ABCMdb

ABCC8 p.Ile1424Val

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Publications

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

182 The I1425V mutation in NBD2 also shows greater Mg-nucleotide-dependent stimulation of the channel activity (Babenko et al. 2006; I1424V in their notation). Login to comment
185 Such naturally occurring mutations TNDM PNDM DEND TNDM PNDM DEND iDEND WT P206L D212N P45L N72S P207S E208K+Y263D D212I T229I A1185E V1522L+Y229I F132L 0 0.05 0.10 0.15 fractionofcurrentremaining in3mMMgATP(a) (b) (i) (ii) Figure 4. Login to comment

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
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
106 Figure 2 shows that the normalized activities of mutant channels (containing the I1424V or H1023Y variant) in intact cells and in 1 mM magnesium ATP are nearly four and seven times as great, respectively, as those of wild-type channels under similar nucleotide conditions. Login to comment
111 To exclude the possibility that overactivity of the mutant I1424V and H1023Y channels is caused by either a gain in the intrinsic, ligand-independent, activity or by attenuation of the inhibitory action of ATP on Kir6.2, we measured the mean ligand-independent PO values and steady-state ATP-inhibitory curves (i.e., without magnesium) (Fig. 3). Login to comment
113 We conclude that mutant I1424V and H1023Y channels overactivate beta-cell KATP channels under physiologic magnesium-nucleotide conditions by increasing the magne- 2006462 sium-nucleotide-dependent stimulatory action of SUR1 on the pore. Login to comment
115 A concentration of 200 μM tolbutamide, which saturates the high-affinity binding site of wild-type SUR1,25 inhibited wild-type and mutant channels (containing the I1424V or H1023Y variant) to a similar degree in the absence of magnesium nucleotides (Fig. 4A). Login to comment
116 This inhibition indicated that tolbutamide binding to SUR1 and its functional coupling to the Kir6.2 pore were not altered by the I1424V or H1023Y mutations. Login to comment
122 Our results are consistent with a report that neonatal diabetes develops in transgenic mice expressing a mutant Kir6.2 subunit with P<0.001 P<0.01 P<0.001 P<0.001 P<0.001 P<0.001 P<0.05 P<0.05 P<0.001 P<0.001 Intact Cells 1 mM Magnesium ATP 1 mM ATP 5% of Ligand- indepen- dent activity 5% of Ligand- indepen- dent activity 5% of Ligand- indepen- dent activity 5% of Ligand- indepen- dent activity Channel with I1424V Mutation Wild-Type Channel Channel with H1023Y Mutation Channels with H1023Y Mutation and Wild-Type Figure 2. Login to comment
142 In clinical practice, there is no way to distin- Ligand-IndependentPO RelativeActivity ofKATPChannels 0.2 0.4 0.0 Channel with I1424V Mutation Wild-Type Channel Channel with H1023Y Mutation 0.6 A B 0.6 0.8 0.4 0.2 0.0 0 1 10 100 1000 ATP (μM) 1.0 Channel with I1424V mutation Channel with H1023Y mutation Wild-type channel IC50(ATP)=7.99±0.42 μM h=1.18±0.06 R2=0.998 IC50(ATP)=8.85±0.36 μM h=1.14±0.1 R2=0.999 IC50(ATP)=6.97±0.39 μM h=1.24±0.08 R2=0.997 Figure 3. Login to comment
149 2006464 Normal Beta Cell Normal Beta Cell Without Nucleotides With 0.5 mM Magnesium ATP and 0.5 mM ADP Mutant Beta Cell Mutant Beta Cell in the Presence of Sulfonylurea RelativeActivityin50mMTIb I1424V Mutant Wild-Type Channel H1023Y Mutant I1424V Mutant Wild-Type Channel H1023Y Mutant Normal SUR1 0.5 ATP K+ K+ Ca2+ 0.4 0.3 0.2 0.1 0.0 RelativeActivityin200mMTIb 0.5 0.4 0.3 0.2 0.1 0.0 Stimulatory action of magnesium nucleotides (low ATP:ADP ratio) Normal SUR1 ATP K+ K+ Ca2+ Stimulatory action of magnesium nucleotides (elevated ATP:ADP ratio) Stimulates insulin secretion Mutant SUR1 ATP Ca2+ Stimulatory action of magnesium nucleotides (elevated ATP:ADP ratio) Mutant SUR1 Sulfonylurea ATP K+ Ca2+ Reduced stimulatory action of magnesium nucleotides (elevated ATP:ADP ratio) Stimulates insulin secretion Decreased insulin secretion Hyperglycemia X X Decreased Ca2+ influx K+ Membrane depolarization Increased glucose Increased glucose Increased glucose Membrane depolarization A C E B D F The New England Journal of Medicine Downloaded from nejm.org at UNIV OF NC/ACQ SRVCS on March 7, 465 guish patients with ABCC8 or KCNJ11 mutations from those with abnormalities in chromosome 6q24. 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
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
108 Figure 2 shows that the normalized activities of mutant channels (containing the I1424V or H1023Y variant) in intact cells and in 1 mM magnesium ATP are nearly four and seven times as great, respectively, as those of wild-type channels under similar nucleotide conditions. Login to comment
117 A concentration of 200 bc;M tolbutamide, which saturates the high-affinity binding site of wild-type SUR1,25 inhibited wild-type and mutant channels (containing the I1424V or H1023Y variant) to a similar degree in the absence of magnesium nucleotides (Fig. 4A). Login to comment
118 This inhibition indicated that tolbutamide binding to SUR1 and its functional coupling to the Kir6.2 pore were not altered by the I1424V or H1023Y mutations. Login to comment
124 Our results are consistent with a report that neonatal diabetes develops in transgenic mice expressing a mutant Kir6.2 subunit with P<0.001 P<0.01 P<0.001 P<0.001 P<0.001 P<0.001 P<0.05 P<0.05 P<0.001 P<0.001 Intact Cells 1 mM Magnesium ATP 1 mM ATP 5% of Ligand- indepen- dent activity 5% of Ligand- indepen- dent activity 5% of Ligand- indepen- dent activity 5% of Ligand- indepen- dent activity Channel with I1424V Mutation Wild-Type Channel Channel with H1023Y Mutation Channels with H1023Y Mutation and Wild-Type Figure 2. Login to comment
144 In clinical practice, there is no way to distin- Ligand-Independent P O Relative Activity of K ATP Channels 0.2 0.4 0.0 Channel with I1424V Mutation Wild-Type Channel Channel with H1023Y Mutation 0.6 A B 0.6 0.8 0.4 0.2 0.0 0 1 10 100 1000 ATP (bc;M) 1.0 Channel with I1424V mutation Channel with H1023Y mutation Wild-type channel IC50(ATP)=7.99&#b1;0.42 bc;M h=1.18&#b1;0.06 R2=0.998 IC50(ATP)=8.85&#b1;0.36 bc;M h=1.14&#b1;0.1 R2=0.999 IC50(ATP)=6.97&#b1;0.39 bc;M h=1.24&#b1;0.08 R2=0.997 Figure 3. Login to comment
151 Normal Beta Cell Normal Beta Cell Without Nucleotides With 0.5 mM Magnesium ATP and 0.5 mM ADP Mutant Beta Cell Mutant Beta Cell in the Presence of Sulfonylurea Relative Activity in 50 mM TIb I1424V Mutant Wild-Type Channel H1023Y Mutant I1424V Mutant Wild-Type Channel H1023Y Mutant Normal SUR1 0.5 ATP K+ K+ Ca2+ 0.4 0.3 0.2 0.1 0.0 Relative Activity in 200 mM TIb 0.5 0.4 0.3 0.2 0.1 0.0 Stimulatory action of magnesium nucleotides (low ATP:ADP ratio) Normal SUR1 ATP K+ K+ Ca2+ Stimulatory action of magnesium nucleotides (elevated ATP:ADP ratio) Stimulates insulin secretion Mutant SUR1 ATP Ca2+ Stimulatory action of magnesium nucleotides (elevated ATP:ADP ratio) Mutant SUR1 Sulfonylurea ATP K+ Ca2+ Reduced stimulatory action of magnesium nucleotides (elevated ATP:ADP ratio) Stimulates insulin secretion Decreased insulin secretion Hyperglycemia X X Decreased Ca2+ influx K+ Membrane depolarization Increased glucose Increased glucose Increased glucose Membrane depolarization A C E B D F guish patients with ABCC8 or KCNJ11 mutations from those with abnormalities in chromosome 6q24. Login to comment

PMID: 16897043 [PubMed] Bryan J et al: "ABCC8 and ABCC9: ABC transporters that regulate K+ channels."

No. Sentence Comment

141 Analysis of two SUR1 mutant channels, I1424V or H1023Y, demonstrated they were more active than wild-type channels both in on-cell recordings from intact mammalian cells and in isolated patches exposed to a quasiphysiologic concentration of MgATP (1 mM). Login to comment
142 In the absence of Mg2+ , when the stimulatory action of SUR1 on the pore was abolished, there was no significant difference in the ATP inhibitory curves of mutant and wild-type channels, indicating the I1424V or H1023Y receptors exert an enhanced stimulatory action on the pore. Login to comment

PMID: 17317760 [PubMed] Masia R et al: "A mutation in the TMD0-L0 region of sulfonylurea receptor-1 (L225P) causes permanent neonatal diabetes mellitus (PNDM)."

No. Sentence Comment

149 Two reports have identified three SUR1 mutations associated with PNDM (F132L, L213R, and I1424V) and five associated with transient neonatal diabetes (11,12). Login to comment
150 Common to F132L and I1424V is an increased sensitivity of the channel to Mg nucleotides, such that channel overactivity results at physiological nucleotide concentrations. Login to comment
151 Our results are consistent with these previous studies, as L225P increases channel sensitivity to Mg nucleotides without altering intrinsic gating or inhibition by ATP. Login to comment
152 The effects of L225P are similar to those of the PNDM-associated I1424V mutation (12) but not as severe as those of the DEND (Developmental Delay, Epilepsy, and Neonatal Diabetes Syndrome)-associated F132L mutation (11). Login to comment
157 The carrier of the I1424V mutation (which is mechanistically similar to L225P) has also been successfully treated with sulfonyureas (12). Login to comment
153 The effects of L225P are similar to those of the PNDM-associated I1424V mutation (12) but not as severe as those of the DEND (Developmental Delay, Epilepsy, and Neonatal Diabetes Syndrome)-associated F132L mutation (11). Login to comment
158 The carrier of the I1424V mutation (which is mechanistically similar to L225P) has also been successfully treated with sulfonyureas (12). 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

112 Mutation Reference KG KT (+Mg2+) b2; KT (-Mg2+) b2; KD (+Mg2+) b2; nM &#b5;M &#b5;M &#b5;M E1506Qa (8) 0.6 &#b1; 0.2 0.9 &#b1; 0.2 40 &#b1; 20 94 &#b1; 9 40 &#b1; 11 211 &#b1; 34 7 .6 &#b1; 2.2 E1506Da (15) 0.4 &#b1; 0.04 3.2 &#b1; 1 8.6 &#b1; 1.5 5570 &#b1; 1200 7 .2 &#b1; 1.5 289 &#b1; 122 4.7 &#b1; 2.2 Q1178Rb (24) 1.0 &#b1; 0.1 9.2 &#b1; 1.3 10 &#b1; 1 1030 &#b1; 200 9.1 &#b1; 1.7 13.9 &#b1; 2.0 20.7 &#b1; 8.9 I1424V (24) 0.5 &#b1; 0.03 7 .1 &#b1; 2.2 5.6 &#b1; 0.7 2840 &#b1; 700 7 .6 &#b1; 1.5 12.1 &#b1; 3.7 14.8 &#b1; 6.5 R1182Qb (24) 0.5 &#b1; 0.15 13.1 &#b1; 2.3 10.3 &#b1; 1.4 11100 &#b1; 1600 4.1 &#b1; 0.4 13.1 &#b1; 2.2 16.4 &#b1; 4.6 WT 0.25 &#b1; 0.02 200 &#b1; 18 13 &#b1; 1 10900 &#b1; 3400 16 &#b1; 11 60 &#b1; 16 14 &#b1; 6.6 S1185Ac (9) 0.3 &#b1; 0.05 416 &#b1; 75 4.9 &#b1; 0.5 19100 &#b1; 3600 6.4 &#b1; 1.5 36.6 &#b1; 8 10.4 &#b1; 2.5 C1174Fc (9) 0.5 &#b1; 0.04 2690 &#b1; 725 5.9 &#b1; 2.3 >20000 13 &#b1; 6 66 &#b1; 13 7 .6 &#b1; 1.7 E1506K (25) 0.3 &#b1; 0.03 8450 &#b1; 1200 5.5 &#b1; 0.6 256 &#b1; 55 5.3 &#b1; 0.4 >1000 n.d. G1479R (26) 0.5 &#b1; 0.04 >10000 n.d. >20000 n.d. >1000 n.d. a Includes data from Ref. (8). Login to 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