ABCMdb

ABCC8 p.Arg1379Cys

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

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[hide] 17beta-Estradiol modulates apoptosis in pancreatic... J Biol Chem. 2009 Feb 20;284(8):4905-13. Epub 2008 Dec 18. Ackermann S, Hiller S, Osswald H, Losle M, Grenz A, Hambrock A
17beta-Estradiol modulates apoptosis in pancreatic beta-cells by specific involvement of the sulfonylurea receptor (SUR) isoform SUR1.
J Biol Chem. 2009 Feb 20;284(8):4905-13. Epub 2008 Dec 18., [PMID:19095654]

Abstract [show]
Apoptosis of pancreatic beta-cells is an important factor in the pathophysiology of diabetes. Previously, we have shown that the "phytoestrogen" resveratrol can induce beta-cell apoptosis dependent on the expression of sulfonylurea receptor (SUR) 1, the regulatory subunit of pancreatic ATP-sensitive K(+) channels. Here, we investigate whether 17beta-estradiol also influences beta-cell apoptosis in a SUR1-dependent manner. Therefore, islets from wild type or SUR1 knock-out mice, clonal beta-cells, or HEK293 cells expressing different SUR forms were treated with 17beta-estradiol or estrone. Different apoptotic parameters were determined and estrogen binding to SUR was analyzed. In murine islets, 17beta-estradiol treatment resulted in significant apoptotic changes, which in their nature (either apoptotic or anti-apoptotic) were dependent on the age of the animal. These effects were not observed in SUR1 knock-out mice. Furthermore, 17beta-estradiol, which specifically binds to SUR, induced enhanced apoptosis in SUR1-expressing HEK293 cells and clonal beta-cells, whereas apoptosis in recombinant cells expressing SUR2A or SUR2B (cardiac or vascular SUR-isoforms) or sham-transfected control cells was significantly lower. The apoptotic potency of 17beta-estradiol was much higher than that of resveratrol or estrone. SUR1-specific 17beta-estradiol-induced apoptosis was either abolished by the mutation M1289T in transmembrane helix 17 of SUR1 or clearly enhanced by two mutations in nucleotide binding fold 2 (R1379C, R1379L). In conclusion, 17beta-estradiol treatment modulates beta-cell apoptosis under specific involvement of SUR1 in an age-dependent manner. 17beta-Estradiol-induced apoptosis can be influenced by certain SUR1 mutations. These findings may contribute to the understanding of pathophysiological changes in beta-cell mass and could, for instance, provide interesting aspects concerning the etiology of gestational diabetes.

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9 SUR1-specific 17beta-estradiol-induced apoptosis was either abolished by the mutation M1289T in transmembrane helix 17 of SUR1 or clearly enhanced by two mutations in nucleotide binding fold 2 (R1379C, R1379L). Login to comment
43 In addition, we explored in which manner the action of 17beta-estradiol was influenced by mutations (M1289T, R1379C, R1379L) in the SUR1 gene (ABCC8) that are of special importance for SUR function (18-20). Login to comment
46 EXPERIMENTAL PROCEDURES Mutagenesis, Transfection, and Cell Culture-HEK293 cells (German Collection of Microorganisms and Cell Cultures, DSMZ, Braunschweig, Germany) were stably transfected with pcDNA3.1 expression vector (Invitrogen) containing the coding sequence of rat SUR1 (GenBankTM accession number X97279), SUR1(M1289T), SUR1(R1379C), SUR1(R1379L), murine SUR2A (GenBank D86037), SUR2A(Y1206S), murine SUR2B (GenBank D86038), or SUR2B(Y1206S), or they were transfected with empty pcDNA3.1 expression vector (Invitrogen). Login to comment
105 By contrast, apoptosis in cells expressing mutants SUR1(R1379C) or SUR1(R1379L) was potentiated to a large extent (Figs. Login to comment
120 After treatment of SUR1-, SUR1(M1289T)-, SUR2A-, and SUR2B-expressing HEK293 cells (A and B) or of SUR1, SUR1(R1379C), and SUR1(R1379L) cells (C) with 17beta-estradiol (100 ␮mol/liter, 24 h), cell detachmentorchangesinnuclearmorphologyweredeterminedandcomparedwiththeresultsobtainedwith pcDNA control cells (please note the different scales in A and C). Login to comment
145 HEK293 cells stably expressing SUR1, SUR1(M1289T), SUR1(R1379C), or pcDNA control cells (A) were compared with cells from the clonal beta-cell lines HIT-T15 and RIN-m5F (B) or to isolated islets from SUR1-expressing wild type mice (SUR1wt) or SUR1KO mice (C) after treatment with 100 ␮mol/liter 17beta-estradiol (E2) or solvent (solv.) Login to comment
184 This SUR1-dependent effect of 17beta-estradiol is either abolished by mutation M1289T or enhanced by mutations R1379C or R1379L in SUR1. Login to comment
225 The mutation M1289T completely abolishes the SUR1-specific apoptotic effects of KATP channel blockers glibenclamide (3) or resveratrol (4), or 17beta-estradiol obviously without directly affecting binding of these substances to SUR1. Login to comment
227 To see whether SUR1-mediated apoptosis is linked with ATP hydrolysis, we explored the effects of mutations R1379C and R1379L in nucleotide binding fold 2 of SUR1 on 17beta-estradiol action. Login to comment
44 In addition, we explored in which manner the action of 17beta-estradiol was influenced by mutations (M1289T, R1379C, R1379L) in the SUR1 gene (ABCC8) that are of special importance for SUR function (18-20). Login to comment
47 EXPERIMENTAL PROCEDURES Mutagenesis, Transfection, and Cell Culture-HEK293 cells (German Collection of Microorganisms and Cell Cultures, DSMZ, Braunschweig, Germany) were stably transfected with pcDNA3.1 expression vector (Invitrogen) containing the coding sequence of rat SUR1 (GenBankTM accession number X97279), SUR1(M1289T), SUR1(R1379C), SUR1(R1379L), murine SUR2A (GenBank D86037), SUR2A(Y1206S), murine SUR2B (GenBank D86038), or SUR2B(Y1206S), or they were transfected with empty pcDNA3.1 expression vector (Invitrogen). Login to comment
104 By contrast, apoptosis in cells expressing mutants SUR1(R1379C) or SUR1(R1379L) was potentiated to a large extent (Figs. 3C and 4A): compared with SUR1, cell detachment was increased by a factor of 3.0 or 2.7, respectively, and the rate of apoptotic nuclei was elevated b07;3-fold. Login to comment
118 After treatment of SUR1-, SUR1(M1289T)-, SUR2A-, and SUR2B-expressing HEK293 cells (A and B) or of SUR1, SUR1(R1379C), and SUR1(R1379L) cells (C) with 17beta-estradiol (100 òe;mol/liter, 24 h), cell detachmentorchangesinnuclearmorphologyweredeterminedandcomparedwiththeresultsobtainedwith pcDNA control cells (please note the different scales in A and C). Login to comment
143 HEK293 cells stably expressing SUR1, SUR1(M1289T), SUR1(R1379C), or pcDNA control cells (A) were compared with cells from the clonal beta-cell lines HIT-T15 and RIN-m5F (B) or to isolated islets from SUR1-expressing wild type mice (SUR1wt) or SUR1KO mice (C) after treatment with 100 òe;mol/liter 17beta-estradiol (E2) or solvent (solv.) Login to comment
182 This SUR1-dependent effect of 17beta-estradiol is either abolished by mutation M1289T or enhanced by mutations R1379C or R1379L in SUR1. Login to comment
106 By contrast, apoptosis in cells expressing mutants SUR1(R1379C) or SUR1(R1379L) was potentiated to a large extent (Figs. Login to comment
121 After treatment of SUR1-, SUR1(M1289T)-, SUR2A-, and SUR2B-expressing HEK293 cells (A and B) or of SUR1, SUR1(R1379C), and SUR1(R1379L) cells (C) with 17beta-estradiol (100 òe;mol/liter, 24 h), cell detachmentorchangesinnuclearmorphologyweredeterminedandcomparedwiththeresultsobtainedwith pcDNA control cells (please note the different scales in A and C). Login to comment
147 HEK293 cells stably expressing SUR1, SUR1(M1289T), SUR1(R1379C), or pcDNA control cells (A) were compared with cells from the clonal beta-cell lines HIT-T15 and RIN-m5F (B) or to isolated islets from SUR1-expressing wild type mice (SUR1wt) or SUR1KO mice (C) after treatment with 100 òe;mol/liter 17beta-estradiol (E2) or solvent (solv.) Login to comment
186 This SUR1-dependent effect of 17beta-estradiol is either abolished by mutation M1289T or enhanced by mutations R1379C or R1379L in SUR1. Login to comment
229 To see whether SUR1-mediated apoptosis is linked with ATP hydrolysis, we explored the effects of mutations R1379C and R1379L in nucleotide binding fold 2 of SUR1 on 17beta-estradiol action. Login to comment

[hide] Activating mutations in the ABCC8 gene in neonatal... N Engl J Med. 2006 Aug 3;355(5):456-66. Babenko AP, Polak M, Cave H, Busiah K, Czernichow P, Scharfmann R, Bryan J, Aguilar-Bryan L, Vaxillaire M, Froguel P
Activating mutations in the ABCC8 gene in neonatal diabetes mellitus.
N Engl J Med. 2006 Aug 3;355(5):456-66., [PMID:16885549]

Abstract [show]
BACKGROUND: The ATP-sensitive potassium (K(ATP)) channel, composed of the beta-cell proteins sulfonylurea receptor (SUR1) and inward-rectifying potassium channel subunit Kir6.2, is a key regulator of insulin release. It is inhibited by the binding of adenine nucleotides to subunit Kir6.2, which closes the channel, and activated by nucleotide binding or hydrolysis on SUR1, which opens the channel. The balance of these opposing actions determines the low open-channel probability, P(O), which controls the excitability of pancreatic beta cells. We hypothesized that activating mutations in ABCC8, which encodes SUR1, cause neonatal diabetes. METHODS: We screened the 39 exons of ABCC8 in 34 patients with permanent or transient neonatal diabetes of unknown origin. We assayed the electrophysiologic activity of mutant and wild-type K(ATP) channels. RESULTS: We identified seven missense mutations in nine patients. Four mutations were familial and showed vertical transmission with neonatal and adult-onset diabetes; the remaining mutations were not transmitted and not found in more than 300 patients without diabetes or with early-onset diabetes of similar genetic background. Mutant channels in intact cells and in physiologic concentrations of magnesium ATP had a markedly higher P(O) than did wild-type channels. These overactive channels remained sensitive to sulfonylurea, and treatment with sulfonylureas resulted in euglycemia. CONCLUSIONS: Dominant mutations in ABCC8 accounted for 12 percent of cases of neonatal diabetes in the study group. Diabetes results from a newly discovered mechanism whereby the basal magnesium-nucleotide-dependent stimulatory action of SUR1 on the Kir pore is elevated and blockade by sulfonylureas is preserved.

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43 A homology model26 of the human SUR1 core was used to map the mutant residues.27 Results ABCC8 Mutations in Patients with Permanent or Transient Neonatal Diabetes We identified seven heterozygous ABCC8 mutations in 9 of 34 patients with neonatal diabetes: L213R and I1424V in 2 with permanent neonatal diabetes and C435R, L582V, H1023Y, R1182Q, and R1379C in patients with transient neonatal diabetes. Login to comment
48 The L213R, H1023Y, and I1424V were noninherited mutations, as were the L582V and R1379C mutations in one family each. Login to comment
54 Diabetes developed in the father of the proband (with an R1379C mutation) in Family 17 when he was 32 years old, and he is receiving glyburide. Login to comment
55 The R1379C allele was also identified in the proband`s paternal grandmother who had had gestational diabetes and is currently being treated with diet and in a paternal great-aunt who was given a diagnosis of diabetes at 44 years of age and is currently being treated with sulfonylureas. Login to comment
67 After identification of the mutations in the patients with permanent neonatal diabetes, glyburide therapy was initiated and found to be successful and insulin was discontinued after 2 days in the proband from Family 12 and after 15 days in the proband from A Permanent Neonatal Diabetes B Transient Neonatal Diabetes NN NN NN NN NN NN NN NNNM NM NM NM NM NMNM NM NM* NM* NA NA NA NA NANANANANA NA NA NA NA Family 12 (L213R) NNNN NM Family 36 (L582V) 16 NN NN NNNM NMNM Family 28 (H1023Y) Family 34 (R1182Q) Family 16 (L582V) Family 17 (R1379C) Family 16 (I1424V) I II III I II III IV V 1 1 2 1 2 3 4 5 2 1 2 1 2 1 2 1 2 3 4 5 6 7 3 1 4 6 NNNN NN NNNM NMNM* Family 13 (C435R) Family 19 (R1379C) Transient Neonatal Diabetes Figure 1. Login to comment
42 A homology model26 of the human SUR1 core was used to map the mutant residues.27 Results ABCC8 Mutations in Patients with Permanent or Transient Neonatal Diabetes We identified seven heterozygous ABCC8 mutations in 9 of 34 patients with neonatal diabetes: L213R and I1424V in 2 with permanent neonatal diabetes and C435R, L582V, H1023Y, R1182Q, and R1379C in patients with transient neonatal diabetes. Login to comment
47 The L213R, H1023Y, and I1424V were noninherited mutations, as were the L582V and R1379C mutations in one family each. Login to comment
53 Diabetes developed in the father of the proband (with an R1379C mutation) in Family 17 when he was 32 years old, and he is receiving glyburide. Login to comment
66 After identification of the mutations in the patients with permanent neonatal diabetes, glyburide therapy was initiated and found to be successful and insulin was discontinued after 2 days in the proband from Family 12 and after 15 days in the proband from A Permanent Neonatal Diabetes B Transient Neonatal Diabetes NN NN NN NN NN NN NN NN NM NM NM NM NM NM NM NM NM* NM* NA NA NA NA NA NA NA NA NA NA NA NA NA Family 12 (L213R) NN NN NM Family 36 (L582V) 16 NN NN NN NM NM NM Family 28 (H1023Y) Family 34 (R1182Q) Family 16 (L582V) Family 17 (R1379C) Family 16 (I1424V) I II III I II III IV V 1 1 2 1 2 3 4 5 2 1 2 1 2 1 2 1 2 3 4 5 6 7 3 1 4 6 NN NN NN NN NM NM NM* Family 13 (C435R) Family 19 (R1379C) Transient Neonatal Diabetes Figure 1. Login to comment
92 Mutation Sex Wk of Gestation Birth Weight At Diagnosis At Metabolic Testing Current Treatment Age Weight Presentation Glucose Age Height Weight Insulin g (percentile) days g mmol/liter yr cm (SD)ߤ kg (percentile) U/kg/day Permanent neonatal diabetes 12 L213R Male 41 3065 (22) 125 5320 Polyuria, polydipsia 28.6 4.75 107.5 (0) 17 (50) 0.12 Glb, 10 mg/day 16 I1424V Male 40 3080 (25) 33 3360 Ketoacidosis 66 16.5 178 (+0.9) 69 (85) 0.88 Glb, 15 mg/day Transient neonatal diabetes 13 C435R Male 40 3040 (25) 32 3575 Polyuria, polydipsia 44.5 4.75 108.8 (+0.5) 17.5 (75) 16 L582V Male 40 3350 (50) 15 3210 Polyuria, polydipsia 51.4 5.25 117 (+1.9) 18.4 (50) 17 R1379C Female 40 2050 (<3) 3 2100 Hyperglycemia 6.9 5.25 114.5 (+1.6) 19.5 (82) 19 R1379C Female 40 2330 (<3) 60 4900 Polyuria, polydipsia 22 15.7 158 (-0.8) 54 (70) 1.2 Glb, 10 mg/day 28 H1023Y Male 40 3400 (55) 21 NA Ketoacidosis 37.8 16 180 (+1.2) 59.5 (60) 0.5 Glp, 10 mg/day 34 R1182Q Male 34 1830 (8) 4 1680 Hyperglycemia 13.6 2 82 (-1.5) 10.3 (8) 36 L582V Male 40 3570 (67) 74 6100 Polyuria, polydipsia 34 1.8 92 (+2) 14 (90) * Glb denotes glyburide, NA not available, and Glp glipizide. Login to comment

[hide] A rare mutation in ABCC8/SUR1 leading to altered A... Diabetes. 2008 Jun;57(6):1595-604. Epub 2008 Mar 17. Tarasov AI, Nicolson TJ, Riveline JP, Taneja TK, Baldwin SA, Baldwin JM, Charpentier G, Gautier JF, Froguel P, Vaxillaire M, Rutter GA
A rare mutation in ABCC8/SUR1 leading to altered ATP-sensitive K+ channel activity and beta-cell glucose sensing is associated with type 2 diabetes in adults.
Diabetes. 2008 Jun;57(6):1595-604. Epub 2008 Mar 17., [PMID:18346985]

Abstract [show]
OBJECTIVE: ATP-sensitive K(+) channels (K(ATP) channels) link glucose metabolism to the electrical activity of the pancreatic beta-cell to regulate insulin secretion. Mutations in either the Kir6.2 or sulfonylurea receptor (SUR) 1 subunit of the channel have previously been shown to cause neonatal diabetes. We describe here an activating mutation in the ABCC8 gene, encoding SUR1, that is associated with the development of type 2 diabetes only in adults. RESEARCH DESIGN AND METHODS: Recombinant K(ATP) channel subunits were expressed using pIRES2-based vectors in human embryonic kidney (HEK) 293 or INS1(832/13) cells and the subcellular distribution of c-myc-tagged SUR1 channels analyzed by confocal microscopy. K(ATP) channel activity was measured in inside-out patches and plasma membrane potential in perforated whole-cell patches. Cytoplasmic [Ca(2+)] was imaged using Fura-Red. RESULTS: A mutation in ABCC8/SUR1, leading to a Y356C substitution in the seventh membrane-spanning alpha-helix, was observed in a patient diagnosed with hyperglycemia at age 39 years and in two adult offspring with impaired insulin secretion. Single K(ATP) channels incorporating SUR1-Y356C displayed lower sensitivity to MgATP (IC(50) = 24 and 95 micromol/l for wild-type and mutant channels, respectively). Similar effects were observed in the absence of Mg(2+), suggesting an allosteric effect via associated Kir6.2 subunits. Overexpression of SUR1-Y356C in INS1(832/13) cells impaired glucose-induced cell depolarization and increased in intracellular free Ca(2+) concentration, albeit more weakly than neonatal diabetes-associated SUR1 mutants. CONCLUSIONS: An ABCC8/SUR1 mutation with relatively minor effects on K(ATP) channel activity and beta-cell glucose sensing causes diabetes in adulthood. These data suggest a close correlation between altered SUR1 properties and clinical phenotype.

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83 (E), wild type; (F), Y356C; (f), K1521N; (Ⅺ), H1023Y; (Œ), R248Q; (‚), L582V; (ૺ), R1379C. Login to comment
120 To test whether the mutations associated with type 2 diabetes might affect stimulus-secretion coupling in beta-cells, we next measured the sensitivity to ATP of recombinant KATP channels carrying SUR-Y356C, -R248Q, and -K1521N and compared these to the ATP sensitivity of TND-associated mutants (4), L582V, H1023Y, and R1379C. Login to comment

[hide] Phenotypic heterogeneity in monogenic diabetes: th... Mol Genet Metab. 2014 Dec;113(4):315-20. doi: 10.1016/j.ymgme.2014.09.007. Epub 2014 Sep 28. Alkorta-Aranburu G, Carmody D, Cheng YW, Nelakuditi V, Ma L, Dickens JT, Das S, Greeley SA, del Gaudio D
Phenotypic heterogeneity in monogenic diabetes: the clinical and diagnostic utility of a gene panel-based next-generation sequencing approach.
Mol Genet Metab. 2014 Dec;113(4):315-20. doi: 10.1016/j.ymgme.2014.09.007. Epub 2014 Sep 28., [PMID:25306193]

Abstract [show]
Single gene mutations that primarily affect pancreatic beta-cell function account for approximately 1-2% of all cases of diabetes. Overlapping clinical features with common forms of diabetes makes diagnosis of monogenic diabetes challenging. A genetic diagnosis often leads to significant alterations in treatment, allows better prediction of disease prognosis and progression, and has implications for family members. Currently, genetic testing for monogenic diabetes relies on selection of appropriate individual genes for analysis based on the availability of often-limited phenotypic information, decreasing the likelihood of making a genetic diagnosis. We thus developed a targeted next-generation sequencing (NGS) assay for the detection of mutations in 36 genes known to cause monogenic forms of diabetes, including transient or permanent neonatal diabetes mellitus (TNDM or PNDM), maturity-onset diabetes of the young (MODY) and rare syndromic forms of diabetes. A total of 95 patient samples were analyzed: 19 with known causal mutations and 76 with a clinically suggestive phenotype but lacking a genetic diagnosis. All previously identified mutations were detected, validating our assay. Pathogenic sequence changes were identified in 19 out of 76 (25%) patients: 7 of 32 (22%) NDM cases, and 12 of 44 (27%) MODY cases. In 2 NDM patients the causal mutation was not expected as consanguinity was not reported and there were no clinical features aside from diabetes. A 3 year old patient with NDM diagnosed at 3 months of age, who previously tested negative for INS, KCNJ11 and ABCC8 mutations, was found to carry a novel homozygous mutation in EIF2AK3 (associated with Wolcott-Rallison syndrome), a gene not previously suspected because consanguinity, delayed growth, abnormal bone development and hepatic complications had not been reported. Similarly, another infant without a history of consanguinity was found to have a homozygous GCK mutation causing PNDM at birth. This study demonstrates the effectiveness of multi-gene panel analysis in uncovering molecular diagnoses in patients with monogenic forms of diabetes.

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57 Patient Gender Gene Nucleotide Amino acid Zygosity 1 M ABCC8 c.3440TNG, c.4135CNT p.Leu1147Arg, p.Arg1379Cys Comp HET 2 M EIF2AK3 c.1267dup p.Ile423Asnfs*26 HOMO 3 M GATA6 c.1088_1098del p.Gln363Argfs*96 HET 4 F KCNJ11 c.602GNA p.Arg201His HET 5 F KCNJ11 c.5TNC p.Leu2Pro HET 6 M RFX6 c.779ANC p.Lys260Thr HOMO 7 F FOXP3 c.1044+5GNA p.? Login to comment