ABCMdb

PMID: 16885549

Babenko AP, Polak M, Cave H, Busiah K, Czernichow P, Scharfmann R, Bryan J, Aguilar-Bryan L, Vaxillaire M, Froguel P
Activating mutations in the ABCC8 gene in neonatal diabetes mellitus.
N Engl J Med. 2006 Aug 3;355(5):456-66., [PubMed]

Sentences

No. Mutations Sentence Comment

42 ABCC8 p.His1023Tyr ABCC8 p.Leu582Val ABCC8 p.Cys435Arg ABCC8 p.Leu213Arg ABCC8 p.Ile1424Val ABCC8 p.Arg1379Cys ABCC8 p.Arg1182Gln 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 43 ABCC8 p.His1023Tyr ABCC8 p.Leu582Val ABCC8 p.Cys435Arg ABCC8 p.Leu213Arg ABCC8 p.Ile1424Val ABCC8 p.Arg1379Cys ABCC8 p.Arg1182Gln 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 ABCC8 p.His1023Tyr ABCC8 p.Leu582Val ABCC8 p.Leu213Arg ABCC8 p.Ile1424Val ABCC8 p.Arg1379Cys The L213R, H1023Y, and I1424V were noninherited mutations, as were the L582V and R1379C mutations in one family each. Login to comment 48 ABCC8 p.His1023Tyr ABCC8 p.Leu582Val ABCC8 p.Leu582Val ABCC8 p.Cys435Arg ABCC8 p.Leu213Arg ABCC8 p.Ile1424Val ABCC8 p.Arg1379Cys ABCC8 p.Arg1182Gln The L213R, H1023Y, and I1424V were noninherited mutations, as were the L582V and R1379C mutations in one family each. Login to comment 49 ABCC8 p.Leu582Val ABCC8 p.Cys435Arg ABCC8 p.Arg1182Gln The L582V and R1397C mutations were also inherited in one family each, as were the C435R and R1182Q mutations. Login to comment 50 ABCC8 p.Cys435Arg ABCC8 p.Cys435Arg 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 51 ABCC8 p.Cys435Arg ABCC8 p.Cys435Arg ABCC8 p.Arg1182Gln 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 ABCC8 p.Arg1182Gln 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 53 ABCC8 p.Arg1379Cys Diabetes developed in the father of the proband (with an R1379C mutation) in Family 17 when he was 32 years old, and he is receiving glyburide. Login to comment 54 ABCC8 p.Arg1379Cys ABCC8 p.Arg1379Cys Diabetes developed in the father of the proband (with an R1379C mutation) in Family 17 when he was 32 years old, and he is receiving glyburide. Login to comment 55 ABCC8 p.Arg1379Cys The R1379C allele was also identified in the proband`s paternal grandmother who had had gestational diabetes and is currently being treated with diet and in a paternal great-aunt who was given a diagnosis of diabetes at 44 years of age and is currently being treated with sulfonylureas. Login to comment 66 ABCC8 p.His1023Tyr ABCC8 p.Leu582Val ABCC8 p.Leu582Val ABCC8 p.Cys435Arg ABCC8 p.Leu213Arg ABCC8 p.Ile1424Val ABCC8 p.Arg1379Cys ABCC8 p.Arg1379Cys ABCC8 p.Arg1182Gln 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 67 ABCC8 p.His1023Tyr ABCC8 p.Leu582Val ABCC8 p.Leu582Val ABCC8 p.Cys435Arg ABCC8 p.Leu213Arg ABCC8 p.Ile1424Val ABCC8 p.Arg1379Cys ABCC8 p.Arg1379Cys ABCC8 p.Arg1182Gln 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 92 ABCC8 p.His1023Tyr ABCC8 p.Leu582Val ABCC8 p.Leu582Val ABCC8 p.Cys435Arg ABCC8 p.Leu213Arg ABCC8 p.Ile1424Val ABCC8 p.Arg1379Cys ABCC8 p.Arg1379Cys ABCC8 p.Arg1182Gln 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 106 ABCC8 p.His1023Tyr ABCC8 p.Ile1424Val 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 108 ABCC8 p.His1023Tyr ABCC8 p.Ile1424Val 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 ABCC8 p.His1023Tyr ABCC8 p.Ile1424Val 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 ABCC8 p.His1023Tyr ABCC8 p.His1023Tyr ABCC8 p.Ile1424Val ABCC8 p.Ile1424Val 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 ABCC8 p.His1023Tyr ABCC8 p.His1023Tyr ABCC8 p.Ile1424Val ABCC8 p.Ile1424Val 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 ABCC8 p.His1023Tyr ABCC8 p.Ile1424Val 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 117 ABCC8 p.His1023Tyr ABCC8 p.Ile1424Val 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 ABCC8 p.His1023Tyr ABCC8 p.Ile1424Val 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 ABCC8 p.His1023Tyr ABCC8 p.His1023Tyr ABCC8 p.Ile1424Val 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 124 ABCC8 p.His1023Tyr ABCC8 p.His1023Tyr ABCC8 p.Ile1424Val 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 ABCC8 p.His1023Tyr ABCC8 p.His1023Tyr ABCC8 p.Ile1424Val ABCC8 p.Ile1424Val 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 144 ABCC8 p.His1023Tyr ABCC8 p.His1023Tyr ABCC8 p.Ile1424Val ABCC8 p.Ile1424Val 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 149 ABCC8 p.His1023Tyr ABCC8 p.His1023Tyr ABCC8 p.Ile1424Val ABCC8 p.Ile1424Val 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 151 ABCC8 p.His1023Tyr ABCC8 p.His1023Tyr ABCC8 p.Ile1424Val ABCC8 p.Ile1424Val 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. 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