ABCC9 p.Ser1402Cys
Predicted by SNAP2: | A: D (75%), C: D (80%), D: D (91%), E: D (91%), F: D (85%), G: D (85%), H: D (85%), I: D (85%), K: D (91%), L: D (85%), M: D (85%), N: D (75%), P: D (91%), Q: D (85%), R: D (91%), T: N (93%), V: D (80%), W: D (91%), Y: D (85%), |
Predicted by PROVEAN: | A: N, C: D, D: N, E: N, F: D, G: D, H: D, I: D, K: N, L: D, M: D, N: N, P: D, Q: N, R: D, T: N, V: N, W: D, Y: D, |
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[hide] ABCC9 is a novel Brugada and early repolarization ... Int J Cardiol. 2014 Feb 15;171(3):431-42. doi: 10.1016/j.ijcard.2013.12.084. Epub 2014 Jan 4. Hu D, Barajas-Martinez H, Terzic A, Park S, Pfeiffer R, Burashnikov E, Wu Y, Borggrefe M, Veltmann C, Schimpf R, Cai JJ, Nam GB, Deshmukh P, Scheinman M, Preminger M, Steinberg J, Lopez-Izquierdo A, Ponce-Balbuena D, Wolpert C, Haissaguerre M, Sanchez-Chapula JA, Antzelevitch C
ABCC9 is a novel Brugada and early repolarization syndrome susceptibility gene.
Int J Cardiol. 2014 Feb 15;171(3):431-42. doi: 10.1016/j.ijcard.2013.12.084. Epub 2014 Jan 4., [PMID:24439875]
Abstract [show]
BACKGROUND: Genetic defects in KCNJ8, encoding the Kir6.1 subunit of the ATP-sensitive K(+) channel (I(K-ATP)), have previously been associated with early repolarization (ERS) and Brugada (BrS) syndromes. Here we test the hypothesis that genetic variants in ABCC9, encoding the ATP-binding cassette transporter of IK-ATP (SUR2A), are also associated with both BrS and ERS. METHODS AND RESULTS: Direct sequencing of all ERS/BrS susceptibility genes was performed on 150 probands and family members. Whole-cell and inside-out patch-clamp methods were used to characterize mutant channels expressed in TSA201-cells. Eight ABCC9 mutations were uncovered in 11 male BrS probands. Four probands, diagnosed with ERS, carried a highly-conserved mutation, V734I-ABCC9. Functional expression of the V734I variant yielded a Mg-ATP IC(5)(0) that was 5-fold that of wild-type (WT). An 18-y/o male with global ERS inherited an SCN5A-E1784K mutation from his mother, who displayed long QT intervals, and S1402C-ABCC9 mutation from his father, who displayed an ER pattern. ABCC9-S1402C likewise caused a gain of function of IK-ATP with a shift of ATP IC(5)(0) from 8.5 +/- 2 mM to 13.4 +/- 5 muM (p<0.05). The SCN5A mutation reduced peak INa to 39% of WT (p<0.01), shifted steady-state inactivation by -18.0 mV (p<0.01) and increased late I(Na) from 0.14% to 2.01% of peak I(Na) (p<0.01). CONCLUSION: Our study is the first to identify ABCC9 as a susceptibility gene for ERS and BrS. Our findings also suggest that a gain-of-function in I(K-ATP) when coupled with a loss-of-function in SCN5A may underlie type 3 ERS, which is associated with a severe arrhythmic phenotype.
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No. Sentence Comment
7 An 18-y/o male with global ERS inherited an SCN5A-E1784K mutation from his mother, who displayed long QT intervals, and S1402C-ABCC9 mutation from his father, who displayed an ER pattern.
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ABCC9 p.Ser1402Cys 24439875:7:120
status: NEW8 ABCC9-S1402C likewise caused a gain of function of IK-ATP with a shift of ATP IC50 from 8.5 &#b1; 2 mM to 13.4 &#b1; 5 bc;M (p b 0.05).
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ABCC9 p.Ser1402Cys 24439875:8:6
status: NEW50 Mutagenesis, cell transfection and electrophysiological recordings Variations (S1402C and V734I) in the regulatory ABCC9 subunit (human) were introduced in pECE plasmid by PCR amplification of both DNA strands with complementary primers containing the desired amino acid changes (QuickChange, Stratagene, Agilent Technologies, Inc., Santa Clara, CA, USA).
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ABCC9 p.Ser1402Cys 24439875:50:79
status: NEW119 Age for Dx (y/o) Gender Dx VT/VF FH a Syncope SCD Other b Name SIFT score Polyphen score Exon Change in amino acid Global MAF (1000 genome) Global MAF (ESP) 1 27 M ERS3 Y Y Y - Y - - R663C 0.02 0.99 14 c.1987C N T 0 0.000154 2 38 M ERS3 - - Y Y - - - A665T 0.57 0.002 14 c.1993G N A 0.001 N/A 3 63 M BrS + CAD - Y - Y Y ICD - N733D 0.05 0.069 16 c.2197A N G 0 0 4 20 M ERS3 + bradycardia - Y Y - Y - - V734I 0.43 0.002 17 c.2200G N A 0.005 0.009236 5 20 M ERS3 + bradycardia Y Y Y Y Y ICD, quinidine - 6 40 M ERS3 + AVB + bradycardia Y - Y Y - ICD SCN5A 7 20 M ERS2 + bradycardia - - Y - - - CACNA1C 8 25 M ERS2 - - - Y - - SCN10A V1137I 0.76 0.005 27 c.3409G N A 0.0041 0.0082 9 65 M BrS + SQTS Y - Y Y - ICD SCN10A, CACNA1C R1197C 0.05 0.999 29 c.3589C N T 0 0 10 18 M BrS + SAB - Y Y - Y - SCN5A S1402C 0 0.996 34 c.4205C N G 0 0.000077 11 39 M BrS Y - Y Y Y ICD - L1524K fs*5 N/A N/A 38 4570-4572 delTTA InsAAAT 0 0 -: No; Dx: diagnosis; VT/VF: ventricular tachycardia/ventricular fibrillation; SCD: sudden cardiac death; MAF: the minor-allele frequency; 1000 genome: the 1000 Human Genome Project Database; ESP: exome sequencing project; ERS3: early repolarization syndrome type 3; BrS: Brugada syndrome; CAD: coronary artery disease; ICD: implantable cardioverter defibrillator; AVB: atrioventricular block; ERS2: ERS type 2; SQTS: short QT syndrome; SAB: sinoatrial block.
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ABCC9 p.Ser1402Cys 24439875:119:799
status: NEW136 Clinical characteristics of proband and family members with S1402C mutation An 18-year-old male (II-1 in Fig. 3, Patient 10 in Table 2) presented with two episodes of syncope.
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ABCC9 p.Ser1402Cys 24439875:136:60
status: NEW154 Genetic analysis of proband and family members with ABCC9-S1402C mutation The pedigree of Patient 10 in Table 2 is presented in Fig. 3A.
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ABCC9 p.Ser1402Cys 24439875:154:58
status: NEW157 His father carried a heterozygous C4205G transition in ABCC9 predicting a missense mutation S1402C.
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ABCC9 p.Ser1402Cys 24439875:157:92
status: NEW163 Functional expression of ABCC9-S1402C mutation The S1402C missense mutation is located in a highly-conserved region of nucleotide-binding domain (NBD) 2 (Fig. 5A and B).
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ABCC9 p.Ser1402Cys 24439875:163:31
status: NEWX
ABCC9 p.Ser1402Cys 24439875:163:51
status: NEW164 Furthermore, NBD1/NBD2 dimer homology modeling mapped the S1402C substitution adjacent to the conserved linker and chemical knockout/gene complementation (CKC) motifs (Fig. 5C).
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ABCC9 p.Ser1402Cys 24439875:164:58
status: NEW166 Thus, the S1402C mutation, due to its vicinity to the linker motifs, may alter nucleotide-dependent plasmalemmal KATP channel gating.
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ABCC9 p.Ser1402Cys 24439875:166:10
status: NEW167 K2ATP sensitivity of KCNJ11-WT/ABCC9-WT channels was compared with that of KCNJ11-WT/ABCC9-S1402C using excised inside-out patches.
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ABCC9 p.Ser1402Cys 24439875:167:91
status: NEW170 Fig. 6 shows normalized current traces for KCNJ11-WT/ABCC9-WT (Fig. 6A) and KCNJ11-WT/ABCC9-S1402C (Fig. 6B) in control and after exposure to K2ATP.
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ABCC9 p.Ser1402Cys 24439875:170:92
status: NEW173 The IC50 of K2ATP inhibition of KCNJ11-WT/ ABCC9-WT channels (13.4 &#b1; 5 bc;M; n = 6) was significantly higher when compared with that of KCNJ11-WT/ABCC9-S1402C channels (8.5 &#b1; 2 mM; n = 6, p b 0.05).
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ABCC9 p.Ser1402Cys 24439875:173:159
status: NEW220 Thus, mutations that alter nucleotide binding or compromise the cooperative nucleotide-dependent NBD interaction within the regulatory channel subunit, such as S1402C and V734I described in this study, are primary candidates for metabolic sensing deficits underlying cardiac channelopathies.
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ABCC9 p.Ser1402Cys 24439875:220:160
status: NEW227 Mutations that alter nucleotide binding or compromise the cooperative nucleotide-dependent NBD interaction within the regulatory channel subunit, such as the S1402C and V734I described in this study, are primary candidates for metabolic sensing deficits underlying cardiac.
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ABCC9 p.Ser1402Cys 24439875:227:158
status: NEW233 C: Sequence analysis of exon 34 of ABCC9 in patients I-1 and II-1, showing the heterozygous C to G transversion at nucleotide 4205 (arrow), predicting a substitution of cysteine (TGC) for serine (TCC) at position 1402 (S1402C).
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ABCC9 p.Ser1402Cys 24439875:233:219
status: NEW247 0668 0669 0666 0667 Age 44 43 18 16 Sex Male Female Male Male Symptom - - 2 syncopes - ICD implanted - - - - Electrocardiogram HR (bpm) 93 63 (79) 71 (90) 62 PR interval (ms) 155 220 (240) 190 (210) 152 QRS wave (ms) 100 90 (140) 110 (160) 88 QT interval (ms) 350 480 (440) 400 (410) 384 QTc interval (ms) 436 492 (505) 436 (500) 390 ER pattern/J wave + (II, III, avF, V6) + (avR, V1, V2) + (avR, V1, V2) - Ajmaline test N/A + + N/A Cardiac rhythm ERS, PVB CCD, BrS + LQT3 BrS - Genotype SCN5A-E1784K -/- +/- +/- -/- SUR2A-S1402C +/- -/- +/- -/- Values in the parentheses are those after Ajmaline test.
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ABCC9 p.Ser1402Cys 24439875:247:523
status: NEW250 S1402C mutation in ABCC9.
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ABCC9 p.Ser1402Cys 24439875:250:0
status: NEW251 A: Location of S1402C mutation in SUR2A structure within nucleotide binding domain (NBD) 2 is indicated by red dot. WA and WB denote the conserved Walker motifs within ABC protein family that are critical for nucleotide binding.
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ABCC9 p.Ser1402Cys 24439875:251:15
status: NEW253 C: Homology structural model of the NBD1/NBD2 heterodimer maps S1402C mutation to the region adjacent to the conserved NBD2 linker and CKC motifs.
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ABCC9 p.Ser1402Cys 24439875:253:63
status: NEW280 ABCC9-S1402C mutation reduces sensitivity of ATP-sensitive potassium channel (KATP) to ATP.
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ABCC9 p.Ser1402Cys 24439875:280:6
status: NEW283 C: Concentration-response curves for the effects of K2ATP on KCNJ11-wild type (WT)/ABCC9-WT and KCNJ11-WT/ABCC9-S1402C mutant channels.
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ABCC9 p.Ser1402Cys 24439875:283:112
status: NEW285 The half-maximal inhibitory concentration (IC50) value of K2ATP with KCNJ11-WT/ABCC9-WT (13.4 &#b1; 5 bc;M; n = 6) was significantly higher for the KCNJ11-WT/ABCC9-S1402C mutant channel (8.5 &#b1; 2 mM; n = 6, p b 0.05).
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ABCC9 p.Ser1402Cys 24439875:285:167
status: NEW299 An ABCC9-S1402C missense mutation, highly conserved among species and absent in N200 ethnically-matched controls, and a previously reported MI-related ABCC9-V734I mutation, are shown to cause a significant gain of function in KATP current when co-expressed in a heterologous expression system and evaluated using inside-out patch clamp experiments.
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ABCC9 p.Ser1402Cys 24439875:299:9
status: NEW