ABCMdb

ABCC8 p.Arg370Ser

Predicted by SNAP2:	A: D (53%), C: D (59%), D: D (85%), E: D (59%), F: D (66%), G: D (53%), H: N (66%), I: D (63%), K: N (82%), L: D (59%), M: D (66%), N: N (61%), P: D (71%), Q: N (57%), S: N (61%), T: N (66%), V: D (53%), W: D (91%), Y: D (71%),
Predicted by PROVEAN:	A: N, C: D, D: D, E: N, F: D, G: D, H: N, I: D, K: N, L: D, M: D, N: N, P: D, Q: N, S: N, T: N, 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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7 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. Login to comment
20 Here we report a novel, de novo heterozygous mutation in the SUR1 gene (ABCC8) (R370S) causing CHI in early infancy followed by overt diabetes presenting at age 10.5 years, suggesting that this mutation facilitates the development of early-onset nonautoimmune diabetes. Login to comment
56 The R370S point mutation of SUR1 was introduced into hamster SUR1 cDNA in the pECE plasmid using the QuikChange site-directed mutagenesis kit (Stratagene). Login to comment
89 A novel heterozygous missense mutation was detected in exon 7 of ABCC8 (AGG3AGC at the 1,111 nucleotide position) (Fig. 2A), predicting an arginine to serine mutation at the 370th amino acid of the SUR1 protein (R370S). Login to comment
95 Cotransfection of Kir6.2 and mutant SUR1 (SUR1- R370S) in COSm6 cells demonstrated normal channel expression on the cell membrane (Fig. 3A). Login to comment
109 DISCUSSION Here, we report a patient with a de novo heterozygous mutation in the SUR1 gene (R370S) resulting in congenital A No treatment Repaglinide Postprandial time (min) Glucose(mmol/l) Fasting 2hr after breakfast 2hr after lunch 2hr after dinner Glucose(mmol/l) No treatment Glibenclamide D Glucose(mmol/l) Time of Day 10/06/200609/06/2006 Time of Day B Glucose(mmol/l) * * * * * Time (min) Insulin(pmoI/l) Glucose Insulin Glucose No treatment Repaglinide C FIG. 1. Login to comment
118 Wild type Mutant BA R370S ABCC8 Proband Sequence T G C A A A C A T T TA G G A G C FIG. 2. Login to comment
119 The R370S mutation. Login to comment
126 Although the amino acid location of the R370S mutation could not predict its dominant effect, we demonstrated normal membrane expression, a finding common to previously reported dominant SUR1 gene mutations (16,19). Login to comment
127 As the KATP channel is a hetero-octamer containing four SUR1 subunits, a normally processed and translocated heterozygous mutant SUR1 0 10 20 30 40 50 60 70 80 90 100 0.1 mM ATP 0.1 mM ATP/0.5mM ADP %Current 0 1000 2000 3000 4000 5000 6000 unt WT R370S 0 10 20 30 40 50 60 70 80 90 100 WT WT:R370S R370S WT WT:R370S R370S WT WT:R370S R370S 0.1 mM ATP 0.1mM ATP/0.3mM Diazoxide 0 10 20 30 40 50 60 70 80 90 100 10 nM Glib 100 nM Glib 0 10 20 30 40 50 60 70 80 90 100 0 10 20 30 40 Untr R370S WT R370S:WT WT+Glib R370S+Glib %Efflux Time (min) %Current %Current 10s WT R370S WT R370S WT R370S WT R370S 1 mM ATP 0.1 mM ATP 0.1 mM ATP+ 0.5 mM ADP 1 mM ATP 0.1 mM ATP 0.1 mM ATP+ 0.3 mM Diaz 1 mM ATP 10nM Glibenclamide Relative chemiluminescenceunits A B C D E F G H 10s 0.5nA 10s 1nA 10s 10s 1nA0.5nA 20s 1nA 20s 1nA unt R370SWT FIG. 3. Login to comment
129 COS cells were untransfected (unt) or transiently transfected with Kir6.2 and SUR1 of WT, R370S, or WT and R370S at 1:1 equal molar cDNA ratio (WT:R370S) and subjected to various expression and functional analyses. Login to comment
131 The relative chemiluminescence units of untransfected, WT, and R370S samples are 234 ؎ 8 (n ‫؍‬ 11), 4,788 ؎ 509 (n ‫؍‬ 14), and 4,736 ؎ 485 (n ‫؍‬ 15), respectively. Login to comment
132 The WT and R370S expression levels are not significantly different (P > 0.5). Login to comment
135 Cells expressing the R370S mutant had near background flux levels, and cells expressing a mixture of WT and R370S showed intermediate flux level between WT and the mutant. Login to comment
136 C: Representative current traces of WT and R370S channels in response to MgADP stimulation obtained by inside-out patch clamp recording. Login to comment
140 In 0.1 mmol/l ATP/0.5 mmol/l ADP, the percent current of WT, WT:R370S, and R370S was 64.3 ؎ 7.9 (n ‫؍‬ 10), 23.4 ؎ 4.7 (n ‫؍‬ 6), and 5.4 ؎ 2.3 (n ‫؍‬ 7), respectively; the values of both WT:R370S and R370S are significantly lower than that of WT (P < 0.05 and 0.005, respectively). Login to comment
142 The percent current in 0.1 mmol/l ATP/0.3 mmol/l diazoxide for WT, WT:R370S, and R370S was 43.0 ؎ 5.2, 22.8 ؎ 3.0, and 3.9 ؎ 1.0, respectively. Login to comment
147 The percent current in 10 nmol/l glibenclamide was 53.3 ؎ 6.0 (n ‫؍‬ 8), 70.6 ؎ 8.1 (n ‫؍‬ 4), and 55.4 ؎ 4.8 (n ‫؍‬ 5) for WT, WT:R370S, and R370S, respectively; these values are not significantly different (P > 0.1). Login to comment
149 subunit such as R370S would be expected to be present in 15 of 16 of the channels on the membrane and thus may alter their function. Login to comment
158 Our data in COS cells suggest equal biogenesis efficiency (data not shown) and surface expression of the WT and mutant R370S proteins at the plasma membrane. Login to comment
174 However, the surprising response of the mutated R370S KATP channel to sulfonylureas in vitro suggested the use of these medications for glycemic control. The good response to glibenclamide enabled our patient to be treated with oral medications rather than insulin injections, a significant advantage given her poor compliance. Login to comment
181 Our findings suggest a critical role for the ABCC8 R370S mutation in the early presentation of diabetes in this patient. 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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76 A recent report identified a de novo heterozygous inactivating ABCC8 mutation (R370S) in a girl who presented CHI early in life, but developed insulinopenic antibody-negative diabetes and obesity later in childhood (10). 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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24 Similarly, a child with a heterozygous SUR1-R370S mutation causing neonatal hyperinsulinism developed diabetes at 10 years of age (15). 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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62 On the other hand, Abdulhadi-Atwan et al. reported diabetes mellitus development at 10.5 yr after mild hypoglycemia during infancy in a patient carrying a heterozygous R370S mutation in ABCC8 (8). Login to comment