ABCMdb

ABCC8 p.Leu225Pro

None has been submitted yet.

Publications

PMID: 17919176 [PubMed] Patch AM et al: "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."

No. Sentence 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
247 Functional data have only been published for 8/39 ABCC8 missense mutations to date (F132L [16]; I1425V and H1024Y [13]; mutations (P207S, T229I, A1185E and V1523L [14]; L225P [16]). Login to comment

PMID: 20922570 [PubMed] Edghill EL et al: "Permanent neonatal diabetes due to activating mutations in ABCC8 and KCNJ11."

No. Sentence Comment

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

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: 22020219 [PubMed] Babenko AP et al: "Mechanism of KATP hyperactivity and sulfonylurea tolerance due to a diabetogenic mutation in L0 helix of sulfonylurea receptor 1 (ABCC8)."

No. Sentence 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

PMID: 20810569 [PubMed] Zhou Q et al: "Neonatal diabetes caused by mutations in sulfonylurea receptor 1: interplay between expression and Mg-nucleotide gating defects of ATP-sensitive potassium channels."

No. Sentence Comment

52 The mature form of SUR1 is clearly reduced in V324M compared with WT, E208K, or L225P. Login to comment
57 Representative recordings of WT, V324M, and L225P channels are shown. Login to comment
77 These experiments showed that V324M markedly increases the Mg-nucleotide response (most evident at the 0.5/0.1 mM ATP/ADP ratio; Fig. 1C), even more so than L225P, another SUR1 mutation reported to cause permanent ND by a similar gating abnormality (15). Login to comment
96 Each bar is the mean Ϯ SEM of 30 (WT), eight (E208K), six (L225P), five (V324M), nine (E208K/L225P), six (E208K/V324M), and six (L225P/V324M) patches. Login to comment
100 To determine the relationship between the activating effect caused by V324M in TMD1 and that caused by E208K or L225P in TMD0-L0, we compared Mg-nucleotide responsivity in channels harboring a combination of these mutations. Login to comment
101 Currents measured in 0.1 mM ATP (free [Mg2ϩ ] ϳ1 mM) showed that channels harboring double mutations were more active than those with only one mutation such that the effects of E208K, L225P, or V324M are additive. Login to comment
106 Although V324M renders a marked increase in Mg-nucleotide response, even more so than L225P previously reported to cause permanent ND (15), the effect of E208K is subtle, only statistically significant at 0.1 mM ATP/0.1 mM ADP; yet both E208K and V324M are associated with transient ND. Login to comment
108 We previously proposed that in ND surface expression efficiency of a mutant modifies the extent of manifestation of the gating defect to determine diseaseoutcome(18,19).Supportingthis,whereasE208K (and also L225P; Fig. 1B) exhibited surface expression similar to WT, V324M was expressed at only approximately 50% that of WT (Fig. 1B). Login to comment
114 This suggests that similar to L225P (15), the two mutations affect transduction of MgATP binding/hydrolysis signal from the SUR1-NBFs to Kir6.2. Login to comment
117 That the effect of E208K or L225P and of V324M are additive suggests that there may be multiple transduction pathways to regulate Kir6.2 gating. Login to comment
121 Alternatively, transduction of the glibenclamide blocking effect may employ a pathway separate from that affected by V324M, as suggested for the L225P mutation (15). Login to comment

PMID: 17584766 [PubMed] Proks P et al: "Mechanism of action of a sulphonylurea receptor SUR1 mutation (F132L) that causes DEND syndrome."

No. Sentence Comment

46 Furthermore, changes in gating were not observed for the L225P mutation that also lies within TMD0 (19). Login to comment
172 This idea is also in agreement with the fact that there are many disease-causing mutations in this region and that they do not all act in the same way: for example, the L225P mutation does not alter single-channel gating (19). 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

1 De Leon,2 Courtney MacMullen,2 Heather McKnight,2 Charles A. Stanley,2 and Colin G. Nichols1 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 Kϩ channel (KATP channel). Login to comment
2 RESEARCH DESIGN AND METHODS-The effects of L225P on the properties of recombinant KATP channels in transfected COS cells were assessed by patch-clamp experiments on excised membrane patches and by macroscopic Rb-flux experiments in intact cells. Login to comment
3 RESULTS-L225P-containing KATP channels were significantly more active in the intact cell than in wild-type channels. Login to comment
4 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 Mg2ϩ . Login to comment
5 The effects of L225P were abolished by SUR1 mutations that prevent nucleotide hydrolysis at the nucleotide binding folds. Login to comment
6 L225P did not alter channel inhibition by sulfonylurea drugs, and, consistent with this, the patient responded to treatment with oral sulfonylureas. Login to comment
7 CONCLUSIONS-L225P underlies KATP 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. Login to comment
15 Here we describe a patient with permanent neonatal diabetes mellitus (PNDM) with a novel heterozygous SUR1 mutation (L225P) located in L0. Login to comment
16 L225P causes increased stimulation of recombinant KATP channels by Mg nucleotides and increased activity in the intact cell. Login to comment
17 The effects of L225P are abolished by mutations in the NBFs of SUR1 that prevent nucleotide hydrolysis, indicating that L225P likely acts on the transduction mechanism that links nucleotide hydrolysis at the NBFs to channel gating. Login to comment
21 Two mutations were found in ABCC8: t674c, predicted to cause an L225P amino acid change, was de novo, and g2638a, predicted to cause a D880N amino acid change, was maternally transmitted. Login to comment
54 RESULTS AND DISCUSSION A neonatal diabetes patient with a L225P mutation in SUR1. Login to comment
61 Reconstituted KATP channels containing L225P exhibit increased Mg-nucleotide stimulation. Login to comment
64 Heterozygous t674c mutation in the proband leads to heterozygous L225P point mutation. Login to comment
65 B: On-cell current relative to maximal postexcision current (Irel) for wild-type (WT), L225P-containing, and D880N-containing channels expressed in COS cells. Login to comment
82 However, two heterozygous point mutations were found in ABCC8 (SUR1): L225P, which was de novo (Fig. 1A), and D880N, which was maternally transmitted. Login to comment
83 L225P channels are more stimulated by Mg nucleotides. Login to comment
84 L225P and D880N were engineered into SUR1 to examine their functional consequences. Login to comment
86 Channel activity in the on-cell configuration (before excision) was significantly increased by L225P but not altered by D880N (Fig. 1B). Login to comment
88 Compared with wild-type channels, L225P did not alter (Po,zero) (0.55 Ϯ 0.02 vs. 0.58 Ϯ 0.03) nor did it alter sensitivity to inhibitory ATP in the absence of Mg2ϩ (half-maximal inhibitory [ATP], K1/2, was 8.2 Ϯ 1.2 vs. 8.9 Ϯ 1.5 ␮mol/l, Fig. 1D). Login to comment
89 However, L225P-containing channels were significantly more active in MgATP compared with wild type (K1/2 ϭ 19.0 Ϯ 2.6 vs. 67.6 Ϯ 15.8 ␮mol/l, P Ͻ 0.05 by Student`s t test) and were significantly more stimulated by MgADP than wild type (Fig. 1E and F), while D880N-containing channels were stimulated comparably with wild type (data not shown). Login to comment
90 These results indicate that L225P causes KATP channel overactivity by specifically increasing channel stimulation by Mg nucleotides and is therefore the likely cause of PNDM in the patient. Login to comment
91 L225P channels are more active in the intact cell. Login to comment
93 Consistent with expectations, L225P flux was significantly higher than wild-type flux under both basal conditions and metabolic inhibition (Fig. 2A and B). Login to comment
94 The fractional activity of L225P channels under basal conditions (relative to metabolic inhibition) was significantly increased compared with WT (Fig. 2C), indicating that L225P channels are already close to maximal activity under basal conditions. Login to comment
95 Since L225P did not significantly alter current density in excised membrane patches compared with wild type (1.3 Ϯ 0.2 vs. 1.2 Ϯ 0.1 pA/patch), the FIG. 2. Login to comment
96 L225P-containing channels are more active in the intact cell. Login to comment
97 A and B: Relative efflux of 86 Rb؉ as a function of time in basal conditions (A) or in metabolic inhibition (B) for wild-type (WT), mixed wild-type ؉ L225P, L225P, and [L225P, D1506A] channels, as well as untransfected controls. Login to comment
103 *P < 0.05 compared with L225P by Student`s t test. Login to comment
104 increased Rb fluxes measured for L225P channels must reflect differences in activity rather than in expression. Login to comment
105 Since the patient is heterozygous for L225P, we measured Rb fluxes from cells transfected with a 1:1 mixture of wild-type and L225P cDNA. Login to comment
106 The resulting mixed WT ϩ L225P channels exhibited fluxes that were intermediate between wild-type and homomeric L225P channels (Fig. 2A and B). Login to comment
107 The fractional activity of mixed wild-type ϩ L225P channels was also significantly increased compared with wild type (Fig. 2C), consistent with KATP channel overactivity leading to suppression of insulin secretion and diabetes in the heterozygous patient. Login to comment
108 L225P does not alter sulfonylurea sensitivity of the channel. Login to comment
109 Sulfonylurea sensitivity of recombinant KATP channels was unaffected by L225P, both in excised membrane patches and in intact cells (Fig. 3B-D). Login to comment
114 L225P effects are dependent on intact nucleotide hydrolysis at the NBFs. Login to comment
117 Consistent with this, the effects of L225P on channel activity in the intact cell were abolished by combination with either of two NBF mutations (K719M or D1506A) that abolish Mg-nucleotide stimulation of the channel (19,20) (Fig. 2D). Login to comment
120 To address this question, we measured Rb fluxes for all permutations of wild-type, L225P, D1506A, and (L225P, D1506A) combinations (at a 1:1 cDNA transfection ratio) (Fig. 4C). Login to comment
123 L225P does not alter sulfonylurea sensitivity of KATP channels. Login to comment
124 A: Representative currents recorded from inside-out membrane patches from COS cells expressing wild-type (top) or L225P (bottom) channels. Login to comment
131 Similarly, the activity of L225P:D1506A corresponded with (50%) L225P activity, the activity of wild type:L225P yielded an arithmetic sum of wild-type and L225P activities ([50%] wild type ϩ [50%] L225P), and the activity of L225P:[L225P, D1506A] yielded (50%) L225P activity (Fig. 4C). Login to comment
132 When L225P is mixed with D1506A, however, the resulting activity should then be (50%) L225P, if stimulation occurs through the TMD0-L0 of the same subunit, or (50%) wild type if it occurs through the TMD0-L0 of the adjacent subunit (Fig. 4B). Login to comment
133 The actual result was (50%) L225P activity (Fig. 4C), consistent with the "same subunit" model. Login to comment
134 Likewise, when wild type and [L225P, D1506A] are mixed, the activity should be (50%) wild type if stimulation occurs through the same subunit or (50%) L225P if it occurs through the adjacent subunit (Fig. 4B). Login to comment
136 L225P alters transduction of Mg-nucleotide stimulation from the core of the same SUR1 subunit. Login to comment
138 L225P and D1506A are indicated by green and red circles, respectively. Login to comment
140 B: Predicted activity of two SUR1 mixtures (wild type [WT]:[L225P, D1506A] and L225P:D1506A) based on the "same subunit" model (left, in orange) or the "adjacent subunit" model (right, in blue). Login to comment
144 Horizontal dashed lines indicate predicted (50%) wild-type activity, predicted (50%) L225P activity, and predicted (50%) wild type ؉ (50%) L225P activity, calculated from actual wild-type and L225P data. Login to comment
147 The lack of an effect of L225P on sulfonylurea sensitivity indicates that the mutation does not affect transduction of high-affinity sulfonylurea block to the Kir6.2 pore, suggesting that there may be structurally segregated transduction pathways in TMD0-L0 for each of these regulatory inputs from the SUR1 core. 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
154 In contrast with L225P, D880N did not affect Mg-nucleotide stimulation or on-cell channel activity. Login to comment
156 Consistent with lack of effect of L225P on sulfonylurea sensitivity of recombinant channels, the patient was successfully treated with oral sulfonylureas. 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
159 NOTE ADDED IN PROOF We have now sequenced SUR1 exon 5 from 50 healthy control subjects and have not found the L225P mutation in 98 alleles. Login to comment
55 RESULTS AND DISCUSSION A neonatal diabetes patient with a L225P mutation in SUR1. Login to comment
62 Reconstituted KATP channels containing L225P exhibit increased Mg-nucleotide stimulation. Login to comment
66 B: On-cell current relative to maximal postexcision current (Irel) for wild-type (WT), L225P-containing, and D880N-containing channels expressed in COS cells. Login to comment
85 L225P and D880N were engineered into SUR1 to examine their functional consequences. Login to comment
87 Channel activity in the on-cell configuration (before excision) was significantly increased by L225P but not altered by D880N (Fig. 1B). Login to comment
92 L225P channels are more active in the intact cell. Login to comment
98 A and B: Relative efflux of 86 Rbd19; as a function of time in basal conditions (A) or in metabolic inhibition (B) for wild-type (WT), mixed wild-type d19; L225P, L225P, and [L225P, D1506A] channels, as well as untransfected controls. Login to comment
110 Sulfonylurea sensitivity of recombinant KATP channels was unaffected by L225P, both in excised membrane patches and in intact cells (Fig. 3B-D). Login to comment
115 L225P effects are dependent on intact nucleotide hydrolysis at the NBFs. Login to comment
118 Consistent with this, the effects of L225P on channel activity in the intact cell were abolished by combination with either of two NBF mutations (K719M or D1506A) that abolish Mg-nucleotide stimulation of the channel (19,20) (Fig. 2D). Login to comment
121 To address this question, we measured Rb fluxes for all permutations of wild-type, L225P, D1506A, and (L225P, D1506A) combinations (at a 1:1 cDNA transfection ratio) (Fig. 4C). Login to comment
125 A: Representative currents recorded from inside-out membrane patches from COS cells expressing wild-type (top) or L225P (bottom) channels. Login to comment
135 Likewise, when wild type and [L225P, D1506A] are mixed, the activity should be (50%) wild type if stimulation occurs through the same subunit or (50%) L225P if it occurs through the adjacent subunit (Fig. 4B). Login to comment
137 L225P alters transduction of Mg-nucleotide stimulation from the core of the same SUR1 subunit. Login to comment
139 L225P and D1506A are indicated by green and red circles, respectively. Login to comment
141 B: Predicted activity of two SUR1 mixtures (wild type [WT]:[L225P, D1506A] and L225P:D1506A) based on the "same subunit" model (left, in orange) or the "adjacent subunit" model (right, in blue). Login to comment
145 Horizontal dashed lines indicate predicted (50%) wild-type activity, predicted (50%) L225P activity, and predicted (50%) wild type d19; (50%) L225P activity, calculated from actual wild-type and L225P data. Login to comment
148 The lack of an effect of L225P on sulfonylurea sensitivity indicates that the mutation does not affect transduction of high-affinity sulfonylurea block to the Kir6.2 pore, suggesting that there may be structurally segregated transduction pathways in TMD0-L0 for each of these regulatory inputs from the SUR1 core. 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
155 In contrast with L225P, D880N did not affect Mg-nucleotide stimulation or on-cell channel activity. 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
160 NOTE ADDED IN PROOF We have now sequenced SUR1 exon 5 from 50 healthy control subjects and have not found the L225P mutation in 98 alleles. Login to comment

PMID: 17668386 [PubMed] Ellard S et al: "Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects."

No. Sentence Comment

27 Apparent spontaneous mutations were confirmed by testing parental and proband DNA samples with use of a panel of six microsatellite markers on chromosome 11p15.11 Heterozygous de novo mutations V86A, V86G, F132L, F132V, D209E, Q211K, and L225P were present in eight patients (table 2). Login to comment
75 Birth weight percentiles were calculated using population-based data,15 and, when information on gestational age was not available ( ), a gestational age of 40 wk was assumed.n p 3 b Patients ISPAD 68, 123, and 134 have been reported by us elsewhere.9,10,14 c The L225P mutation has been reported in another patient by Masia et al.8 Figure 3. Schematic representation of KATP channels in family ISPAD 78. Login to comment
76 The unaffected parents are heterozygous for the c.536del4 frameshift or P207S missense mutation. Login to comment
154 Masia R, Deleon DD, Macmullen C, McKnight H, Stanley CA, Nichols CG (2007) A mutation in the TMD0-L0 region of SUR1 (L225P) causes permanent neonatal diabetes mellitus (PNDM). Login to comment
157 Masia R, Deleon DD, Macmullen C, McKnight H, Stanley CA, Nichols CG (2007) A mutation in the TMD0-L0 region of SUR1 (L225P) causes permanent neonatal diabetes mellitus (PNDM). Login to comment

PMID: 26621776 [PubMed] Cooper PE et al: "Differential mechanisms of Cantu syndrome-associated gain of function mutations in the ABCC9 (SUR2) subunit of the KATP channel."

No. Sentence Comment

218 A mutation in the TMD0-L0 region of sulfonylurea receptor-1 (L225P) causes permanent neonatal diabetes mellitus (PNDM). Login to comment

PMID: 22562119 [PubMed] Lin YW et al: "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."

No. Sentence Comment

170 A mutation in the TMD0-L0 region of sulfonylurea receptor-1 (L225P) causes permanent neonatal diabetes mellitus (PNDM). Login to comment