches. Surface expression was measured by enzyme-linked immunosorbance assay, using HA-epitope-tagged subunits. RESULTS: Two mutations (A1457T and V1550D) prevented trafficking of the channel to the plasma membrane. The L1551V mutation reduced surface expression 40-fold, and caused loss of MgADP and diazoxide activation. Both these factors will contribute to the lack of K(ATP) current activation observed in response to metabolic inhibition in intact oocytes. The L1551V mutation also increased the channel open probability, thereby producing a reduction in ATP-sensitivity (from 10 micro mol/l to 120 micro mol/l). The fourth mutation (K67N mutation in Kir6.2) did not affect surface expression nor alter the properties of K(ATP) channels in excised patches, but resulted in a reduced K(ATP) current amplitude in intact cells on metabolic inhibition, through an unidentified mechanism. CONCLUSION/INTERPRETATION: The four CHI mutations disrupted K(ATP) channel activity by different mechanisms. Our results are discussed in relation to the CHI phenotype observed in patients with these mutations.

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36 The Finnish SUR1 mutation E1506K is one exception, showing a dominant mode of inheritance [5]. Login to comment
64 The mutations V187D and E1506K have been described previously [3, 5]. Login to comment
190 Although CHI is usually a recessive condition, dominant SUR1 mutations (e.g. SUR1-E1506K) have been reported [5]. Login to comment

[hide] Congenital hyperinsulinism. Semin Fetal Neonatal Med. 2005 Aug;10(4):369-76. Hussain K
Congenital hyperinsulinism.
Semin Fetal Neonatal Med. 2005 Aug;10(4):369-76., [PMID:15916932]

Abstract [show]
Congenital hyperinsulinism is a cause of persistent hypoglycaemia in the neonatal period. It is a heterogeneous disease with respect to clinical presentation, molecular biology, genetic aetiology and response to medical therapy. The clinical heterogeneity may range from severe life-threatening disease to very mild clinical symptoms. Recent advances have begun to clarify the molecular pathophysiology of this disease, but despite these advances treatment options remain difficult and there are many long-term complications. So far mutations in five different genes have been identified in patients with congenital hyperinsulinism. Most cases are caused by mutations in genes coding for either of the two subunits of the beta-cell K(ATP) channel (ABCC8 and KCNJ11). Two histological subtypes of the disease - diffuse and focal - have been described. The preoperative histological differentiation of these two subtypes is now mandatory as surgical management will be radically different. The ability to distinguish diffuse from focal lesions has profound implications for therapeutic approaches, prognosis and genetic counselling.

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116 Natural history of CHI There is now some evidence to show that the natural history of CHI is a slow progressive loss of b-cell function, and this may be due to the increased b-cell apoptosis.46 It has been shown that patients with CHI who have had their pancreas removed, and who have mutations in the ABCC8 (SUR1) gene, have increased number of apoptotic cells in focal lesions.47 The precise mechanism of apoptosis is unclear but may be related to the increased intracellular calcium concentrations as a result of unregulated calcium entry.48 A unique example of the natural history of CHI is illustrated by the dominant heterozygous missense mutation (E1506K) in the sulphonylurea receptor ABCC8 gene in a large Finnish family.49 In the infancy period heterozygous E1506K carriers of this mutation have a mild form of CHI which is responsive to diazoxide.49 In early adulthood this mutation causes loss of insulin secretory capacity with glucose intolerance, and then in middle age diabetes mellitus develops. Login to comment

[hide] Co-inheritance of two ABCC8 mutations causing an u... Gene. 2013 Mar 1;516(1):122-5. doi: 10.1016/j.gene.2012.12.055. Epub 2012 Dec 22. Faletra F, Snider K, Shyng SL, Bruno I, Athanasakis E, Gasparini P, Dionisi-Vici C, Ventura A, Zhou Q, Stanley CA, Burlina A
Co-inheritance of two ABCC8 mutations causing an unresponsive congenital hyperinsulinism: clinical and functional characterization of two novel ABCC8 mutations.
Gene. 2013 Mar 1;516(1):122-5. doi: 10.1016/j.gene.2012.12.055. Epub 2012 Dec 22., [PMID:23266803]

Abstract [show]
Congenital hyperinsulinism (CHI) occurs as a consequence of unregulated insulin secretion from the pancreatic beta-cells. Severe recessive mutations and milder dominant mutations have been described in the ABCC8 and KCNJ11 genes encoding SUR1 and Kir6.2 subunits of the beta-cell ATP-sensitive K(+) channel. Here we report two patients with CHI unresponsive to medical therapy with diazoxide. Sequencing analysis identified a compound heterozygous mutation in ABCC8 in both patients. The first one is a carrier for the known mild dominant mutation p.Glu1506Lys jointly with the novel mutation p.Glu1323Lys. The second carries the p.Glu1323Lys mutation and a second novel mutation, p.Met1394Arg. Functional studies of both novel alleles showed reduced or null cell surface expression, typical of recessive mutations. Compound heterozygous mutations in congenital hyperinsulinism result in complex interactions. Studying these mechanisms can improve the knowledge of this disease and modify its therapy.

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4 The first one is a carrier for the known mild dominant mutation p.Glu1506Lys jointly with the novel mutation p.Glu1323Lys. Login to comment
70 The first one was the known dominant mutation p.Glu1506Lys; c.4516G>A (Huopio et al., 2002). Login to comment
75 The p.Glu1506Lys mutation has been reported in several families and causes a dominant CHI well controlled by diazoxide (Huopio et al., 2003). Login to comment
76 Although there is still controversy on this issue, p.Glu1506Lys has been suggested to Fig. 1. Login to comment
77 A pedigree of family and compound heterozygosity of the patient 1, formed by the p.Glu1506Lys mutation (in gray), inherited from his father and also present in the paternal aunt and paternal grandmother, and the p.Glu1323Lys mutation (in black), inherited from the mother and maternal grandmother. Login to comment
79 The worst condition of the patient 1 compared to other patients with the p.Glu1506Lys mutation could be due to the simultaneous inheritance of this and the p.Glu1323Lys mutation. Login to comment
85 Functional analysis was previously performed on the p.Glu1506Lys mutation (Vieira et al., 2010). Login to comment
114 Since this trafficking defect it could be possible that most of the KATP channels expressed at the cell surface contain only the E1506K SUR1 mutant. Login to comment
115 We hypothesize that the combined effect of these two mutations could explain the worst phenotype compared to others with the only p.Glu1506Lys. Login to comment

[hide] Congenital hyperinsulinism: clinical and molecular... Gene. 2013 May 25;521(1):160-5. doi: 10.1016/j.gene.2013.03.021. Epub 2013 Mar 16. Faletra F, Athanasakis E, Morgan A, Biarnes X, Fornasier F, Parini R, Furlan F, Boiani A, Maiorana A, Dionisi-Vici C, Giordano L, Burlina A, Ventura A, Gasparini P
Congenital hyperinsulinism: clinical and molecular analysis of a large Italian cohort.
Gene. 2013 May 25;521(1):160-5. doi: 10.1016/j.gene.2013.03.021. Epub 2013 Mar 16., [PMID:23506826]

Abstract [show]
Congenital hyperinsulinism (CHI) is a genetic disorder characterized by profound hypoglycemia related to an inappropriate insulin secretion. It is a heterogeneous disease classified into two major subgroups: "channelopathies" due to defects in ATP-sensitive potassium channel, encoded by ABCC8 and KCNJ11 genes, and "metabolopathies" caused by mutation of several genes (GLUD1, GCK, HADH, SLC16A1, HNF4A and HNF1A) and involved in different metabolic pathways. To elucidate the genetic etiology of CHI in the Italian population, we conducted an extensive sequencing analysis of the CHI-related genes in a large cohort of 36 patients: Twenty-nine suffering from classic hyperinsulinism (HI) and seven from hyperinsulinism-hyperammonemia (HI/HA). Seventeen mutations have been found in fifteen HI patients and five mutations in five HI/HA patients. Our data confirm the major role of ATP-sensitive potassium channel in the pathogenesis of Italian cases (~70%) while the remaining percentage should be attributed to other. A better knowledge of molecular basis of CHI would lead to improve strategies for genetic screening and prenatal diagnosis. Moreover, genetic analysis might also help to distinguish the two histopathological forms of CHI, which would lead to a clear improvement in the treatment and in genetic counseling.

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119 HI-group mutations identified Patient E/I nt changea aa changea Zygosity/inheritance References (A) Genetic variants found in ABCC8, KCNJ11, HNF4A and GCK genes from HI-group ABCC8 (NM_000352.3) 21 E 10 c.1580_1581dup p.Lys528Glyfs*4 Heterozygosity/paternal Present study 29 E 10 c.1617T>A p.Tyr539* Heterozygosity/ND Present study 24 E 16 c.2146G>A p.Gly716Ser Heterozygosity/ND Present study 13 E 23 c.2780G>A p.Trp927* Heterozygosity/ND Present studyb 20 E 24 c.2857C>T p.Gln953* Heterozygosity/ND Nestorowicz et al. (1998) 20 I 32 c.3989-2A>G Aberrant splicing Heterozygosity/ND Present study 19 E 35 c.4278_4280dup p.Gln1426_Asp1427insGlu Heterozygosity/ND Present study 15,25 E 36 c.4356delinsTA p.Glu1452Aspfs*61 Heterozygosity/paternal Present study 8 E 37 c.4477C>T p.Arg1493Trp Heterozygosity/ND Verkarre et al. (1998) 3 E 37 c.4516G>A p.Glu1506Lys Heterozygosity/maternal Huopio et al. (2000) 28 E 39 c.4684C>G p.Pro1562Ala Heterozygosity/ND Present study KCNJ11 (NM_000525.3) 7 E 1 c.151G>T p.Glu51* Heterozygosity/ND Present study 6 E 1 c.1017G>T p.Val339Val Heterozygosity/paternal Present study HNF4A (NM_000457.3) 27 E 5 c.511G>A p.Gly171Arg Heterozygosity/maternal Present study GCK (NM_000162.3) 6 E 1 c.31G>A p.Ala11Thr Heterozygosity/paternal Chiu et al. (1993) 12 E 6 c.600G>A p.Val200Val Heterozygosity/ND Present study (B) Genetic variants found in GLUD1 gene from HI/HA-group GLUD1 (NM_005271.3) 33 E 7 c.943C>T p.His315Tyr Heterozygosity/de novo Halldorsdottir et al. (2000) 35 E 7 c.955T>C p.Tyr319His Heterozygosity/ND Stanley (2004) 30 E 10 c.1387A>T p.Asn463Tyr Heterozygosity/ND Present study 36 E 11 c.1493C>T p.Ser498Leu Heterozygosity/ND Stanley et al. (1998) 31 E 12 c.1498G>A p.Ala500Thr Heterozygosity/maternal Stanley et al. (2000) E = exon; I = intron.; ND = not determined. Login to comment

[hide] A mouse model of human hyperinsulinism produced by... Diabetes. 2013 Nov;62(11):3797-806. doi: 10.2337/db12-1611. Epub 2013 Jul 31. Shimomura K, Tusa M, Iberl M, Brereton MF, Kaizik S, Proks P, Lahmann C, Yaluri N, Modi S, Huopio H, Ustinov J, Otonkoski T, Laakso M, Ashcroft FM
A mouse model of human hyperinsulinism produced by the E1506K mutation in the sulphonylurea receptor SUR1.
Diabetes. 2013 Nov;62(11):3797-806. doi: 10.2337/db12-1611. Epub 2013 Jul 31., [PMID:23903354]

Abstract [show]
Loss-of-function mutations in the KATP channel genes KCNJ11 and ABCC8 cause neonatal hyperinsulinism in humans. Dominantly inherited mutations cause less severe disease, which may progress to glucose intolerance and diabetes in later life (e.g., SUR1-E1506K). We generated a mouse expressing SUR1-E1506K in place of SUR1. KATP channel inhibition by MgATP was enhanced in both homozygous (homE1506K) and heterozygous (hetE1506K) mutant mice, due to impaired channel activation by MgADP. As a consequence, mutant beta-cells showed less on-cell KATP channel activity and fired action potentials in glucose-free solution. HomE1506K mice exhibited enhanced insulin secretion and lower fasting blood glucose within 8 weeks of birth, but reduced insulin secretion and impaired glucose tolerance at 6 months of age. These changes correlated with a lower insulin content; unlike wild-type or hetE1506K mice, insulin content did not increase with age in homE1506K mice. There was no difference in the number and size of islets or beta-cells in the three types of mice, or evidence of beta-cell proliferation. We conclude that the gradual development of glucose intolerance in patients with the SUR1-E1506K mutation might, as in the mouse model, result from impaired insulin secretion due a failure of insulin content to increase with age.

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0 A Mouse Model of Human Hyperinsulinism Produced by the E1506K Mutation in the Sulphonylurea Receptor SUR1 Kenju Shimomura,1 Maija Tusa,2 Michaela Iberl,1 Melissa F. Brereton,1 Stephan Kaizik,1 Peter Proks,1 Carolina Lahmann,1 Nagendra Yaluri,2 Shalem Modi,2 Hanna Huopio,3 Jarkko Ustinov,4 Timo Otonkoski,4,5 Markku Laakso,2 and Frances M. Ashcroft1 Loss-of-function mutations in the KATP channel genes KCNJ11 and ABCC8 cause neonatal hyperinsulinism in humans. Login to comment
1 Dominantly inherited mutations cause less severe disease, which may progress to glucose intolerance and diabetes in later life (e.g., SUR1-E1506K). Login to comment
2 We generated a mouse expressing SUR1-E1506K in place of SUR1. Login to comment
8 We conclude that the gradual development of glucose intolerance in patients with the SUR1-E1506K mutation might, as in the mouse model, result from impaired insulin secretion due a failure of insulin content to increase with age. Login to comment
23 Members of one family, who are heterozygous carriers of the SUR1-E1506K mutation, have mild neonatal HI but are at increased risk of diabetes in middle age (9,14); 4 out of 11 had overt diabetes, and 5 of those without diabetes showed impaired glucose tolerance. Login to comment
26 Despite their impaired glucose tolerance, blood glucose levels were normal in heterozygous carriers of the SUR1-E1506K mutation without diabetes, and only slightly increased in those with diabetes (14). Login to comment
27 Electrophysiological studies indicate that the E1506K mutation does not impair membrane trafficking but results in channels that are no longer activated by MgATP (9,16). Login to comment
39 Why this translates into reduced insulin secretion later in life is unclear, as is why impaired insulin secretion was observed in all carriers of the E1506K mutation but diabetes in only some of them. Login to comment
47 To address these questions, we generated a mouse carrying a human HI mutation, SUR1-E1506K, which causes neonatal hypoglycemia and predisposes to diabetes late in life (9,14). Login to comment
49 RESEARCH DESIGN AND METHODS Generation of E1506K mice. Login to comment
50 Knock-in mice expressing the murine SUR1 (Abcc8) gene containing a G-to-A missense mutation corresponding to the human SUR1-E1506K mutation were produced by targeted mutagenesis. Login to comment
52 The GAA-to-AAA change, corresponding to the GAG-to-AAG mutation in human SUR1-E1506K carriers, was introduced into mouse genomic DNA spanning 8.6 kb over the Abcc8 gene exons 30-39. Login to comment
59 These mice were then back-crossed to C57Bl/6J mice to segregate the cre transgene, and Sur1wt/E1506K /neo2/2 /cre2/2 offspring were used for further breeding. Login to comment
123 Targeted mutagenesis of the murine Abcc8 gene and production of the SUR1-E1506K knock-in mice. Login to comment
125 The Abcc8w/E1506K /neo2/2 /cre2/2 offspring were used for further breeding. Login to comment
148 RESULTS Generation of SUR1-E1506K mice. Login to comment
149 Mice homozygously expressing the E1506K mutation in SUR1 were generated by targeted mutagenesis of the SUR1 (Abcc8) gene (Fig. 1A) and back-crossed for eight generations onto a C57BL/6J background. Login to comment
150 Genotyping demonstrated the presence of the mutant allele in heterozygous SUR1-E1506K (hetE1506K) and homozygous E1506K (homE1506K) mice (Fig. 1B). Login to comment
151 C57BL/6J mice were used as controls and to generate heterozygous E1506K mice. Login to comment
161 The E1506K mutation increased the sensitivity of the KATP channel to MgATP, half-maximal inhibition being produced by 33, 14, and 10 mmol/L in inside-out patches from WT, hetE1506K, and homE1506K b-cells, respectively (Fig. 3B and Supplementary Table 1). Login to comment
164 These data also show that, as suggested from studies of heterologously expressed channels (9), mutant SUR1-E1506K subunits do not exert a dominant-negative effect on WT subunits in vivo. Login to comment
245 Similarly, some patients heterozygous for the E1506K mutation have severely reduced insulin secretion but no overt diabetes or glucose intolerance (9,14). Login to comment
268 It is possible that the enhanced basal insulin secretion caused by the E1506K mutation, which necessitates increased insulin production to maintain the same insulin content, places an additional stress on the b-cell that eventually leads to impaired insulin synthesis and/or trafficking (31). Login to comment
270 Interestingly, in vitro studies have shown that chronic exposure to glibenclamide (which simulates the effect of the E1506K mutation) also reduces insulin content (32). Login to comment
278 Although the E1506K mutation is dominant, homE1506K mice mimic the human disease more closely than hetE1506K mice. Why this is the case is unclear but presumably reflects differences in genetic background, lifestyle, or compensatory changes. Login to comment

[hide] Nateglinide is Effective for Diabetes Mellitus wit... Clin Pediatr Endocrinol. 2012 Jul;21(3):45-52. doi: 10.1297/cpe.21.45. Epub 2012 Jul 25. Saito-Hakoda A, Yorifuji T, Kanno J, Kure S, Fujiwara I
Nateglinide is Effective for Diabetes Mellitus with Reactive Hypoglycemia in a Child with a Compound Heterozygous ABCC8 Mutation.
Clin Pediatr Endocrinol. 2012 Jul;21(3):45-52. doi: 10.1297/cpe.21.45. Epub 2012 Jul 25., [PMID:23926410]

Abstract [show]
ABCC8 encodes the sulfonylurea receptor 1 (SUR1) subunits of the beta-cell ATP-sensitive potassium (K-ATP) channel playing a critical role in the regulation of insulin secretion, and inactivating mutations in ABCC8 cause congenital hyperinsulinism. Recently, ABCC8 inactivating mutations were reported to be involved in the development of diabetes mellitus later in life. We report a girl who was born macrosomic with transient hypoglycemia and thereafter developed diabetes mellitus accompanied by severe reactive hypoglycemia at the age of 11 yr. An OGTT (oral glucose tolerance test) revealed hyperglycemia due to poor early insulin response and subsequent hypoglycemia due to delayed prolonged insulin secretion. Hypoglycemia was improved by the combination of nateglinide, which stimulates early insulin secretion, and an alpha-glucosidase inhibitor, voglibose. Sequencing of the ABCC8 identified a compound heterozygous mutation (R1420H/F591fs604X), suggesting that this mutation may alter regulation of insulin secretion with advancing age, leading to diabetes mellitus with reactive hypoglycemia from hyperinsulinism. Therefore, long-term follow-up and periodic OGTTs are important for early detection of insulin dysregulation in congenital hyperinsulinism patients carrying the ABCC8 mutation, even though hypoglycemia resolves spontaneously during infancy. Furthermore, nateglinide may be useful therapeutically in the treatment of not only diabetes mellitus but also reactive hypoglycemia.

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60 Huopio et al. reported that a heterozygous E1506K mutation in ABCC8 caused CHI in infancy, loss of insulin secretory capacity in early childhood and diabetes mellitus in middle age (7, 13). Login to comment

[hide] Molecular mechanisms of congenital hyperinsulinism... J Mol Endocrinol. 2015 Apr;54(2):R119-29. doi: 10.1530/JME-15-0016. Epub 2015 Mar 2. Rahman SA, Nessa A, Hussain K
Molecular mechanisms of congenital hyperinsulinism.
J Mol Endocrinol. 2015 Apr;54(2):R119-29. doi: 10.1530/JME-15-0016. Epub 2015 Mar 2., [PMID:25733449]

Abstract [show]
Congenital hyperinsulinism (CHI) is a complex heterogeneous condition in which insulin secretion from pancreatic beta-cells is unregulated and inappropriate for the level of blood glucose. The inappropriate insulin secretion drives glucose into the insulin-sensitive tissues, such as the muscle, liver and adipose tissue, leading to severe hyperinsulinaemic hypoglycaemia (HH). At a molecular level, genetic abnormalities in nine different genes (ABCC8, KCNJ11, GLUD1, GCK, HNF4A, HNF1A, SLC16A1, UCP2 and HADH) have been identified which cause CHI. Autosomal recessive and dominant mutations in ABCC8/KCNJ11 are the commonest cause of medically unresponsive CHI. Mutations in GLUD1 and HADH lead to leucine-induced HH, and these two genes encode the key enzymes glutamate dehydrogenase and short chain 3-hydroxyacyl-CoA dehydrogenase which play a key role in amino acid and fatty acid regulation of insulin secretion respectively. Genetic abnormalities in HNF4A and HNF1A lead to a dual phenotype of HH in the newborn period and maturity onset-diabetes later in life. This state of the art review provides an update on the molecular basis of CHI.

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75 Journal of Molecular Endocrinology Review S A RAHMAN, A NESSA and others Congenital hyperinsulinism 54:2 R121 http://jme.endocrinology-journals.org &#d1; 2015 Society for Endocrinology DOI: 10.1530/JME-15-0016 E1506K is a dominant heterozygous mutation, which changes the amino acid at position 1506 from glutamic acid(E)tolysine(K),andcausedCHIinsevenrelatedpatients (Huopio et al. 2000). Login to comment
76 The functional consequences of the E1506K mutant were determined using a Xenopus laevis oocytes expression system, and studied using electrophysiological techniques. Login to comment
79 This indicates that, unlike recessive ABCC8 mutations, the E1506K mutant SUR1 subunit could form KATP channels with Kir6.2 which can be activated by diazoxide. Login to comment

[hide] Neonatal Diabetes and Congenital Hyperinsulinism C... Front Endocrinol (Lausanne). 2015 Apr 15;6:48. doi: 10.3389/fendo.2015.00048. eCollection 2015. Ortiz D, Bryan J
Neonatal Diabetes and Congenital Hyperinsulinism Caused by Mutations in ABCC8/SUR1 are Associated with Altered and Opposite Affinities for ATP and ADP.
Front Endocrinol (Lausanne). 2015 Apr 15;6:48. doi: 10.3389/fendo.2015.00048. eCollection 2015., [PMID:25926814]

Abstract [show]
ATP-sensitive K(+) (KATP) channels composed of potassium inward-rectifier type 6.2 and sulfonylurea receptor type 1 subunits (Kir6.2/SUR1)4 are expressed in various cells in the brain and endocrine pancreas where they couple metabolic status to membrane potential. In beta-cells, increases in cytosolic [ATP/ADP]c inhibit KATP channel activity, leading to membrane depolarization and exocytosis of insulin granules. Mutations in ABCC8 (SUR1) or KCNJ11 (Kir6.2) can result in gain or loss of channel activity and cause neonatal diabetes (ND) or congenital hyperinsulinism (CHI), respectively. SUR1 is reported to be a Mg(2+)-dependent ATPase. A prevailing model posits that ATP hydrolysis at SUR1 is required to stimulate openings of the pore. However, recent work shows nucleotide binding, without hydrolysis, is sufficient to switch SUR1 to stimulatory conformations. The actions of nucleotides, ATP and ADP, on ND (SUR1E1506D) and CHI (SUR1E1506K) mutants, without Kir6.2, were compared to assess both models. Both substitutions significantly impair hydrolysis in SUR1 homologs. SUR1E1506D has greater affinity for MgATP than wildtype; SUR1E1506K has reduced affinity. Without Mg(2+), SUR1E1506K has a greater affinity for ATP(4-) consistent with electrostatic attraction between ATP(4-), unshielded by Mg(2+), and the basic lysine. Further analysis of ND and CHI ABCC8 mutants in the second transmembrane and nucleotide-binding domains (TMD2 and NBD2) found a relation between their affinities for ATP (+/-Mg(2+)) and their clinical phenotype. Increased affinity for ATP is associated with ND; decreased affinity with CHI. In contrast, MgADP showed a weaker relationship. Diazoxide, known to reduce insulin release in some CHI cases, potentiates switching of CHI mutants from non-stimulatory to stimulatory states consistent with diazoxide stabilizing a nucleotide-bound conformation. The results emphasize the greater importance of nucleotide binding vs. hydrolysis in the regulation of KATP channels in vivo.

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37 The E1506D substitution increases the affinity of SUR1 for MgATP while E1506K reduces affinity. Login to comment
38 In the absence of Mg2+, however, the E1506K substitution increases affinity for ATP4-, supporting the argument that the Mg2+ counterion normally shields the catalytic carboxylate, but is repelled by the substituted lysine. Login to comment
39 Both substitutions reduce affinity for MgADP, consistent with electrophysiological data indicating that E1506D and E1506K produce channels that are less sensitive to stimulation by MgADP. Login to comment
91 Two substitutions, E1506D and E1506K, causes of ND and CHI, respectively, have opposite effects on the affinity for MgATP Several ND mutations in SUR1 increase the apparent affinity for ATP (8, 9). Login to comment
92 To extend these observations two SUR1 substitutions, E1506D and E1506K, well studied at the electrophysiological level (15) and identified with ND and CHI, respectively, were analyzed. Login to comment
98 The substitution of lysine for glutamate at position 1506 replaces a negative with a positive charge. Login to comment
100 Wildtype SUR1 is potentially in a steady-state, slowly hydrolyzing MgATP, while the E1506D and E1506K substitutions are both expected to impair hydrolysis. Login to comment
102 Comparison of the approximate EC50 values, 50 mM, 900 &#b5;M and 10 &#b5;M for E1506K, WT and E1506D, respectively, suggests there is an ~5000-fold range in affinities. Login to comment
112 Mutation Reference KG KT (+Mg2+) b2; KT (-Mg2+) b2; KD (+Mg2+) b2; nM &#b5;M &#b5;M &#b5;M E1506Qa (8) 0.6 &#b1; 0.2 0.9 &#b1; 0.2 40 &#b1; 20 94 &#b1; 9 40 &#b1; 11 211 &#b1; 34 7 .6 &#b1; 2.2 E1506Da (15) 0.4 &#b1; 0.04 3.2 &#b1; 1 8.6 &#b1; 1.5 5570 &#b1; 1200 7 .2 &#b1; 1.5 289 &#b1; 122 4.7 &#b1; 2.2 Q1178Rb (24) 1.0 &#b1; 0.1 9.2 &#b1; 1.3 10 &#b1; 1 1030 &#b1; 200 9.1 &#b1; 1.7 13.9 &#b1; 2.0 20.7 &#b1; 8.9 I1424V (24) 0.5 &#b1; 0.03 7 .1 &#b1; 2.2 5.6 &#b1; 0.7 2840 &#b1; 700 7 .6 &#b1; 1.5 12.1 &#b1; 3.7 14.8 &#b1; 6.5 R1182Qb (24) 0.5 &#b1; 0.15 13.1 &#b1; 2.3 10.3 &#b1; 1.4 11100 &#b1; 1600 4.1 &#b1; 0.4 13.1 &#b1; 2.2 16.4 &#b1; 4.6 WT 0.25 &#b1; 0.02 200 &#b1; 18 13 &#b1; 1 10900 &#b1; 3400 16 &#b1; 11 60 &#b1; 16 14 &#b1; 6.6 S1185Ac (9) 0.3 &#b1; 0.05 416 &#b1; 75 4.9 &#b1; 0.5 19100 &#b1; 3600 6.4 &#b1; 1.5 36.6 &#b1; 8 10.4 &#b1; 2.5 C1174Fc (9) 0.5 &#b1; 0.04 2690 &#b1; 725 5.9 &#b1; 2.3 >20000 13 &#b1; 6 66 &#b1; 13 7 .6 &#b1; 1.7 E1506K (25) 0.3 &#b1; 0.03 8450 &#b1; 1200 5.5 &#b1; 0.6 256 &#b1; 55 5.3 &#b1; 0.4 >1000 n.d. G1479R (26) 0.5 &#b1; 0.04 >10000 n.d. >20000 n.d. >1000 n.d. a Includes data from Ref. (8). Login to comment
118 Patients with E1506K (27) and G1479R (26, 28) mutations are responsive to diazoxide. Login to comment
119 10-2 10-1 100 101 102 103 104 105 0.0 0.2 0.4 0.6 0.8 1.0 WT E1506D E1506K E1506Q Specific Bound GBC [MgATP] (&#b5;M) 10 -1 10 0 10 1 10 2 10 3 10 4 10 5 0.0 0.2 0.4 0.6 0.8 1.0 WT E1506K E1506D E1506Q Specific Bound GBC [ATP 4- ] (&#b5;M) B A C FIGURE 2 | (A) Representation of NBD2 based on Sav1866. Login to comment
122 to the current regulatory model, both E1506 substitutions have reduced affinity for MgADP (Figure 4), consistent with electrophysiological data demonstrating that SUR1E1506D/Kir6.2 and 10 -1 10 0 10 1 10 2 10 3 10 4 10 5 0.0 0.2 0.4 0.6 0.8 1.0 E1506Q Q1178R E1506D R1182Q I1424V WT S1185A C1174F E1506K G1479R Specific Bound GBC [MgATP] (&#b5;M) 10 -1 10 0 10 1 10 2 10 3 10 4 10 5 0.0 0.2 0.4 0.6 0.8 1.0 E1506Q E1506K Q1178R I1424V E1506D R1182Q WT S1185A C1174F G1479R Specific Bound GBC [ATP 4- ] (&#b5;M) B A FIGURE 3 | Comparison of nucleotide-induced conformational switching in WT and SUR1 mutants. Login to comment
151 Figure 5 shows that diazoxide potentiates the 1 10 100 1000 0.0 0.2 0.4 0.6 0.8 1.0 Q1178R I1424V R1182Q S1185A C1174F WT E1506Q E1506D G1479R E1506K Specific Bound GBC [MgADP] (&#b5;M) FIGURE 4 | MgADP-induced conformational switching in WT and SUR1 mutants. Login to comment
157 Patients with the G1479R and E1506K substitutions, as dominant mutations, were responsive to diazoxide (26-29). Login to comment

[hide] ABCC8 R1420H Loss-of-Function Variant in a Southwe... Diabetes. 2015 Dec;64(12):4322-32. doi: 10.2337/db15-0459. Epub 2015 Aug 5. Baier LJ, Muller YL, Remedi MS, Traurig M, Piaggi P, Wiessner G, Huang K, Stacy A, Kobes S, Krakoff J, Bennett PH, Nelson RG, Knowler WC, Hanson RL, Nichols CG, Bogardus C
ABCC8 R1420H Loss-of-Function Variant in a Southwest American Indian Community: Association With Increased Birth Weight and Doubled Risk of Type 2 Diabetes.
Diabetes. 2015 Dec;64(12):4322-32. doi: 10.2337/db15-0459. Epub 2015 Aug 5., [PMID:26246406]

Abstract [show]
Missense variants in KCNJ11 and ABCC8, which encode the KIR6.2 and SUR1 subunits of the beta-cell KATP channel, have previously been implicated in type 2 diabetes, neonatal diabetes, and hyperinsulinemic hypoglycemia of infancy (HHI). To determine whether variation in these genes affects risk for type 2 diabetes or increased birth weight as a consequence of fetal hyperinsulinemia in Pima Indians, missense and common noncoding variants were analyzed in individuals living in the Gila River Indian Community. A R1420H variant in SUR1 (ABCC8) was identified in 3.3% of the population (N = 7,710). R1420H carriers had higher mean birth weights and a twofold increased risk for type 2 diabetes with a 7-year earlier onset age despite being leaner than noncarriers. One individual homozygous for R1420H was identified; retrospective review of his medical records was consistent with HHI and a diagnosis of diabetes at age 3.5 years. In vitro studies showed that the R1420H substitution decreases KATP channel activity. Identification of this loss-of-function variant in ABCC8 with a carrier frequency of 3.3% affects clinical care as homozygous inheritance and potential HHI will occur in 1/3,600 births in this American Indian population.

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136 It has also been shown that Abcc8 (SUR1) knockout mice and mice carrying a knock-in of the hyperinsulinemia- associated SUR1 loss-of-function E1506K mutation all progress to insulin undersecretion or diabetes with age (50,51). Login to comment

[hide] Sirolimus Therapy in Congenital Hyperinsulinism: A... Pediatrics. 2015 Nov;136(5):e1373-6. doi: 10.1542/peds.2015-1132. Minute M, Patti G, Tornese G, Faleschini E, Zuiani C, Ventura A
Sirolimus Therapy in Congenital Hyperinsulinism: A Successful Experience Beyond Infancy.
Pediatrics. 2015 Nov;136(5):e1373-6. doi: 10.1542/peds.2015-1132., [PMID:26504125]

Abstract [show]
Congenital hyperinsulinism (CHI) due to diffuse involvement of the pancreas is a challenging and severe illness in children. Its treatment is based on chronic therapy with diazoxide and/or octreotide, followed by partial pancreatectomy, which is often not resolutive. Sirolimus, a mammalian target of rapamycin inhibitor, was reported to be effective in treating CHI in infants. We report here the case of an 8-year-old boy affected by a severe form of CHI due to a biallelic heterozygous ABCC8 mutation who responded to sirolimus with a dramatic improvement in his glucose blood level regulation and quality of life, with no serious adverse events after 6 months of follow-up. To the best of our knowledge, this is the first report of a successful intervention in an older child. It provides a promising basis for further studies comparing sirolimus with other treatments, particularly in older children.

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16 He was diagnosed with a double heterozygous ABCC8 biallelic mutation (E1323K/E1506K), encoding for the SUR1 subunit of the potassium channel; 18 F-L- dihydroxyphenylalanine positron emission tomography revealed diffuse pancreatic involvement, with no sign of focal lesions. Login to comment

[hide] Epigenetic regulation of glucose-stimulated osteop... Biochem Biophys Res Commun. 2016 Jan 1;469(1):108-13. doi: 10.1016/j.bbrc.2015.11.079. Epub 2015 Nov 22. Cai M, Bompada P, Atac D, Laakso M, Groop L, De Marinis Y
Epigenetic regulation of glucose-stimulated osteopontin (OPN) expression in diabetic kidney.
Biochem Biophys Res Commun. 2016 Jan 1;469(1):108-13. doi: 10.1016/j.bbrc.2015.11.079. Epub 2015 Nov 22., [PMID:26592666]

Abstract [show]
Diabetes nephropathy (DN) is the leading cause of end stage renal disease and it affects up to 40% of diabetic patients. In addition to hyperglycemia, genetic factors are thought to contribute to the development of DN, but few if any genetic factors have been convincingly linked to DN. Other possible mechanisms may involve epigenetic regulation of glucose-stimulated gene activity which was suggested to explain long-term effects of poor glycemic control on risk of diabetic complications, often referred to as metabolic memory. Osteopontin (OPN) is one of the genes upregulated in kidneys from diabetic mouse models as well as humans with DN, and suggested to play an important role in the pathogenesis of DN. In this study, we demonstrated that OPN gene expression is upregulated in the kidneys of a hyperglycemia diabetes mouse model SUR1-E1506K, and glucose-stimulated OPN gene expression is strongly associated with increases in activating histone marks H3K9ac, H3K4me1 and H3K4me3 and decrease in inactivating mark H3K27me3 in the promoter region of OPN gene. These findings were replicated in human mesangial cells treated with high glucose. Further proof for the involvement of histone acetylation and methylation in glucose-induced changes in OPN gene expression was obtained by manipulating histone modifications thereby OPN gene expression by histone deacetylase (HDAC) inhibitor trichostatin A and histone methyltransferase (HMT) inhibitor MM-102. We conclude that glucose is a potent inducer of histone acetylation and methylation, which in turn leads to upregulation of OPN gene expression. Treatment targeting histone marks may therefore represent an alternative method to protect kidneys from deleterious effects of glucose.

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70 Blood glucose and OPN gene expression in the kidney increased in parallel in the diabetic mouse model Sur1-E1506K&#fe;/&#fe; Human carriers of the E1506K mutation in the SUR1 (ABCC8) gene exhibit neonatal hyperinsulinism and hypoglycemia, but develop later in life diabetes due to reduced functional b-cell mass Fig. 2. Login to comment
73 Spp1 expression levels are significantly correlated with H3K9ac (E), H3K4me1 (F), H3K4me3 (G) and H3K27me3 (H) levels in the kidneys of Sur1-E1506K mice of 8, 16, 24 and 32 weeks of age (n &#bc; 44 mice). Login to comment
78 The Sur1-E1506K&#fe;/&#fe; mouse model was developed to recapitulate this human mutation by a knock-in mutation at the equivalent E1506K of the SUR1 subunit [20] in C57Bl mouse strain. Login to comment