ABCMdb

ABCC8 p.Glu208Lys

None has been submitted yet.

Publications

PMID: 17919176 [PubMed] Patch AM et al: "Mutations in the ABCC8 gene encoding the SUR1 subunit of the KATP channel cause transient neonatal diabetes, permanent neonatal diabetes or permanent diabetes diagnosed outside the neonatal period."

No. Sentence Comment

161 Affected probands and family members can be separated into three distinct groups based T229I/T229I ABCC8 mutations Transient Neonatal Diabetes Mellitus Recessive homozygous mutations R826W (2) H1024Y R1183Q (2) R1183W (5) R1314H R1380C (3) R1380H R1380L (2) D209E D212I D212N R306H V324M C435R L451P L582V (2) Dominant heterozygous mutations Permanent Neonatal Diabetes Mellitus E382K/E382K A1185E/A1185E Mosaic N72S Recessive homozygous or mosaic mutations P45L/G1401R E208K/Y263D T229I/V1523L L438F/M1290V P207S/c.536del4 E1327K+V1523A/ c.1327ins10 Recessive compound heterozygous mutations 1K Dominant heterozygous mutations D209E Q21 L213R L225P(2) I1425V V86A V86G F132L (2) F132V L135P Fig. 2 A diagram illustrating the inheritance of ABCC8 mutations in probands with permanent and transient forms of neonatal diabetes. Login to comment
163 Permanent Neonatal Diabetes Mellitus Transient Neonatal Diabetes Mellitus 1 5 10 15 20 25 30 35 39 N72S V86A V86G F132L F132V L135PP45L P207S E208K D209E Q211K L213R L225P T229I Y263D D209E D212I D212N T229I R306H V324M L438F L451P E382K R826W R1183W R1183Q A1185E E1327K R1314H M1290V R1380C R1380H R1380L G1401R V1523A V1523L H1024YC435R L582V I1425V Fig. 3 The location of missense mutations causing neonatal diabetes within the coding sequence of ABCC8. Login to comment
176 No neurological features were reported in R1183W/Q A1185E E1327K G1401R V1523A/L NBD1 NBD2 outside membrane inside P45L N72S F132L/V L135P P207S E208K D209E Q211K D212I/N L213R L225P T229I Y263D E382K V86A/G L438F C435R R1380C/H/L L451P R826W TMD0 TMD1 TMD2 R306H V324M L582V H1024Y I1425V R1314H M1290V Fig. 4 A schematic of the membrane topologies of SUR1 showing the location of the ABCC8 missense mutations causing neonatal diabetes. Login to comment

PMID: 20922570 [PubMed] Edghill EL et al: "Permanent neonatal diabetes due to activating mutations in ABCC8 and KCNJ11."

No. Sentence Comment

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

PMID: 18990670 [PubMed] Aittoniemi J et al: "Review. SUR1: a unique ATP-binding cassette protein that functions as an ion channel regulator."

No. Sentence Comment

204 (a) (b) P45L N72S F132L NH2 A90V V86G COOHL135P exoplasmic cytoplasmic Walker A Walker A linker Walker B linker Walker B V324M E382K C435R L438F L582V R826W H1023Y N1122D R1183Q A1185E R1314H E1327K R1380 L I1425V V1524 L P207S E208K Q211K D212I/N L225P T229I Y263D A269D R306H D209E L213R TMD0 TMD1 TMD2 NBD1 NBD2 CL3 linker site 1 site 2 NBD1 NBD2 R826W R1380 L E1327K I1425V V1524 L Figure 5. Login to comment
207 (a) (b) P45L N72S F132L NH2 A90V V86G COOH L135P exoplasmic cytoplasmic Walker A Walker A linker Walker B linker Walker B V324M E382K C435R L438F L582V R826W H1023Y N1122D R1183Q A1185E R1314H E1327K R1380 L I1425V V1524 L P207S E208K Q211K D212I/N L225P T229I Y263D A269D R306H D209E L213R TMD0 TMD1 TMD2 NBD1 NBD2 CL3 linker site 1 site 2 NBD1 NBD2 R826W R1380 L E1327K I1425V V1524 L Figure 5. Login to comment

PMID: 18025408 [PubMed] Rafiq M et al: "Effective treatment with oral sulfonylureas in patients with diabetes due to sulfonylurea receptor 1 (SUR1) mutations."

No. Sentence Comment

54 Doses Table 1-Clinical characteristics of patients with SUR1 mutations according to success of treatment with sulfonylureas Characteristic All patients Patients with successful sulfonylurea treatment Patients with unsuccessful sulfonylurea treatment P* n 27 23 4 Mutation (number of patients) NA V86G†, P45L/G1401R- (2)†, D209E (3)†, T229I/V1523L†, Q211K†, V86A (2)†, E1507G, V215I/V607M, E208K/Y263D†, R1380L (2)‡, D212I (3)§, T229I/T229I‡, R1183W§, L225P†, R826W, and D209N F132L (2)†, F132V†, and N72S† (mosaic). Login to comment
56 Doses Table 1-Clinical characteristics of patients with SUR1 mutations according to success of treatment with sulfonylureas Characteristic All patients Patients with successful sulfonylurea treatment Patients with unsuccessful sulfonylurea treatment P* n 27 23 4 Mutation (number of patients) NA V86Gߤ, P45L/G1401R- (2)ߤ, D209E (3)ߤ, T229I/V1523Lߤ, Q211Kߤ, V86A (2)ߤ, E1507G, V215I/V607M, E208K/Y263Dߤ, R1380L (2)ߥ, D212I (3)&#a7;, T229I/T229Iߥ, R1183W&#a7;, L225Pߤ, R826W, and D209N F132L (2)ߤ, F132Vߤ, and N72Sߤ (mosaic). Login to comment

PMID: 22020219 [PubMed] Babenko AP et al: "Mechanism of KATP hyperactivity and sulfonylurea tolerance due to a diabetogenic mutation in L0 helix of sulfonylurea receptor 1 (ABCC8)."

No. Sentence Comment

95 Only subtle and insignificant functional effects of E208K [25] are not surprising. Login to comment
96 Unlike L213R, E208K can be carried asymptomatically [41,42] and exchanges similarly hydrophilic side chains on the hydrophilic side of the submembrane amphipathic helix (Fig. 6). Login to comment

PMID: 20810569 [PubMed] Zhou Q et al: "Neonatal diabetes caused by mutations in sulfonylurea receptor 1: interplay between expression and Mg-nucleotide gating defects of ATP-sensitive potassium channels."

No. Sentence Comment

1 Objective: The objective of the study was to determine the mechanisms by which two SUR1 mutations, E208K and V324M, associated with transient neonatal diabetes affect KATP channel function. Login to comment
2 Design: E208K or V324M mutant SUR1 was coexpressed with Kir6.2 in COS cells, and expression and gatingpropertiesoftheresultingchannelswereassessedbiochemicallyandelectrophysiologically. Login to comment
3 Results: Both E208K and V324M augment channel response to MgADP stimulation without altering sensitivity to ATP4- or sulfonylureas. Login to comment
4 Surprisingly, whereas E208K causes only a small increase in MgADP response consistent with the mild transient diabetes phenotype, V324M causes a severe activating gating defect. Login to comment
5 Unlike E208K, V324M also impairs channel expression at the cell surface, which is expected to dampen its functional impact on beta-cells. Login to comment
6 When either mutation was combined with a mutation in the second nucleotide binding domain of SUR1 previously shown to abolish Mg-nucleotide response, the activating effect of E208K and V324M was also abolished. Login to comment
7 Moreover, combination of E208K and V324M results in channels with Mg-nucleotide sensitivity greater than that seen in individual mutations alone. Login to comment
8 Conclusion: The results demonstrate that E208K and V324M, located in distinct domains of SUR1, enhance transduction of Mg-nucleotide stimulation from the SUR1 nucleotide binding folds to Kir6.2. Login to comment
22 We conducted functional analyses of two SUR1 mutations, E208K and V324M, identified in transient ND (7, 8). Login to comment
23 E208K and V324M located in L0 and TMD1, respectively, cause channel overactivity by enhancing MgADP responsivity, establishing their causal role in ND. Login to comment
24 The enhancement effect on MgADP responsivity is greater in V324M than E208K; however, surface expression of the V324M mutant is significantly reduced, suggesting that the greater gain-of-function gating defect caused by V324M is offset by lower surface expression. Login to comment
25 When combined with a SUR1-NBF2 mutation known to abolish MgADP responsivity, effects of E208K and V324M were also abolished, indicating that these residues are involved in transducing the effect of Mg-nucleotides to channel gating. Login to comment
35 Results Mutations and clinical data E208K and V324M are SUR1 mutations identified in patients diagnosed with ND (7, 8, 12) (Supplemental Table 1). Login to comment
40 No functional studies have been conducted on either E208K or V324M. Login to comment
41 Functional analysis of mutant channels Because not all carriers are symptomatic (7, 8, 12), it is important to determine whether E208K and V324M affect KATP channel function. Login to comment
42 In 86 Rbϩ efflux assays, whereas WT channels exhibited the expected low activity due to inhibition by high intracellular ATP, both E208K and V324M channels yielded greater efflux, with V324M being the most active (Fig. 1A). Login to comment
46 Functional characterization of E208K- and V324M-SUR1 mutations. Login to comment
49 Both E208K and V324M exhibited higher efflux than WT, with the V324M mutant showing the highest activity, confirming that E208K- and V324M-SUR1 are activating KATP channel mutations. Login to comment
52 The mature form of SUR1 is clearly reduced in V324M compared with WT, E208K, or L225P. Login to comment
60 D, Similar to panel C, except that the concentrations of ATP and ADP were different, and comparisons between WT and E208K were made. Login to comment
63 Shown are representative recordings of WT, E208K, and V324M channels in response to 10 or 100 nM glibenclamide. Login to comment
69 Because exit of SUR1 from the ER requires coassembly with Kir6.2, abundance of the upper band correlates with the amount of SUR1 at the cell surface that haspassedERqualitycontrol(9,14).Figure1Bshowsthat whereas in E208K-SUR1 both bands were similar in intensity to WT-SUR1, V324M-SUR1 had a clearly reduced upper band, suggesting that V324M may impair channel trafficking from ER to the plasma membrane. Login to comment
70 Immunofluorescence staining of surface channels showed that V324M is indeed expressed at a reduced level compared with WT or E208K, although staining of permeabilized cells indicated that total V324M SUR1 protein levels were not significantly reduced (Supplemental Fig. 2). Login to comment
71 Surface expression was further quantified by chemiluminescence assays that confirmed markedly reduced surface expression of V324M, in contrast to E208K (56.3 Ϯ 6.3 vs. 93.9 Ϯ 10.1% of WT channels, respectively; Fig. 1B). Login to comment
72 Unaltered or reduced surface expression of E208K or V324M suggests that overactivity results from abnormal channel gating. Login to comment
74 ATP dose-response studies showed that E208K and V324M do not affect channel ATP4- sensi- tivity (Supplemental Fig. 3). Login to comment
78 In contrast, E208K subtly increased Mg-nucleotide sensitivity that was statistically significant only in the 0.1/0.1 mM ATP/ADP ratio (compare Figs. 1D and 2B). Login to comment
79 These results indicate that E208K and V324M cause ND by hypersensitizing channels to Mg-nucleotide stimulation. Login to comment
81 To determine whether E208K or V324M affects channel sensitivity to sulfonylureas, we tested channel response to 10 or 100 nM glibenclamide. Login to comment
82 E208K and V324M were inhibited by glibenclamide similar to WT channels at both concentrations (Fig. 1E). Login to comment
84 E208K and V324M enhance transduction of MgADP stimulation Stimulation of KATP channels by Mg-nucleotides originates from Mg-nucleotide interactions with NBFs of SUR1. Login to comment
85 E208K and V324M are outside the NBFs, in the TMD0-L0 and TMD1 domains, respectively (Supplemental Fig. 1). Login to comment
88 Combining E208K or V324M with E1507K completely abrogated the enhancement effects of E208K or V324M on Mg-nucleotide responses (Fig. 2A). Login to comment
90 E208K and V324M enhance channel response to MgADP by affecting transduction of the MgADP effect to Kir6.2. Login to comment
93 A, The E1507K inactivating mutation in NBF2 completely abolished the activating effects of E208K or V324M. Login to comment
96 Each bar is the mean Ϯ SEM of 30 (WT), eight (E208K), six (L225P), five (V324M), nine (E208K/L225P), six (E208K/V324M), and six (L225P/V324M) patches. Login to comment
99 (#), P Ͻ 0.05 between E208K/V324M and E208K but the difference between E208K/V324M and V324M is not significant. Login to comment
100 To determine the relationship between the activating effect caused by V324M in TMD1 and that caused by E208K or L225P in TMD0-L0, we compared Mg-nucleotide responsivity in channels harboring a combination of these mutations. Login to comment
101 Currents measured in 0.1 mM ATP (free [Mg2ϩ ] ϳ1 mM) showed that channels harboring double mutations were more active than those with only one mutation such that the effects of E208K, L225P, or V324M are additive. Login to comment
104 Discussion We show that two heterozygous SUR1 mutations, E208K and V324M, identified in patients with transient ND cause KATP channel overactivity by enhancing channel responsivity to Mg-nucleotides without affecting ATP4- or glibenclamide sensitivity. Login to comment
106 Although V324M renders a marked increase in Mg-nucleotide response, even more so than L225P previously reported to cause permanent ND (15), the effect of E208K is subtle, only statistically significant at 0.1 mM ATP/0.1 mM ADP; yet both E208K and V324M are associated with transient ND. Login to comment
110 Of note, asymptomatic carriers have been described for both E208K and V324M(7, 12). Login to comment
113 The activating effects of E208K and V324M were abrogated by a NBF2 mutation that abolishes the MgADP response. Login to comment
115 E208K is in the TMD0-L0 domain that has been proposed to serve as a coupling module to transduce effects of Mg-nucleotide stimulation to Kir6.2 (4-6). Login to comment
117 That the effect of E208K or L225P and of V324M are additive suggests that there may be multiple transduction pathways to regulate Kir6.2 gating. Login to comment

PMID: 17668386 [PubMed] Ellard S et al: "Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects."

No. Sentence Comment

39 Three probands were compound heterozygotes for the missense mutations P45L/G1401R (ISPAD 47), E208K/Y263D (ISPAD 119), and T229I/V1523L (ISPAD 120). Login to comment
73 Details of ABCC8 Mutations and Clinical Information ISPAD Number Mutation (Protein Effect) Nucleotide Change Zygosity Age at Diagnosis (wk) Birth Weighta (Percentile) Neurological Feature Developmental Delay Muscle Weakness Epilepsy 123 V86Ab c.257TrC Heterozygous 8 2,900 (9) No No No 124 V86G c.257TrG Heterozygous 5 2,900 (13) No No No 68 F132Lb c.394TrC Heterozygous 13 2,200 (!1) Yes Yes Yes 125 F132L c.394TrC Heterozygous 26 2,440 (9) Yes Yes No 82 F132V c.394TrG Heterozygous 20 NA No No No 46 D209E c.627CrA Heterozygous 5 2,720 (13) No No No 134 Q211Kb c.631CrA Heterozygous 16 2,400 (3) No No No 122 L225Pc c.674TrC Heterozygous 4 2,500 (11) No No No 117 E382K c.1144GrA Homozygous 8 2,700 (4) No No No 118 A1185E c.3554CrA Homozygous 0 4,200 (95) No Yes Yes 116 N72S c.215ArG Mosaic 5 3,870 (74) No No No 47 P45L ϩ G1401R [c.134CrT] ϩ [c.4201GrA] Compound heterozygous 6 2,520 (18) Yes Yes No 119 E208K ϩ Y263D [c.622GrA] ϩ [c.787TrG] Compound heterozygous 13 2,950 (28) Yes No No 120 T229I ϩ V1523L [c.686CrT] ϩ [c.4567GrT] Compound heterozygous 4 NA No No No 78 P207S ϩ Y179X [c.619CrT] ϩ [c.536_539delATGG] Compound heterozygous 8 3,290 (29) No No No 121 [E1327K; V1523A] ϩ T1043QfsX74 [c.3979GrA; 4568CrT] ϩ [c.3127_3129delACCinsCAGCCAGGACCTG] Compound heterozygous 1 2,380 (!1) No No No a NA p not available. Login to comment

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

No. Sentence Comment

38 We identified eight heterozygous missense ABCC8 mutations in 8 of the 16 patients with neonatal diabetes, six of which have not yet been reported: E208K (c.622GϾA), A269D (c.806CϾA), V324M (c.970GϾA), R825W (c.2473CϾT), R1379H (c.4136GϾA), and V1523M (c.4567GϾA) (Fig. 1). Login to 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
43 E208K is close to the L213R mutation-previously found in a PND patient (13)-both of which lie in the intracellular L0-linker that controls the channel POmax (17). Login to comment
44 V324M is located in the transmembrane domain (TMD)6 of TMD1, and R1379H and V1523M are in the nucleotide-binding domain 2, the domain argued to hydrolyze MgATP. Login to comment
50 In the families with E208K, L582V, and R825W mutations, the fathers carried the mutation in the heterozygous state, whereas the A269D mutation in the NJ family was inherited from the mother (Table 1). Login to comment
51 The R1182Q and V1523M mutations were not identified in either parent, consistent with de novo mutations. Login to comment
66 Probands SGM-E208K, KS-L582V, and LM-R825W have a mutation inherited from their fathers and proband NJ-A269D from her mother (Table 1). Login to comment
67 In families with the L582V, R825W, and A269D mutations, glucose tolerance tests were performed in the fathers and mother, who were found to be free from diabetes. Login to comment
69 In the case of the father of SGM-E208K, glucose intolerance was documented during the oral glucose tolerance test. 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
70 In the case of the father of SGM-E208K, glucose intolerance was documented during the oral glucose tolerance test. In the comparison of the present cohort of ND-SUR1 cases (n afd; 8) with our cohort of those linked to KCNJ11/ Kir6.2 mutations (n afd; 18), there was no significant difference in distribution of low birth weight, age of diagnosis, or glucose levels at presentation, as assessed in our previous study (13). Login to comment