ABCMdb

ABCC8 p.Leu213Arg

Predicted by SNAP2:	A: N (78%), C: N (61%), D: N (78%), E: N (87%), F: N (72%), G: N (82%), H: N (82%), I: N (82%), K: N (82%), M: N (87%), N: N (82%), P: N (66%), Q: N (87%), R: N (78%), S: N (87%), T: N (87%), V: N (78%), W: D (59%), Y: N (72%),
Predicted by PROVEAN:	A: N, C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: N, Y: N,

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[hide] Mutations in the ABCC8 gene encoding the SUR1 subu... Diabetes Obes Metab. 2007 Nov;9 Suppl 2:28-39. Patch AM, Flanagan SE, Boustred C, Hattersley AT, Ellard S
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.
Diabetes Obes Metab. 2007 Nov;9 Suppl 2:28-39., [PMID:17919176]

Abstract [show]
AIM: Mutations in the ABCC8 gene encoding the SUR1 subunit of the pancreatic ATP-sensitive potassium channel cause permanent neonatal diabetes mellitus (PNDM) and transient neonatal diabetes mellitus (TNDM). We reviewed the existing literature, extended the number of cases and explored genotype-phenotype correlations. METHODS: Mutations were identified by sequencing in patients diagnosed with diabetes before 6 months without a KCNJ11 mutation. RESULTS: We identified ABCC8 mutations in an additional nine probands (including five novel mutations L135P, R306H, R1314H, L438F and M1290V), bringing the total of reported families to 48. Both dominant and recessive mutations were observed with recessive inheritance more common in PNDM than TNDM (9 vs. 1; p < 0.01). The remainder of the PNDM probands (n = 12) had de novo mutations. Seventeen of twenty-five children with TNDM inherited their heterozygous mutation from a parent. Nine of these parents had permanent diabetes (median age at diagnosis: 27.5 years, range: 13-35 years). Recurrent mutations of residues R1183 and R1380 were found only in TNDM probands and dominant mutations causing PNDM clustered within exons 2-5. CONCLUSIONS: ABCC8 mutations cause PNDM, TNDM or permanent diabetes diagnosed outside the neonatal period. There is some evidence that the location of the mutation is correlated with the clinical phenotype.

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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
197 Genotype-phenotype Correlation Most of the dominantly acting mutations located in exons 2-5 of the ABCC8 gene (V86A/G, F132L/V, L135P, D209E, Q211K, L213R and L225P) cause PNDM. Login to comment

[hide] Permanent neonatal diabetes due to activating muta... Rev Endocr Metab Disord. 2010 Sep;11(3):193-8. Edghill EL, Flanagan SE, Ellard S
Permanent neonatal diabetes due to activating mutations in ABCC8 and KCNJ11.
Rev Endocr Metab Disord. 2010 Sep;11(3):193-8., [PMID:20922570]

Abstract [show]
The ATP-sensitive potassium (K(ATP)) channel is composed of two subunits SUR1 and Kir6.2. The channel is key for glucose stimulated insulin release from the pancreatic beta cell. Activating mutations have been identified in the genes encoding these subunits, ABCC8 and KCNJ11, and account for approximately 40% of permanent neonatal diabetes cases. The majority of patients with a K(ATP) mutation present with isolated diabetes however some have presented with the Developmental delay, Epilepsy and Neonatal Diabetes syndrome. This review focuses on mutations in the K(ATP) channel which result in permanent neonatal diabetes, we review the clinical and functional effects as well as the implications for treatment.

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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

[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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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

[hide] Permanent diabetes during the first year of life: ... Diabetologia. 2011 Jul;54(7):1693-701. Epub 2011 Mar 10. Russo L, Iafusco D, Brescianini S, Nocerino V, Bizzarri C, Toni S, Cerutti F, Monciotti C, Pesavento R, Iughetti L, Bernardini L, Bonfanti R, Gargantini L, Vanelli M, Aguilar-Bryan L, Stazi MA, Grasso V, Colombo C, Barbetti F
Permanent diabetes during the first year of life: multiple gene screening in 54 patients.
Diabetologia. 2011 Jul;54(7):1693-701. Epub 2011 Mar 10., [PMID:21544516]

Abstract [show]
AIMS/HYPOTHESIS: The aim of this study was to investigate the genetic aetiology of permanent diabetes mellitus with onset in the first 12 months of age. METHODS: We studied 46 probands with permanent, insulin-requiring diabetes with onset within the first 6 months of life (permanent neonatal diabetes mellitus [PNDM]/monogenic diabetes of infancy [MDI]) (group 1) and eight participants with diabetes diagnosed between 7 and 12 months of age (group 2). KCNJ11, INS and ABCC8 genes were sequentially sequenced in all patients. For those who were negative in the initial screening, we examined ERN1, CHGA, CHGB and NKX6-1 genes and, in selected probands, CACNA1C, GCK, FOXP3, NEUROG3 and CDK4. The incidence rate for PNDM/MDI was calculated using a database of Italian patients collected from 1995 to 2009. RESULTS: In group 1 we found mutations in KCNJ11, INS and ABCC8 genes in 23 (50%), 9 (19.5%) and 4 (8.6%) patients respectively, and a single homozygous mutation in GCK (2.1%). In group 2, we identified one incidence of a KCNJ11 mutation. No genetic defects were detected in other loci. The incidence rate of PNDM/MDI in Italy is estimated to be 1:210,287. CONCLUSIONS/INTERPRETATION: Genetic mutations were identified in ~75% of non-consanguineous probands with PNDM/MDI, using sequential screening of KCNJ11, INS and ABCC8 genes in infants diagnosed within the first 6 months of age. This percentage decreased to 12% in those with diabetes diagnosed between 7 and 12 months. Patients belonging to the latter group may either carry mutations in genes different from those commonly found in PNDM/MDI or have developed an early-onset form of autoimmune diabetes.

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73 A mutation in the same codon, ABCC8/L213R, has been previously reported in association with iDEND [36]. Login to comment

[hide] Mechanism of KATP hyperactivity and sulfonylurea t... FEBS Lett. 2011 Nov 16;585(22):3555-9. Epub 2011 Oct 19. Babenko AP, Vaxillaire M
Mechanism of KATP hyperactivity and sulfonylurea tolerance due to a diabetogenic mutation in L0 helix of sulfonylurea receptor 1 (ABCC8).
FEBS Lett. 2011 Nov 16;585(22):3555-9. Epub 2011 Oct 19., [PMID:22020219]

Abstract [show]
Activating mutations in different domains of the ABCC8 gene-coded sulfonylurea receptor 1 (SUR1) cause neonatal diabetes. Here we show that a diabetogenic mutation in an unexplored helix preceding the ABC core of SUR1 dramatically increases open probability of (SUR1/Kir6.2)(4) channel (KATP) by reciprocally changing rates of its transitions to and from the long-lived, inhibitory ligand-stabilized closed state. This kinetic mechanism attenuates ATP and sulfonylurea inhibition, but not Mg-nucleotide stimulation, of SUR1/Kir6.2. The results suggest a key role for L0 helix in KATP gating and together with previous findings from mutant KATP clarify why many patients with neonatal diabetes require high doses of sulfonylureas.

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12 The first ND mutation found in the L0 linker, L213R, is in the middle of the hotspot region in the putative interface helix [14] and causes severe ND with neurological abnormalities [7]. Login to comment
22 L213R mutation was introduced into hamster SUR1 cDNA. Login to comment
50 Results and discussion Fig. 2 shows that L213R dramatically increases the Po in intact cells while not affecting i and slightly decreasing N. Login to comment
51 The latter effect is consistent with the small negative effect of L213R on the amount of mature receptor, which is in line with observations that a comparable amphipathic L0 helix of ABCC1 attaches to the membrane [23] and L225P in a less conserved portion of the cytoplasmic linker of SUR1 does not affect N [24] or surface expression of SUR1 in the same cell line [25]. Login to comment
52 The results show that L213R can induce pathogenic currents in intact cells by hyperactivating KATP and support the notion that possible negative effects of some ND mutations on N (see also [25]) are overridden by their much stronger effect on PO. Login to comment
61 L213R and other elements of the model discussed in the text are identified using color-coded labels. Login to comment
64 L213R markedly elevates on-cell PO, does not affect the unitary conductance, and slightly decreases functional expression of (SUR1/KIR6.2)4 complexes without altering their labeling with 1 nM 125 I-azidoglibenclamide. Login to comment
69 Analysis of these records (Fig. 3) demonstrated that L213R nearly saturates the channel intrinsic activity, POmax ? Login to comment
73 To test this prediction we first compared the activities of the same macro-population of L213R channels in intact cells, in 1 mM MgATP, and in 1 mM ATP without Mg (Fig. 4A illustrates the protocol) vs similarly recorded activities of WT channels. Login to comment
75 The results suggested that L213R does not alter the Mg-nucleotide stimulatory action but compromises the Mg-independent nucleotide inhibition of KATP. Login to comment
76 Indeed, the steady-state inhibitory ATP dose-response (Fig. 4C) demonstrated that unlike A type mutations tested earlier under identical experimental conditions [7,11], L213R markedly ($20 times) increases IC50(ATP). Login to comment
78 This biophysical mechanism of KATP hyperactivity, called B type mechanism for short, explains why pancreatic b-cells in the L213R patient did not release insulin (remained hyperpolarized) despite his very high blood glucose [7]. Login to comment
79 A dose of glibenclamide above the FDA recommended dose allowed to transfer the L213R patient from insulin injections to SU therapy [7]. Login to comment
81 Our first test (Fig. 5A) indicated reduced inhibition of L213R channels by glibenclamide, but the slow washout of the second generation SU made it difficult to estimate its steady-state effect corrected for rundown (see Section 2 and similar test for WT KATP in [22]). Login to comment
82 Therefore we used the rapidly unbinding SU tolbutamide to quantify the effect of L213R on KATP inhibition by [SU] saturating its specific, but not non-specific, sites [22,31]. Login to comment
83 We compared the SU inhibition of L213R vs WT KATP activity under non-stimulatory conditions, as well as in the presence of the lowest possible submembrane [MgATP] and the highest possible [MgADP] in resting b-cells [32,33], as we did earlier for A type mutant KATP [7,11]. Login to comment
84 We found that unlike A type mutations, L213R compromises SU inhibition under non-stimulatory conditions (Fig. 5B, left bars). Login to comment
85 While saturation of specific SU binding sites with 200 lM tolbutamide reduces spontaneous activity of WT KATP by about 60% [22,31], the same SU treatment of L213R channels produces significantly smaller inhibition. Login to comment
86 Thus, L213R alters the nucleotide-independent component of SU action by uncoupling its high-affinity binding from the channel closure. Login to comment
94 Strong effects of L213R in L0 helix on TB/TIB and KATP inhibition provide a new evidence in support of our working mechanistic model (Fig. 1). 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
101 L213R saturates intrinsic activity of KATP by altering its slow gating kinetics. Login to comment
102 The top panel shows short segments of records of currents trough single WT and L213R KATP in inside-out patches in the nucleotide-free internal solution. Login to comment
104 The next panels show the results of analysis of 10 L213R vs 10 WT KATP records like those shown in the top panel. Login to comment
109 L213R does not alter the direct proximity of L0 to Kir6.2 (Fig. 2 inset), but could disrupt optimized L0/M0 interactions by rotating the L0 helix along its axis (Fig. 6) as L213R changes the helical hydrophobic moment. Login to comment
118 L213R compromises inhibitory nucleotide action. Login to comment
119 (A) L213R KATP currents under conditions indicated. Login to comment
122 (C) The inhibitory ATP dose-response curve for L213R (IC50(ATP) = 101.7 ± 4.1 lM; Hill coefficient = 1.19 ± 0.04) vs those for WT and A type mutant KATP tested earlier under similar conditions (see [7,11] for details); n = 10 and R2 > 0.995 for each curve fit. Login to comment
124 L213R attenuates inhibition of KATP by sulfonylureas. Login to comment
125 (A) L213R KATP currents indicating their reduced response to the normally (tightly) binding, slowly dissociating, insulin secretagogue glibenclamide (Glb). Login to comment
128 (B) The steady-state inhibition of L213R vs WT KATP by tolbutamide (Tlb) under conditions indicated; n = 10 for each bar. Fig. 6. Login to comment
131 The expected L213R-induced rotation of L0 helix is indicated. 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
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

[hide] A mutation in the TMD0-L0 region of sulfonylurea r... Diabetes. 2007 May;56(5):1357-62. Epub 2007 Feb 22. Masia R, De Leon DD, MacMullen C, McKnight H, Stanley CA, Nichols CG
A mutation in the TMD0-L0 region of sulfonylurea receptor-1 (L225P) causes permanent neonatal diabetes mellitus (PNDM).
Diabetes. 2007 May;56(5):1357-62. Epub 2007 Feb 22., [PMID:17317760]

Abstract [show]
OBJECTIVE: We sought to examine the molecular mechanisms underlying permanenent neonatal diabetes mellitus (PNDM) in a patient with a heterozygous de novo L225P mutation in the L0 region of the sulfonylurea receptor (SUR)1, the regulatory subunit of the pancreatic ATP-sensitive K(+) channel (K(ATP) channel). RESEARCH DESIGN AND METHODS: The effects of L225P on the properties of recombinant K(ATP) channels in transfected COS cells were assessed by patch-clamp experiments on excised membrane patches and by macroscopic Rb-flux experiments in intact cells. RESULTS: L225P-containing K(ATP) channels were significantly more active in the intact cell than in wild-type channels. In excised membrane patches, L225P increased channel sensitivity to stimulatory Mg nucleotides without altering intrinsic gating or channel inhibition by ATP in the absence of Mg(2+). The effects of L225P were abolished by SUR1 mutations that prevent nucleotide hydrolysis at the nucleotide binding folds. L225P did not alter channel inhibition by sulfonylurea drugs, and, consistent with this, the patient responded to treatment with oral sulfonylureas. CONCLUSIONS: L225P underlies K(ATP) channel overactivity and PNDM by specifically increasing Mg-nucleotide stimulation of the channel, consistent with recent reports of mechanistically similar PNDM-causing mutations in SUR1. The mutation does not affect sulfonylurea sensitivity, and the patient is successfully treated with sulfonylureas.

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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

[hide] New ABCC8 mutations in relapsing neonatal diabetes... Diabetes. 2007 Jun;56(6):1737-41. Epub 2007 Mar 27. Vaxillaire M, Dechaume A, Busiah K, Cave H, Pereira S, Scharfmann R, de Nanclares GP, Castano L, Froguel P, Polak M
New ABCC8 mutations in relapsing neonatal diabetes and clinical features.
Diabetes. 2007 Jun;56(6):1737-41. Epub 2007 Mar 27., [PMID:17389331]

Abstract [show]
Activating mutations in the ABCC8 gene that encodes the sulfonylurea receptor 1 (SUR1) regulatory subunit of the pancreatic islet ATP-sensitive K(+) channel (K(ATP) channel) cause both permanent and transient neonatal diabetes. Recently, we have described the novel mechanism where basal Mg-nucleotide-dependent stimulatory action of SUR1 on the Kir6.2 pore is increased. In our present study, we identified six new heterozygous ABCC8 mutations, mainly in patients presenting the transient form of neonatal diabetes (six of eight), with a median duration of initial insulin therapy of 17 months (range 0.5-38.0). Most of these mutations map to key functional domains of SUR1. Whereas Kir6.2 mutations are a common cause of permanent neonatal diabetes and in a few cases associate with the DEND (developmental delay, epilepsy, and neonatal diabetes) syndrome, SUR1 mutations are more frequent in transient (52%) compared with permanent (14%) neonatal diabetes cases screened for ABCC8 in our series. Although ketoacidosis is frequent at presentation, SUR1 mutations associate mainly with transient hyperglycemia, with possible recurrence later in life. One-half of the SUR1 neonatal diabetic patients presented with de novo mutations. In some familial cases, diabetes is not always present in the adult carriers of SUR1 mutations, supporting variability in their clinical expressivity that remains to be fully explained.

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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

[hide] Compound heterozygous mutations in the SUR1 (ABCC ... Channels (Austin). 2012 Mar-Apr;6(2):133-8. doi: 10.4161/chan.19980. Epub 2012 Mar 1. Lin YW, Akrouh A, Hsu Y, Hughes N, Nichols CG, De Leon DD
Compound heterozygous mutations in the SUR1 (ABCC 8) subunit of pancreatic K(ATP) channels cause neonatal diabetes by perturbing the coupling between Kir6.2 and SUR1 subunits.
Channels (Austin). 2012 Mar-Apr;6(2):133-8. doi: 10.4161/chan.19980. Epub 2012 Mar 1., [PMID:22562119]

Abstract [show]
KATP channels regulate insulin secretion by coupling beta-cell metabolism to membrane excitability. These channels are comprised of a pore-forming Kir6.2 tetramer which is enveloped by four regulatory SUR1 subunits. ATP acts on Kir6.2 to stabilize the channel closed state while ADP (coordinated with Mg(2+)) activates channels via the SUR1 domains. Aberrations in nucleotide-binding or in coupling binding to gating can lead to hyperinsulinism or diabetes. Here, we report a case of diabetes in a 7-mo old child with compound heterozygous mutations in ABCC8 (SUR1[A30V] and SUR1[G296R]). In unison, these mutations lead to a gain of KATP channel function, which will attenuate the beta-cell response to increased metabolism and will thereby decrease insulin secretion. (86)Rb(+) flux assays on COSm6 cells coexpressing the mutant subunits (to recapitulate the compound heterozygous state) show a 2-fold increase in basal rate of (86)Rb(+) efflux relative to WT channels. Experiments on excised inside-out patches also reveal a slight increase in activity, manifested as an enhancement in stimulation by MgADP in channels expressing the compound heterozygous mutations or homozygous G296R mutation. In addition, the IC 50 for ATP inhibition of homomeric A30V channels was increased ~6-fold, and was increased ~3-fold for both heteromeric A30V+WT channels or compound heterozygous (A30V +G296R) channels. Thus, each mutation makes a mechanistically distinct contribution to the channel gain-of-function that results in neonatal diabetes, and which we predict may contribute to diabetes in related carrier individuals.

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117 The cytosolic linker L0 domain has also been proposed to directly transduce the Mg-nucleotide stimulatory action from the SUR1 core to the Kir6.2 pore14 and a previous study demonstrated that another NDM mutation (L213R) in the L0 region also shifts intrinsic ATP sensitivity.13 The present study thus provides further evidence that mutations in the TMD0-L0 region alter the KATP channel activity and further supports the hypothesis that TMD0-L0 is closely associated with Kir6.2. Login to comment