ABCMdb

ABCC8 p.His1023Tyr

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Publications

PMID: 17635943 [PubMed] Suzuki S et al: "Molecular basis of neonatal diabetes in Japanese patients."

No. Sentence Comment

161 The reported mutations F132L (4) and H1023Y (5) are located in TMD0 and TMD2, respectively, and functional studies confirmed that these mutations reduced ATP sensitivity. 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

184 Finally, some mutations (e.g. H1023Y in TM12, Babenko et al. 2006; L225P in CL3, Masia et al. 2007) enhance Mg-nucleotide activation by unknown mechanisms. Login to 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
187 Finally, some mutations (e.g. H1023Y in TM12, Babenko et al. 2006; L225P in CL3, Masia et al. 2007) enhance Mg-nucleotide activation by unknown mechanisms. 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: 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: 22306677 [PubMed] Mak CM et al: "Personalized medicine switching from insulin to sulfonylurea in permanent neonatal diabetes mellitus dictated by a novel activating ABCC8 mutation."

No. Sentence Comment

91 Another activating mutation at the same amino acid with substitution by tyrosine (p.H1023Y) was reported by Babenko et al12 in 2006. Login to comment
92 Their patient, who harbored a de novo heterozygous p.H1023Y, presented with transient NDM with hyperglycemia of 37.8mmol/L and diabetic ketoacidosis at the age of 21 days. Login to comment
95 The investigators had screened for more than 300 individuals and p.H1023Y was not seen in any individuals. Login to comment
96 Babenko et al. also confirmed the pathogenicity of p.H1023Y by electrophysiological analysis of the KATP-channel. Login to comment
97 Mutant p.H1023Y showed an overreactive channel, which remains sensitive to sulfonylurea. 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
143 The simulation of heterozygosity by expression of 1:1 mixtures of ND-SUR1 H1023Y and wild-type SUR1 with KIR6.2 produced average mean channel activities intermediate between the "homozygous" mutant and wild-type channels. Login to comment

PMID: 18346985 [PubMed] Tarasov AI et al: "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."

No. Sentence Comment

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
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