ABCMdb

ABCC8 p.His1023Tyr

Predicted by SNAP2:	A: D (53%), C: D (66%), D: D (59%), E: D (66%), F: D (71%), G: N (61%), I: D (66%), K: D (59%), L: D (75%), M: D (63%), N: N (78%), P: D (80%), Q: N (82%), R: D (71%), S: N (72%), T: D (63%), V: D (66%), W: D (80%), Y: D (71%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, I: D, K: D, L: D, M: D, N: N, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Molecular basis of neonatal diabetes in Japanese p... J Clin Endocrinol Metab. 2007 Oct;92(10):3979-85. Epub 2007 Jul 17. Suzuki S, Makita Y, Mukai T, Matsuo K, Ueda O, Fujieda K
Molecular basis of neonatal diabetes in Japanese patients.
J Clin Endocrinol Metab. 2007 Oct;92(10):3979-85. Epub 2007 Jul 17., [PMID:17635943]

Abstract [show]
CONTEXT: Neonatal diabetes mellitus (NDM) is classified clinically into a transient form (TNDM), in which insulin secretion recovers within several months, and a permanent form (PNDM), requiring lifelong medication. However, these conditions are genetically heterogeneous. OBJECTIVE: Our objective was to evaluate the contribution of the responsible gene and delineate their clinical characteristics. PATIENTS AND METHODS: The chromosome 6q24 abnormality and KCNJ11 and ABCC8 mutations were analyzed in 31 Japanese patients (16 with TNDM and 15 with PNDM). Moreover, FOXP3 and IPF1 mutations were analyzed in a patient with immune dysregulation, polyendocrinopathy, enteropathy X-linked syndrome and with pancreatic agenesis, respectively. RESULTS: A molecular basis for NDM was found in 23 patients: 6q24 in eleven, KCNJ11 in nine, ABCC8 in two, and FOXP3 in one. All the patients with the 6q24 abnormality and two patients with the KCNJ11 mutation proved to be TNDM. Five mutations were novel: two (p.A174G and p.R50G) [corrected] in KCNJ11, two (p.A90V and p.N1122D) in ABCC8, and one (p.P367L) in FOXP3. Comparing the 6q24 abnormality and KCNJ11 mutation, there were some significant clinical differences: the earlier onset of diabetes, the lower frequency of diabetic ketoacidosis at onset, and the higher proportion of the patients with macroglossia at initial presentation in the patients with 6q24 abnormality. In contrast, two patients with the KCNJ11 mutations manifested epilepsy and developmental delay. CONCLUSIONS: Both the 6q24 abnormality and KCNJ11 mutation are major causes of NDM in Japanese patients. Clinical differences between them could provide important insight into the decision of which gene to analyze in affected patients first.

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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

[hide] Review. SUR1: a unique ATP-binding cassette protei... Philos Trans R Soc Lond B Biol Sci. 2009 Jan 27;364(1514):257-67. Aittoniemi J, Fotinou C, Craig TJ, de Wet H, Proks P, Ashcroft FM
Review. SUR1: a unique ATP-binding cassette protein that functions as an ion channel regulator.
Philos Trans R Soc Lond B Biol Sci. 2009 Jan 27;364(1514):257-67., [PMID:18990670]

Abstract [show]
SUR1 is an ATP-binding cassette (ABC) transporter with a novel function. In contrast to other ABC proteins, it serves as the regulatory subunit of an ion channel. The ATP-sensitive (KATP) channel is an octameric complex of four pore-forming Kir6.2 subunits and four regulatory SUR1 subunits, and it links cell metabolism to electrical activity in many cell types. ATPase activity at the nucleotide-binding domains of SUR results in an increase in KATP channel open probability. Conversely, ATP binding to Kir6.2 closes the channel. Metabolic regulation is achieved by the balance between these two opposing effects. Precisely how SUR1 talks to Kir6.2 remains unclear, but recent studies have identified some residues and domains that are involved in both physical and functional interactions between the two proteins. The importance of these interactions is exemplified by the fact that impaired regulation of Kir6.2 by SUR1 results in human disease, with loss-of-function SUR1 mutations causing congenital hyperinsulinism and gain-of-function SUR1 mutations leading to neonatal diabetes. This paper reviews recent data on the regulation of Kir6.2 by SUR1 and considers the molecular mechanisms by which SUR1 mutations produce disease.

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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

[hide] Activating mutations in the ABCC8 gene in neonatal... N Engl J Med. 2006 Aug 3;355(5):456-66. 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., [PMID:16885549]

Abstract [show]
BACKGROUND: The ATP-sensitive potassium (K(ATP)) channel, composed of the beta-cell proteins sulfonylurea receptor (SUR1) and inward-rectifying potassium channel subunit Kir6.2, is a key regulator of insulin release. It is inhibited by the binding of adenine nucleotides to subunit Kir6.2, which closes the channel, and activated by nucleotide binding or hydrolysis on SUR1, which opens the channel. The balance of these opposing actions determines the low open-channel probability, P(O), which controls the excitability of pancreatic beta cells. We hypothesized that activating mutations in ABCC8, which encodes SUR1, cause neonatal diabetes. METHODS: We screened the 39 exons of ABCC8 in 34 patients with permanent or transient neonatal diabetes of unknown origin. We assayed the electrophysiologic activity of mutant and wild-type K(ATP) channels. RESULTS: We identified seven missense mutations in nine patients. Four mutations were familial and showed vertical transmission with neonatal and adult-onset diabetes; the remaining mutations were not transmitted and not found in more than 300 patients without diabetes or with early-onset diabetes of similar genetic background. Mutant channels in intact cells and in physiologic concentrations of magnesium ATP had a markedly higher P(O) than did wild-type channels. These overactive channels remained sensitive to sulfonylurea, and treatment with sulfonylureas resulted in euglycemia. CONCLUSIONS: Dominant mutations in ABCC8 accounted for 12 percent of cases of neonatal diabetes in the study group. Diabetes results from a newly discovered mechanism whereby the basal magnesium-nucleotide-dependent stimulatory action of SUR1 on the Kir pore is elevated and blockade by sulfonylureas is preserved.

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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

[hide] Personalized medicine switching from insulin to su... Diagn Mol Pathol. 2012 Mar;21(1):56-9. Mak CM, Lee CY, Lam CW, Siu WK, Hung VC, Chan AY
Personalized medicine switching from insulin to sulfonylurea in permanent neonatal diabetes mellitus dictated by a novel activating ABCC8 mutation.
Diagn Mol Pathol. 2012 Mar;21(1):56-9., [PMID:22306677]

Abstract [show]
BACKGROUND: Neonatal diabetes mellitus (NDM) is a rare but important condition affecting approximately 1 in 100,000 newborns. Permanent form requires life-long treatment with difficulties in long-term compliance and metabolic complications. Exact genetic diagnosis can enable improved outcome and patient satisfaction by switching insulin injection to oral sulfonylureas. Successful cases have been reported with most experience on the KCNJ11-mutated permanent form. Here we report a successful experience in an ABCC8-mutated infant with permanent NDM. PATIENT AND METHODS: A 4-month-old Chinese girl was incidentally found to have hyperglycemia with baseline C-peptide of 0.05 nmol/L requiring insulin injection of 0.2 IU/kg/d. Genetic analysis of KCNJ11 and ABCC8 was performed by polymerase chain reaction and direct DNA sequencing at the age of 3 years. Sulfonylurea transition was conducted after the ABCC8 mutation detection. RESULTS: A novel homozygous ABCC8 NM_000352.3: c.3068 A>G; NP_000343.2: p.H1023R mutation was detected. C-peptide level increased to 0.14 nmol/L and HbA1c was normalized to 5.8% from 8.0% after 8 months of oral glibenclamide treatment with a maintenance dosage of 0.65 mg/kg/d. CONCLUSIONS: In this patient with ABCC8-mutated permanent NDM, oral sulfonylurea is also effective in achieving satisfactory diabetic control. Our study adds information to the personalized medicine practice of ABCC8-mutated permanent NDM.

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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

[hide] ABCC8 and ABCC9: ABC transporters that regulate K+... Pflugers Arch. 2007 Feb;453(5):703-18. Epub 2006 Aug 8. Bryan J, Munoz A, Zhang X, Dufer M, Drews G, Krippeit-Drews P, Aguilar-Bryan L
ABCC8 and ABCC9: ABC transporters that regulate K+ channels.
Pflugers Arch. 2007 Feb;453(5):703-18. Epub 2006 Aug 8., [PMID:16897043]

Abstract [show]
The sulfonylurea receptors (SURs) ABCC8/SUR1 and ABCC9/SUR2 are members of the C-branch of the transport adenosine triphosphatase superfamily. Unlike their brethren, the SURs have no identified transport function; instead, evolution has matched these molecules with K(+) selective pores, either K(IR)6.1/KCNJ8 or K(IR)6.2/KCNJ11, to assemble adenosine triphosphate (ATP)-sensitive K(+) channels found in endocrine cells, neurons, and both smooth and striated muscle. Adenine nucleotides, the major regulators of ATP-sensitive K(+) (K(ATP)) channel activity, exert a dual action. Nucleotide binding to the pore reduces the activity or channel open probability, whereas Mg-nucleotide binding and/or hydrolysis in the nucleotide-binding domains of SUR antagonize this inhibitory action to stimulate channel openings. Mutations in either subunit can alter this balance and, in the case of the SUR1/KIR6.2 channels found in neurons and insulin-secreting pancreatic beta cells, are the cause of monogenic forms of hyperinsulinemic hypoglycemia and neonatal diabetes. Additionally, the subtle dysregulation of K(ATP) channel activity by a K(IR)6.2 polymorphism has been suggested as a predisposing factor in type 2 diabetes mellitus. Studies on K(ATP) channel null mice are clarifying the roles of these metabolically sensitive channels in a variety of tissues.

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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

[hide] A rare mutation in ABCC8/SUR1 leading to altered A... Diabetes. 2008 Jun;57(6):1595-604. Epub 2008 Mar 17. Tarasov AI, Nicolson TJ, Riveline JP, Taneja TK, Baldwin SA, Baldwin JM, Charpentier G, Gautier JF, Froguel P, Vaxillaire M, Rutter GA
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.
Diabetes. 2008 Jun;57(6):1595-604. Epub 2008 Mar 17., [PMID:18346985]

Abstract [show]
OBJECTIVE: ATP-sensitive K(+) channels (K(ATP) channels) link glucose metabolism to the electrical activity of the pancreatic beta-cell to regulate insulin secretion. Mutations in either the Kir6.2 or sulfonylurea receptor (SUR) 1 subunit of the channel have previously been shown to cause neonatal diabetes. We describe here an activating mutation in the ABCC8 gene, encoding SUR1, that is associated with the development of type 2 diabetes only in adults. RESEARCH DESIGN AND METHODS: Recombinant K(ATP) channel subunits were expressed using pIRES2-based vectors in human embryonic kidney (HEK) 293 or INS1(832/13) cells and the subcellular distribution of c-myc-tagged SUR1 channels analyzed by confocal microscopy. K(ATP) channel activity was measured in inside-out patches and plasma membrane potential in perforated whole-cell patches. Cytoplasmic [Ca(2+)] was imaged using Fura-Red. RESULTS: A mutation in ABCC8/SUR1, leading to a Y356C substitution in the seventh membrane-spanning alpha-helix, was observed in a patient diagnosed with hyperglycemia at age 39 years and in two adult offspring with impaired insulin secretion. Single K(ATP) channels incorporating SUR1-Y356C displayed lower sensitivity to MgATP (IC(50) = 24 and 95 micromol/l for wild-type and mutant channels, respectively). Similar effects were observed in the absence of Mg(2+), suggesting an allosteric effect via associated Kir6.2 subunits. Overexpression of SUR1-Y356C in INS1(832/13) cells impaired glucose-induced cell depolarization and increased in intracellular free Ca(2+) concentration, albeit more weakly than neonatal diabetes-associated SUR1 mutants. CONCLUSIONS: An ABCC8/SUR1 mutation with relatively minor effects on K(ATP) channel activity and beta-cell glucose sensing causes diabetes in adulthood. These data suggest a close correlation between altered SUR1 properties and clinical phenotype.

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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