ABCMdb

ABCC8 p.Arg1182Gln

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Publications

PMID: 16885549 [PubMed] Babenko AP et al: "Activating mutations in the ABCC8 gene in neonatal diabetes mellitus."

No. Sentence Comment

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
49 The L582V and R1397C mutations were also inherited in one family each, as were the C435R and R1182Q mutations. Login to comment
51 The father of the proband with a C435R mutation in Family 13 was given a diagnosis of diabetes mellitus at 13 years of age; after he was found to have the C435R mutation, he discontinued insulin (after 24 years of treatment) after a successful response to glyburide (10 mg per day). Login to comment
52 An oral glucose-tolerance test showed that the father of the proband with an R1182Q mutation in Family 34 had diabetes; he is currently being treated with diet alone. 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
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

PMID: 18767144 [PubMed] Flanagan SE et al: "Update of mutations in the genes encoding the pancreatic beta-cell K(ATP) channel subunits Kir6.2 (KCNJ11) and sulfonylurea receptor 1 (ABCC8) in diabetes mellitus and hyperinsulinism."

No. Sentence Comment

34 This means that there are discrepancies in nomenclature reported in the literature for mutations that affect residues encoded within exons 17-39 that differ by one amino acid depending on the isoform used (e.g., R1182Q reported by Babenko et al. Login to comment

PMID: 17389331 [PubMed] Vaxillaire M et al: "New ABCC8 mutations in relapsing neonatal diabetes and clinical features."

No. Sentence Comment

39 The two other mutations, L582V (c.1744CϾG) and R1182Q (c.3545GϾA), had been previously described by our group in three independent families with TND cases (13). Login to comment
51 The R1182Q and V1523M mutations were not identified in either parent, consistent with de novo mutations. Login to comment
52 The V324M and R1379H mutations tested negative in the mothers, and the two fathers were not available for genetic testing. Login to comment
77 In the ND-SUR1 patients, an apparently mild phenotype, i.e., without neurological features, is observed in the TND families, except in a few cases presenting with PND (13) TABLE1 ClinicalfeaturesinneonataldiabeticpatientsscreenedpositiveforABCC8mutations Patient SGMGKKSLMCNCDDLNJ MutationE208KV324ML582VR825WR1182QR1379HV1523MA269D SexFemaleMaleMaleFemaleFemaleMaleMaleFemale TypeofdiabetesTNDTNDTNDTNDTNDTNDPND Notyet known Atbirth Weight(g/percentile)1,790/321,660/Ͻ33,250/282,300/Ͻ32,930/103,150/432,710/312,390/Ͻ3 Gestationweek33.53739394138.53739 Atpresentation Age(days)1112361013426766 Weight(g)1,7904,2904,3002,5203,0003,6903,6605,100 PresentationGlucose monitoring KetoacidosisKetoacidosisGlucose monitoring WeightlossKetoacidosisKetoacidosisKetoaciduria Glucose(mmol/l)12.424.160.516.824.164.23627.5 Autoantibodies00000000 Insulindose(units⅐kg-1 ⅐day-1 )0.1012.400.300.720.502.500.72 PancreasultrasonographyNANANNNNNN Currentstatus Age(months)712728134833188.7 Height(cm/SD)63/-1.6134.5/-0.790.2/0.672.5/-0.4101.2/0.296/184/1.370/0.8 Weight(kg/percentile)6.15/323.6/Ͻ313.5/759.62/5614.9/5017.5/Ͼ9711/318.52/50 Diabetes(yes[ϩ],no[-])-ϩ(9)*----ϩϩ Insulindose(units⅐kg-1 ⅐day-1 )00†00000.600.62 A1Catlastexamination(%)4.56.05.15.05.45.05.58.9 Neurologicalfeatures MuscleweaknessNoNoNoNoNoNoNoNo MotordevelopmentaldelayNoNoNoNoNoNoNoNo EpilepsyNoNoNoNoNoNoNoNo MentaldevelopmentaldelayNoNoNoNoNoNoNoNo SpeechdevelopmentaldelayNoYesNoNoNoYesNoNo DysmorphicfeaturesNoNoNoNoNoNoNoNo OtherfeaturesNoNoNoNoNoHyperkinesia, troubleof feeding behavior NoHypotonia ParentwithamutationFatherNone‡FatherFatherNoneNone‡NoneMother Glucosetolerance§IGT-NN---N Ageatexamination(year)41-3129---25 A1Catlastexamination(%)¶5.4-6.1NA---5.2 BMIatlastexamination(kg/m2 )27-2422---NA *Ageatrelapse,inyear.†PatientGK-V324Mwassuccessfullyswitchedtoglibenclamide(gliburide)attheageof9.5years(currentdose2.5mg/day;weight25kg).‡Onlythemotherwas screenedforthemutation;thefatherofGK-V324Mdied,andnoinformationisavailableonthebiologicalfatherofCD-R1379H.§Assessedbyanoralglucosetolerancetest.¶Upperlimit ofnormalvaluesforA1C:5.6%.IGT,impairedglucosetolerance;N,normal;NA,notavailable. Login to comment
40 The two other mutations, L582V (c.1744Cb0e;G) and R1182Q (c.3545Gb0e;A), had been previously described by our group in three independent families with TND cases (13). Login to comment

PMID: 22451668 [PubMed] Ortiz D et al: "Two neonatal diabetes mutations on transmembrane helix 15 of SUR1 increase affinity for ATP and ADP at nucleotide binding domain 2."

No. Sentence Comment

9 Glibenclamide (GBC), a sulfonylurea, was used as a conformational probe to compare nucleotide action on wild type versus Q1178R and R1182Q SUR1 mutants. Login to comment
47 Here we focus on two mutations, Q1178R and R1182Q, located in the 15th helix (transmembrane helix) of the second transmembrane domain (TMD2). Login to comment
48 These substitutions are in a cluster of mutations that cause either neonatal diabetes (Q1178R, R1182Q, and A1184E) or hyperinsulinism (C1174F and S1185A). Login to comment
58 The results imply that outward facing conformations with dimerized NBDs bind GBC and diazoxide with low and high affinity, respectively, and that the enhanced stimulatory action of Q1178R and R1182Q is due to their increased affinity for ATP and ADP. Login to comment
101 Table 1 and Table S1 compare the dissociation constants, determined from saturation binding data, for the WT, Q1178R, and R1182Q aporeceptors (i.e. without nucleotides). Login to comment
105 Q1178R and R1182Q Neonatal Diabetes Mutations Potentiate Negative Allosteric Action of MgATP on GBC Binding to SUR1-To assess quantitatively the effect of MgATP on GBC binding, membranes were incubated with increasing ATP concentrations maintained constant by a regenerating system (34); the level of ATP was constant over the 30-min time period of the incubation, as determined using luciferase assays (supplemental Fig. S1). Login to comment
107 The IC50 values for MgATP are b03;850, 37, and 19 òe;M for the WT, R1182Q, and Q1178R receptors, respectively, an increase in the apparent affinity of SUR1Q1178R for ATP of b03;45-fold. Login to comment
109 Q1178R and R1182Q Receptors Have Higher Affinity for ATP4afa; than WT-All ABC proteins have Walker-type nucleotide binding sites whose physiologic substrate is MgATP. Login to comment
115 In terms of an enzyme-substrate model where hydrolysis is blocked, the results show that the mutant receptors have at least a 10-fold greater affinity for ATP4afa; , with Q1178R having a somewhat higher affinity than R1182Q (Tables 2 and S2). Login to comment
126 The parameters for WT and R1182Q receptors are given in Table 2. Login to comment
139 E, neonatal diabetes (Q1178R in red and R1182Q in green) and hyperinsulinemia (C1174F in blue) causing mutations are clustered on transmembrane helix 15 (yellow), which feeds into NBD1 (light gray). Login to comment
143 Values are means afe; S.E. SUR1 KG nM WT 0.25 afe; 0.02 Q1178R 1.0 afe; 0.1 R1182Q 0.50 afe; .15 SUR1 Nucleotide Affinities in Neonatal Diabetes 17988 JOURNAL OF BIOLOGICAL CHEMISTRY VOLUME 287ߦNUMBER 22ߦMAY 25, 2012 equation for the four-state model can be expressed as a simple binding isotherm (see supplemental material), G afd; ᐵGᐶ ᐵGᐶ af9; Kobs (Eq. 4) where Kobs, the apparent dissociation constant at a specified concentration of ATP4afa; , is given by the following: Kobs afd; betaKG ᐳᐵTᐶ af9; KTᐴ ᐳᐵTᐶ af9; betaKTᐴ (Eq. 5) Kobs values at increasing concentrations of ATP4afa; were determined by homologous competition experiments (Fig. 3, A-D) and used to estimate KT and beta. Login to comment
156 A, the curves through the data are logistic equations with IC50 values of 849 afe; 195, 37 afe; 13, and 19 afe; 7 òe;M for WT, R1182Q, and Q1178R, respectively. Login to comment
163 The allosteric and ATP4afa; dissociation constants (beta/KD) (òe;M) are 14/12,200, 6.8/1250, and 9.3/1000 for the WT, R1182Q, and Q1178R receptors, respectively. Login to comment
166 TABLE 2 KT and beta values for WT and neonatal diabetes SUR1 are shown d1e; S.E. (p values in parentheses) SUR1 beta KT òe;M WT 14 afe; 10 (0.2) 12,200 afe; 4030 (0.02) R1182Q 6.8 afe; 0.9 (b0d;0.001) 1250 afe; 258 (0.003) Q1178R 9.3 afe; 1.8 (b0d;0.001) 1000 afe; 179 (b0d;0.001) Q1178R (Kobs method) 10.5 afe; 0.8 (0.005) 846 afe; 142 (0.03) SUR1 Nucleotide Affinities in Neonatal Diabetes MAY 25, 2012ߦVOLUME 287ߦNUMBER 22 JOURNAL OF BIOLOGICAL CHEMISTRY 17989 An eight-state model that describes the linkage between the diazoxide, GBC, and nucleotide binding sites under equilibrium, non-hydrolysis conditions is given in Fig. 5. Login to comment
203 A, the curvesarebestfitstoalogisticequation.TheIC50 forQ1178Ris39afe;8òe;M.The IC50 for the averaged values of WT and R1182Q is 9.8 afe; 0.3 òe;M; the individual values are 10.1 afe; 0.5 òe;M (WT) and 9.2 afe; 0.8 òe;M (R1182Q). Login to comment
246 The same argument holds for the R1182Q substitution (see Table 2). Login to comment

PMID: 25555642 [PubMed] Bennett JT et al: "Molecular genetic testing of patients with monogenic diabetes and hyperinsulinism."

No. Sentence Comment

120 Gene Nucleotide Protein Pheno dbSNP Times seen Interp. LOVD ClinVar Reference ABCC8 c.1277ANG/c.3545GNA p.N426S/p.R1182Q NDM -/rs193922400 1/2 VUS/PATH -/- -/LP This report/[9] c.1433CNA p.A478D CHI - 1 PATH - - [41] c.1608TNG p.F536L NDM - 1 LP - - This report c.2422CNA p.Q808K "DM1"* rs202189540 1 LB - - This report c.2506CNT/c.4138_4140delinsCA p.R836*/p.T1380Qfs*80 CHI rs72559722/- 1/1 PATH/PATH -/- -/- [42]/this report c.3976GNA p.E1326K CHI rs200563930 1 VUS - - [8] ex 32 del p.? 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

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
128 To support this hypothesis we analyzed additional mutations including I1424V (ND) and G1479R (CHI) in NBD2 and a cluster of disease causing mutations in TMD2: C1174F (CHI), S1185A (CHI), Q1178R (ND), and R1182Q (ND). 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