ABCMdb

ABCC8 p.Tyr356Cys

Predicted by SNAP2:	A: D (71%), C: D (59%), D: D (85%), E: D (85%), F: N (57%), G: D (80%), H: D (80%), I: D (63%), K: D (91%), L: D (53%), M: D (71%), N: D (85%), P: D (91%), Q: D (85%), R: D (91%), S: D (66%), T: D (85%), V: D (63%), W: D (80%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: N, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: N,

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[hide] Permanent neonatal diabetes due to activating muta... Rev Endocr Metab Disord. 2010 Sep;11(3):193-8. Edghill EL, Flanagan SE, Ellard S
Permanent neonatal diabetes due to activating mutations in ABCC8 and KCNJ11.
Rev Endocr Metab Disord. 2010 Sep;11(3):193-8., [PMID:20922570]

Abstract [show]
The ATP-sensitive potassium (K(ATP)) channel is composed of two subunits SUR1 and Kir6.2. The channel is key for glucose stimulated insulin release from the pancreatic beta cell. Activating mutations have been identified in the genes encoding these subunits, ABCC8 and KCNJ11, and account for approximately 40% of permanent neonatal diabetes cases. The majority of patients with a K(ATP) mutation present with isolated diabetes however some have presented with the Developmental delay, Epilepsy and Neonatal Diabetes syndrome. This review focuses on mutations in the K(ATP) channel which result in permanent neonatal diabetes, we review the clinical and functional effects as well as the implications for treatment.

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85 One of the most notable R1183W/Q A1185E E1327K G1401R V1523A/L V1524M R1531A NBD1 NBD2 outside membrane inside P45L N72S F132L/V L135P P207S E208K D209E Q211K D212I/N L213R L225P T229I Y263D A269D/N E382K V86A/G R1380C/H/L C435R L438F M1290V L451P R826W R1314H TMD0 TMD1 TMD2 R306H V324M L582V H1024Y I1425V A90V Y356C R521Q N1123D R1153G T1043TfsX74 Fig. 3 Schematic representation of 50 ABCC8 mutations which cause neonatal diabetes. Login to comment

[hide] Clinical and metabolic features of adult-onset dia... Diabetes Care. 2012 Feb;35(2):248-51. Epub 2011 Dec 30. Riveline JP, Rousseau E, Reznik Y, Fetita S, Philippe J, Dechaume A, Hartemann A, Polak M, Petit C, Charpentier G, Gautier JF, Froguel P, Vaxillaire M
Clinical and metabolic features of adult-onset diabetes caused by ABCC8 mutations.
Diabetes Care. 2012 Feb;35(2):248-51. Epub 2011 Dec 30., [PMID:22210575]

Abstract [show]
OBJECTIVE: Gain-of-function ABCC8/sulfonylurea (SU) receptor 1 mutations cause neonatal diabetes mellitus (NDM) or late-onset diabetes in adult relatives. Given the effectiveness of SU treatment in ABCC8-NDM patients, we further characterized late-onset ABCC8-associated diabetes. RESEARCH DESIGN AND METHODS: Seven adult subjects from three NDM families and one family with type 2 diabetes were studied. Insulin secretion and insulin sensitivity were assessed using clamp techniques. We screened 139 type 2 diabetic patients who were well controlled by SU for ABCC8 mutations. RESULTS: ABCC8 mutation carriers exhibited glucose intolerance, frank diabetes, or insulin-requiring diabetes since diagnosis. HbA(1c) improved in five SU-treated patients. Insulin secretion capacity was impaired in three patients compared with adult control subjects but was restored after a 4-week SU trial in two patients. Cohort screening revealed four SU-treated patients with ABCC8 mutations, two of which are likely causal. CONCLUSIONS: Although of rare occurrence, recognition of adult-onset ABCC8-associated diabetes may help in targeting patients for SU therapy.

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50 The previously published Y356C and R826W mutations (4,6,7,13) were functionally demon- stratedtoalter MgATPsensitivityorATPase activity of SUR1, respectively, leading to KATP channel activation with increased resting whole-cell currents (7,13). Login to comment
44 1-II.1 2-II.1 3-II.1 3-II.2 4-II.1 4-III.1 4-III.2 D-1 D-2 D-3 D-4 Sex Female Male Male Male Male Female Male Female Male Male Female Mutation R1380H C435R L582 V L582 V Y356C Y356C Y356C P201S C418R R620C R826 W c.4139G.A c.1303T.C c.1744C.G c.1744C.G c.1067A.G c.1067A.G c.1067A.G c.601C.G c.1252T.C c.1858C.T c.2476C.T Previous report NDM (11) NDM (2) NDM (2) d Type 2 diabetes (7) d d None rs67254669* rs58241708* TNDM (4,6,13) Features at diagnosis or at ascertainment Status Diabetes Diabetes Diabetes Diabetes Diabetes Impaired glucose toleranceߤ Normal glucose toleranceߤ Type 2 diabetes Type 2 diabetes Type 2 diabetes Type 2 diabetes Age (years)/BMI (kg/m 2 ) 17/24 15/20 36/21 32/37 39/26 35/20 33/22 53/22 53/31 46/25 49/28 Symptoms Polyuria Polyuria None Obesity None None None Tiredness Hyperglycemia Polyuria None Features at last examination Age (years) 63 39 38 37 74 35 33 80 74 56 58 SU treatment 15 mg/day glyburidex 15 mg/day glyburidex 5 mg/day glyburide 160 mg/day gliclazide 3 mg/day glimepiride None None Glyburide| Glimepiride| Glypizide Glimepiride HbA 1c (%)ߥ 7.3 6.7 6.2 6.4 6.5 5.5 ND 7.4 6.2 6.8 6.2 C-peptide (pmol/mL) 0.08 0.14 ND ND 3.00 ND ND 1.17 2.08 1.90 3.80 All mutations were identified heterozygously in the patients. Login to comment
58 The previously published Y356C and R826W mutations (4,6,7,13) were functionally demon- stratedtoalter MgATPsensitivityorATPase activity of SUR1, respectively, leading to KATP channel activation with increased resting whole-cell currents (7,13). Login to comment

[hide] Ser1369Ala variant in sulfonylurea receptor gene A... Diabetes Care. 2008 Oct;31(10):1939-44. Epub 2008 Jul 3. Feng Y, Mao G, Ren X, Xing H, Tang G, Li Q, Li X, Sun L, Yang J, Ma W, Wang X, Xu X
Ser1369Ala variant in sulfonylurea receptor gene ABCC8 is associated with antidiabetic efficacy of gliclazide in Chinese type 2 diabetic patients.
Diabetes Care. 2008 Oct;31(10):1939-44. Epub 2008 Jul 3., [PMID:18599530]

Abstract [show]
OBJECTIVE: The purpose of this study was to investigate whether genetic variants could influence the antidiabetic efficacy of gliclazide in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A total of 1,268 type 2 diabetic patients whose diabetes was diagnosed within the past 5 years and who had no recent hypoglycemic treatment were enrolled from 23 hospitals in China. All of the patients were treated with gliclazide for 8 weeks. Fasting and oral glucose tolerance test 2-h plasma glucose, fasting insulin, and A1C were measured at baseline and after 8 weeks of treatment. We used two independent cohorts to test the associations of 25 single nuclear polymorphisms in 11 candidate genes with the antidiabetic efficacy of gliclazide. A general linear regression model was used to test the association with adjustment for important covariates. RESULTS: After 8 weeks of gliclazide therapy, mean fasting plasma glucose (FPG) was reduced from 11.1 mmol/l at baseline to 7.7 mmol/l. In cohort 1, we genotyped all 25 SNPs (n = 661) and found that Ser1369Ala of the ABCC8 gene and rs5210 of the KCNJ11 gene were significantly associated with decreases in FPG (P = 0.002). We further genotyped Ser1369Ala in cohort 2 (n = 607) and confirmed the association identified in cohort 1. In the pooled analysis, compared with subjects with the Ser/Ser genotype, subjects with the Ala/Ala genotype had a 7.7% greater decrease in FPG (P < 0.001), an 11.9% greater decrease in 2-h plasma glucose (P = 0.003), and a 3.5% greater decrease in A1C (P = 0.06) after 8 weeks of treatment with gliclazide. CONCLUSIONS: In two independent cohorts of Chinese type 2 diabetic patients, we found consistent evidence that the Ser1369Ala variant in the ABCC8 gene can influence the antidiabetic efficacy of gliclazide.

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134 Genetic variants of ABCC8, such as exon 16 -3t/c, exon 18 T759T, and most recently the missense mutation Y356C, have been reported to be associated with type 2 diabetes (3,5,12,13). 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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6 RESULTS-A mutation in ABCC8/SUR1, leading to a Y356C substitution in the seventh membrane-spanning ␣-helix, was observed in a patient diagnosed with hyperglycemia at age 39 years and in two adult offspring with impaired insulin secretion. Login to comment
7 Single KATP channels incorporating SUR1-Y356C displayed lower sensitivity to MgATP (IC50 ϭ 24 and 95 ␮mol/l for wild-type and mutant channels, respectively). Login to comment
9 Overexpression of SUR1-Y356C in INS1(832/13) cells impaired glucose-induced cell depolarization and increased in intracellular free Ca2ϩ concentration, albeit more weakly than neonatal diabetes-associated SUR1 mutants. Login to comment
23 Through electrophysiology and Ca2ϩ imaging, we demonstrate that one of the mutations, Y356C, affects the ATP sensitivity of KATP channels and glucose-induced Ca2ϩ influx but to a far smaller extent than TND-associated mutations. Login to comment
83 (E), wild type; (F), Y356C; (f), K1521N; (Ⅺ), H1023Y; (Œ), R248Q; (‚), L582V; (ૺ), R1379C. Login to comment
88 A: Currents from inside-out patches excised from HEK293 cells overexpressing recombinant Kir6.2/SUR1-wild type (WT), Kir6.2/SUR1-Y356C, and Kir6.2/SUR1-L582V in Mg2؉ -containing (left) and Mg2؉ -free (right) solution. Login to comment
92 B: MgATP concentration-inhibition curves for wild-type and Kir6.2/SUR1-Y356C KATP channels. Login to comment
93 C: ATP (Mg2؉ -free) concentration-inhibition curves for wild-type and Kir6.2/SUR1-Y356C KATP channels. Login to comment
113 One of the patients with normal BMI, diagnosed with hyperglycemia at age 39 years, having developed overt diabetes at age 45 years, presented an ABCC8 missense mutation causing a substitution of tyrosine 356 with cysteine (Y356C) in the SUR1 subunit of the KATP channel (Fig. 1B and online appendix Fig. 1). Login to comment
116 The Y356C mutation was not found in 170 unrelated normoglycaemic individuals of European Caucasian origin. 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
129 By contrast, KATP channels carrying SUR1-Y356C showed an approximately fourfold decrease in ATP sensitivity (Fig. 1C). Login to comment
130 This prompted us to investigate in detail how the Y356C mutation affected the ATP sensitivity and/or surface expression of KATP channels. Login to comment
138 The ATP sensitivity of heterozygous SUR1-Y356C (hetY356C) (Fig. 2A and B) (Table 1) was higher than that of homozygous SUR1-Y356C (homY356C) channels. Login to comment
143 Gain-of-function mutations in either subunit frequently act by enhancing the Mg2ϩ -dependent activation (4,27), so we tested if this was the case for SUR1-Y356C. Login to comment
147 Thus, the gain-of-function effect of L582V mutation was mediated via Mg2ϩ -dependent activation, while the effect of Y356C apparently occurred through a different mechanism. Login to comment
148 Y356C does not alter surface expression of KATP channels. Login to comment
151 Introduction of the Y356C mutation into SUR1 did not affect cytoplasmic (Fig. 3C) or membrane (Fig. 3D) localization. Login to comment
158 We therefore studied the effect on these two phenomena of the Y356C and L582V mutations in SUR1. Login to comment
171 This effect is not typical for native beta-cells, where the firing frequency increases monotonously, with the KATP TABLE 1 Clinical characteristics of nondiabetic carriers of the SUR1-Y356C mutation compared with normoglycemic control subjects Daughter* Son* Control subjects (n ϭ 18) Age at examination (years) 35 33 26.79 Ϯ 6.56 BMI (kg/m2 ) 19.37 22.22 22.9 Ϯ 3.3 Fasting blood concentrations Glucose (mmol/l) 4.9 5.0 4.6 Ϯ 0.3 Insulin (␮U/ml) 1.33 4.11 5.5 Ϯ 3.8 Insulinogenic index (␮UI/␮mol)† 2.58 7.95 16.9 Ϯ 10.7 Insulin sensitivity (mg ⅐ kg-1 ⅐ min-1 )‡ 12.32 6.71 10.88 Ϯ 2.36 Disposition index (␮UI/mol)§ 31.78 53.34 184.21 Ϯ 25.16 Glycemic status Nondiabetic Nondiabetic Nondiabetic Data are means Ϯ SD. *Daughter and son of the diabetic proband identified with the Y356C mutation. Login to comment
177 TABLE 2 Parameters of ATP inhibition for KATP channels with mutant SUR1 subunit IC50 WT Y356C L582V ЉheteroЉ ЉhomoЉ ЉheteroЉ ЉhomoЉ 2 Mg2ϩ mmol/l 24 Ϯ 3 (5) 61 Ϯ 11 (10)* 95 Ϯ 9 (10)* 869 Ϯ 48 (6)* 1140 Ϯ 346 (6)* 0 Mg2ϩ mmol/l 8 Ϯ 1 (6) 25 Ϯ 5 (7)* 38 Ϯ 8 (8)* 17 Ϯ 3 (5)† 17 Ϯ 3 (6)† Data are means Ϯ SE (number of experiments). Login to comment
182 Thus, despite a relatively small shift in the ATP sensitivity of KATP channels, beta-cell lines expressing SUR1-Y356C demonstrated impaired coupling between nutrient stimulation and electrical activity. Login to comment
186 The addition of 20 mmol/l glucose had different effects on the two groups: in the majority of wild-type cells we observed oscillations of [Ca2ϩ ]cyt, which were not detected in Y356C cells. Login to comment
190 In the case of SUR1-Y356C this was indeed observed. Login to comment
195 However, the Y356C mutation that we describe appears to cause diabetes outside the range described (34) (maximum age recorded A C E D F B FIG. 3. Login to comment
198 A, C, and E: Representative confocal images of cells expressing the SUR1 (wild-type [A], Y356C [C], and L582V [E]) subunit alone. Login to comment
200 B, D, and F: Representative images of cells expressing SUR1 (wild-type [B], Y356C [D], and L582V [F]) subunits together with Kir6.2. Login to comment
205 The relatively small shift in ATP sensitivity (from 24 to 95 ␮mol/l as measured in inside-out patches) caused by the Y356C mutation in ABCC8/SUR1, clearly affected glucose-induced changes in beta-cell electrical activity. Login to comment
206 This result strongly suggests that the Y356C mutation may lead to a diabetic phenotype. Login to comment
207 Indeed, the oral glucose tolerance test and euglycemic- hyperinsulinic clamp performed in the two nondiabetic carriers of the Y356C mutation showed a mild decrease of insulinogenic and disposition indexes (Table 1). Login to comment
210 We observed that two mutations (Y356C and L582V) that are associated with phenotypes of different severity in heterozygous patients cause different shifts in the ATP sensitivity of the KATP channel (Fig. 2B and D). Login to comment
221 Thus, the Y356C mutant lead to a substantially less marked inhibition of glucose-induced [Ca2ϩ ]cyt increase than L582V (Fig. 5B). Login to comment
224 Molecular mechanism of Y356C effect on ATP sensitivity. Login to comment
245 involving the SUR1 NBDs, would be consistent with the observation that the removal of Mg2ϩ (which abolishes the activatory effect of adenine-nucleotides on NBDs) (24) did not abolish the activatory effect of Y356C (Fig. 3C). Login to comment
248 In contrast to Y356C, the activatory effect of mutations L582V (Fig. 3D) and H1023Y (4) was not observed under Mg2ϩ -free conditions, suggesting that these mutations exert their effects via the SUR1 NBDs. Login to comment

[hide] ABCC8 genetic variants and risk of diabetes mellit... Gene. 2014 Jul 25;545(2):198-204. doi: 10.1016/j.gene.2014.04.040. Epub 2014 Apr 21. Haghverdizadeh P, Sadat Haerian M, Haghverdizadeh P, Sadat Haerian B
ABCC8 genetic variants and risk of diabetes mellitus.
Gene. 2014 Jul 25;545(2):198-204. doi: 10.1016/j.gene.2014.04.040. Epub 2014 Apr 21., [PMID:24768178]

Abstract [show]
Diabetes mellitus (DM) is a major health problem worldwide and it will rapidly increase. This disease is characterized by hyperglycemia caused by defects in insulin secretion, insulin action or both. DM has three types: T1DM, T2M and gestational DM (GDM), of them T2DM is more frequent. Multiple genes and their interactions are involved in insulin secretion pathway. Sulfonylurea receptor encoded by ABCC8 gene, together with inward-rectifier potassium ion channel (Kir6.2) regulates insulin secretion by ATP-sensitive K(+) (KATP) channel located in the plasma membranes. Disruption of these molecules by different mutations is responsible for risk of DM. Several single nucleotide polymorphisms (SNPs) of ABCC8 gene and their interaction are involved in pathogenicity of DM. This review summarizes the current evidence of contribution of ABC8 genetic variants to the development of DM.

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129 Polymorphism Location MAF Allele Amino Acid Association Reference Chromosome Gene Diabetes Association 1 rs757110 17,375,052 Exon 0.26 G N T Ala1369Ser T2DM Yes 42,52,61,78,77 No 11, 12,18,22,34,64, 67, 105 2 rs1799854 17,405,279 Intron 0.41 G N A - T2DM Yes 11,12,34,41,67,90,95,101 No 3,18,32,42,52,56,62,73,85,91,92,103,105 GDM Yes 71 No 10 3 rs1799859 17,375,854 Exon 0.33 G N A Arg1273Arg T2DM Yes 11,12,34,40,54,74,96,102 No 18,67 T2DM/GDM Yes 98 4 rs1801261 17,393,440 Exon 0.01 C N T Thr759Thr T2DM Yes 84,92,105 No 3,91,101 T2DM/GDM No 98 5 rs2074308 17,409,155 Intron 0.14 C N T - T2DM Yes 78 No 18,52 6 rs2074312 17,378,365 Intron 0.29 G N A - T2DM No 42,52 7 rs1799858 17,406,504 Exon 0.15 G N A Lys649Lys T2DM Yes 18,78 T2DM/GDM No 98 8 rs2188966 17,456,460 5'-UTR 0.36 C N T - T2DM No 54,74 9 rs2237984 17,402,596 Intron 0.41 T N C - T2DM No 42,52 10 rs3758947 17,501,210 Intron 0.19 G N A - T2DM Yes 54 No 74 11 rs3758953 17,456,122 5'-UTR 0.49 A N G - T2DM Yes 54 No 74 12 rs4148646 17,371,765 Intron 0.28 C N G - T2DM Yes 78 No 52 13 rs1048099 17,453,091 Exon 0.44 T N A Pro69Pro T2DM No 18,52 14 rs1805036 17,390,859 Exon 0.10 C N T Leu829Leu T2DM/GDM No 98 15 rs2073583 17,383,911 Intron 0.22 G N C - T2DM No 52 16 rs2074311 17,378,435 Intron 0.31 A N G - T2DM No 18 17 rs2237976 17,433,091 Intron 0.43 T N G - T2DM No 52 18 rs2237981 17,417,474 Intron 0.43 T N C - T2DM No 42 19 rs2237991 17,396,804 Intron 0.36 A N G - T2DM No 52 20 rs2237992 17,387,508 Intron 0.21 A N G - T2DM No 52 21 rs2283257 17,446,020 Intron 0.12 C N T - T2DM No 52 22 rs2301703 17,441,546 Intron 0.47 G N A - T2DM No 52 23 rs4148628 17,392,768 Intron NI C N T - T2DM Yes 78 24 rs4148630 17,392,541 Intron 0.24 G N A - T2DM No 52 25 rs59852838 17,431,350 Exon 0.06 T N C Tyr356Cys T2DM Yes 44 26 rs72559731 17,448,289 Exon NI C N G Ala116Pro T2DM No 11 27 rs7947326 17,425,068 Intron 0.38 A N C - T2DM No 52 28 rs8192695 17,448,305 Exon 0.55 G N A Ala110Ala T2DM No 11 29 rs886293 17,418,795 Intron 0.32 A N G T2DM No 52 function. Login to comment