ABCMdb

PMID: 24439875

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., [PubMed]

Sentences

No. Mutations Sentence Comment

5 ABCC9 p.Val734Ile Four probands, diagnosed with ERS, carried a highly-conserved mutation, V734I-ABCC9. Login to comment 6 ABCC9 p.Val734Ile Functional expression of the V734I variant yielded a Mg-ATP IC50 that was 5-fold that of wild-type (WT). Login to comment 7 ABCC9 p.Ser1402Cys 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. Login to comment 8 ABCC9 p.Ser1402Cys 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). Login to comment 50 ABCC9 p.Val734Ile ABCC9 p.Ser1402Cys 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). Login to comment 102 ABCC9 p.Val734Ile ABCC9 p.Val734Ile Clinical characteristics and genetic analysis of probands with ABCC9-V734I mutation Four probands were found to carry an ABCC9-V734I mutation. Login to comment 119 ABCC9 p.Val734Ile ABCC9 p.Ser1402Cys ABCC9 p.Arg663Cys ABCC9 p.Arg1197Cys ABCC9 p.Ala665Thr ABCC9 p.Asn733Asp ABCC9 p.Leu1524Lys 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. Login to comment 126 ABCC9 p.Val734Ile ABCC9 p.Val734Ile Genetic screening revealed that all four cases had a c.2200G N A transition in exon 17 predicting substitution of an isoleucine for a valine at position 734 of ABBCC9 (V734I, Fig. 2B). Login to comment 131 ABCC9 p.Val734Ile ABCC9 p.Val734Ile Functional expression of ABCC9-V734I mutation Expression studies using inside-out patch clamp techniques to evaluate the effect of the mutation were performed with ABCC9-V734I coexpressed with KCNJ11-WT. Login to comment 133 ABCC9 p.Val734Ile ABCC9 p.Val734Ile The IC50 value of Mg-ATP for the mutant KCNJ11-WT/ABCC9-V734I was 5 fold that of WT (97 &#b1; 22 bc;M for WT, n = 5; 510 &#b1; 29 bc;M for V734I, n = 5; Fig. 2D & E). Login to comment 136 ABCC9 p.Ser1402Cys 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. Login to comment 141 ABCC9 p.Val734Ile Electrocardiograms (ECGs) of ABCC9-V734I variant carriers (Probands 4, 5 and 6 in Table 2). Login to comment 154 ABCC9 p.Ser1402Cys Genetic analysis of proband and family members with ABCC9-S1402C mutation The pedigree of Patient 10 in Table 2 is presented in Fig. 3A. Login to comment 157 ABCC9 p.Ser1402Cys His father carried a heterozygous C4205G transition in ABCC9 predicting a missense mutation S1402C. Login to comment 163 ABCC9 p.Ser1402Cys ABCC9 p.Ser1402Cys 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). Login to comment 164 ABCC9 p.Ser1402Cys Furthermore, NBD1/NBD2 dimer homology modeling mapped the S1402C substitution adjacent to the conserved linker and chemical knockout/gene complementation (CKC) motifs (Fig. 5C). Login to comment 166 ABCC9 p.Ser1402Cys Thus, the S1402C mutation, due to its vicinity to the linker motifs, may alter nucleotide-dependent plasmalemmal KATP channel gating. Login to comment 167 ABCC9 p.Ser1402Cys K2ATP sensitivity of KCNJ11-WT/ABCC9-WT channels was compared with that of KCNJ11-WT/ABCC9-S1402C using excised inside-out patches. Login to comment 170 ABCC9 p.Ser1402Cys 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. Login to comment 173 ABCC9 p.Ser1402Cys 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). Login to comment 177 ABCC9 p.Val734Ile ABCC9-V734I mutation causes a gain of function in ATP-sensitive potassium channel (KATP) activity by reducing sensitivity of KATP channels to ATP. Login to comment 179 ABCC9 p.Val734Ile B: Chromatogram showing a heterozygous G-to-A transition at nucleotide 2200 (exon 17) in ABCC9, predicting a substitution of Isoleucine (I) for Valine (V) at residue 734 (V734I). Login to comment 181 ABCC9 p.Val734Ile D: Sensitivity to ATP of KCNJ11-WT/ABCC9-WT and KCNJ11-WT/ABCC9-V734I channels measured using an excised inside-out patch. Login to comment 182 ABCC9 p.Val734Ile E: Graph depicting IC50 for Mg-ATP inhibition of IK-ATP for ABCC9-WT and V734I channels. Login to comment 220 ABCC9 p.Val734Ile ABCC9 p.Ser1402Cys 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. Login to comment 221 ABCC9 p.Val734Ile Using synchrotron radiation X-ray scattering, we also demonstrated that V734I can disrupt protein-protein interaction critical for the structural integrity of the KATP channel complex [20]. Login to comment 227 ABCC9 p.Val734Ile ABCC9 p.Ser1402Cys 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. Login to comment 233 ABCC9 p.Ser1402Cys 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). Login to comment 234 ABCC9 p.Val734Ile scattering, we recently demonstrated that V734I of SUR2A can disrupt protein-protein interaction critical for the structural integrity of the KATP channel complex [20]. Login to comment 236 ABCC9 p.Val734Ile In a cohort of patients with MI at an early age, a rare missense variant V734I in the ABCC9 gene was found to be over-represented [34]. Login to comment 247 ABCC9 p.Ser1402Cys 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. Login to comment 250 ABCC9 p.Ser1402Cys S1402C mutation in ABCC9. Login to comment 251 ABCC9 p.Ser1402Cys 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. Login to comment 253 ABCC9 p.Ser1402Cys C: Homology structural model of the NBD1/NBD2 heterodimer maps S1402C mutation to the region adjacent to the conserved NBD2 linker and CKC motifs. Login to comment 257 ABCC9 p.Val734Ile A gain of function in IK-ATP secondary to a mutation in ABCC9, V734I, was also found to be associated with an ERS phenotype in Probands 4 to 7 in Table 2. Login to comment 258 ABCC9 p.Val734Ile With this finding, our study expands the spectrum of ABCC9-V734I variant beyond MI-related arrhythmogenesis, demonstrating its association with ERS-mediated ventricular arrhythmias. Login to comment 262 ABCC9 p.Val734Ile Interestingly, a recent study reported that V734I reduced the sensitivity of Kir6.2/SUR2B channels but not of Kir6.2/SUR2A or Kir6.1/ SUR2B channels, to MgATP inhibition [36]. Login to comment 280 ABCC9 p.Ser1402Cys ABCC9-S1402C mutation reduces sensitivity of ATP-sensitive potassium channel (KATP) to ATP. Login to comment 283 ABCC9 p.Ser1402Cys C: Concentration-response curves for the effects of K2ATP on KCNJ11-wild type (WT)/ABCC9-WT and KCNJ11-WT/ABCC9-S1402C mutant channels. Login to comment 285 ABCC9 p.Ser1402Cys 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). Login to comment 299 ABCC9 p.Val734Ile ABCC9 p.Ser1402Cys 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. Login to comment 315 ABCC9 p.Val734Ile ABCC9 p.Arg1197Cys R1197C was identified as a newly-identified mutation and V734I was the most frequently encountered variant. Login to comment