ABCMdb

ABCC8 p.Glu1506Lys

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PMID: 18390792 [PubMed] Abdulhadi-Atwan M et al: "Novel de novo mutation in sulfonylurea receptor 1 presenting as hyperinsulinism in infancy followed by overt diabetes in early adolescence."

No. Sentence Comment

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

PMID: 20042013 [PubMed] Vieira TC et al: "Hyperinsulinemic hypoglycemia evolving to gestational diabetes and diabetes mellitus in a family carrying the inactivating ABCC8 E1506K mutation."

No. Sentence Comment

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

PMID: 15561899 [PubMed] Campbell JD et al: "Identification of a functionally important negatively charged residue within the second catalytic site of the SUR1 nucleotide-binding domains."

No. Sentence Comment

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

PMID: 15963039 [PubMed] Hussain K et al: "From congenital hyperinsulinism to diabetes mellitus: the role of pancreatic beta-cell KATP channels."

No. Sentence Comment

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

PMID: 12565699 [PubMed] Seino S et al: "Physiological and pathophysiological roles of ATP-sensitive K+ channels."

No. Sentence Comment

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

PMID: 16380471 [PubMed] Otonkoski T et al: "Noninvasive diagnosis of focal hyperinsulinism of infancy with [18F]-DOPA positron emission tomography."

No. Sentence Comment

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

PMID: 12110524 [PubMed] Huopio H et al: "K(ATP) channels and insulin secretion disorders."

No. Sentence Comment

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

PMID: 12819907 [PubMed] Gribble FM et al: "Sulphonylurea action revisited: the post-cloning era."

No. Sentence Comment

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

PMID: 21674179 [PubMed] Kapoor RR et al: "Hyperinsulinaemic hypoglycaemia and diabetes mellitus due to dominant ABCC8/KCNJ11 mutations."

No. Sentence Comment

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

PMID: 12559865 [PubMed] Huopio H et al: "A new subtype of autosomal dominant diabetes attributable to a mutation in the gene for sulfonylurea receptor 1."

No. Sentence Comment

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

PMID: 20943781 [PubMed] Yorifuji T et al: "Molecular and clinical analysis of Japanese patients with persistent congenital hyperinsulinism: predominance of paternally inherited monoallelic mutations in the KATP channel genes."

No. Sentence Comment

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

PMID: 15807877 [PubMed] Ohkubo K et al: "Genotypes of the pancreatic beta-cell K-ATP channel and clinical phenotypes of Japanese patients with persistent hyperinsulinaemic hypoglycaemia of infancy."

No. Sentence Comment

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

PMID: 20573158 [PubMed] Flanagan SE et al: "Dominantly acting ABCC8 mutations in patients with medically unresponsive hyperinsulinaemic hypoglycaemia."

No. Sentence Comment

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

PMID: 12364426 [PubMed] Huopio H et al: "Acute insulin response tests for the differential diagnosis of congenital hyperinsulinism."

No. Sentence Comment

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

PMID: 14593442 [PubMed] Campbell JD et al: "Potassium channel regulation."

No. Sentence Comment

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

PMID: 15868462 [PubMed] de Lonlay P et al: "Dominantly inherited hyperinsulinaemic hypoglycaemia."

No. Sentence Comment

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

PMID: 15356046 [PubMed] Magge SN et al: "Familial leucine-sensitive hypoglycemia of infancy due to a dominant mutation of the beta-cell sulfonylurea receptor."

No. Sentence Comment

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

PMID: 21617188 [PubMed] Mannikko R et al: "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."

No. Sentence Comment

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

PMID: 12627323 [PubMed] Reimann F et al: "Characterisation of new KATP-channel mutations associated with congenital hyperinsulinism in the Finnish population."

No. Sentence Comment

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

PMID: 15916932 [PubMed] Hussain K et al: "Congenital hyperinsulinism."

No. Sentence Comment

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

PMID: 23266803 [PubMed] Faletra F et al: "Co-inheritance of two ABCC8 mutations causing an unresponsive congenital hyperinsulinism: clinical and functional characterization of two novel ABCC8 mutations."

No. Sentence Comment

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

PMID: 23506826 [PubMed] Faletra F et al: "Congenital hyperinsulinism: clinical and molecular analysis of a large Italian cohort."

No. Sentence Comment

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

PMID: 23903354 [PubMed] Shimomura K et al: "A mouse model of human hyperinsulinism produced by the E1506K mutation in the sulphonylurea receptor SUR1."

No. Sentence Comment

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

PMID: 23926410 [PubMed] Saito-Hakoda A et al: "Nateglinide is Effective for Diabetes Mellitus with Reactive Hypoglycemia in a Child with a Compound Heterozygous ABCC8 Mutation."

No. Sentence Comment

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

PMID: 25733449 [PubMed] Rahman SA et al: "Molecular mechanisms of congenital hyperinsulinism."

No. Sentence Comment

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

PMID: 25926814 [PubMed] Ortiz D et al: "Neonatal Diabetes and Congenital Hyperinsulinism Caused by Mutations in ABCC8/SUR1 are Associated with Altered and Opposite Affinities for ATP and ADP."

No. Sentence Comment

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

PMID: 26246406 [PubMed] Baier LJ et al: "ABCC8 R1420H Loss-of-Function Variant in a Southwest American Indian Community: Association With Increased Birth Weight and Doubled Risk of Type 2 Diabetes."

No. Sentence Comment

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

PMID: 26504125 [PubMed] Minute M et al: "Sirolimus Therapy in Congenital Hyperinsulinism: A Successful Experience Beyond Infancy."

No. Sentence Comment

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

PMID: 26592666 [PubMed] Cai M et al: "Epigenetic regulation of glucose-stimulated osteopontin (OPN) expression in diabetic kidney."

No. Sentence Comment

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