ABCMdb

ABCC9 p.Ala1513Thr

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Publications

PMID: 20033705 [PubMed] Olson TM et al: "Human K(ATP) channelopathies: diseases of metabolic homeostasis."

No. Sentence Comment

168 Another mutated allele harbored a missense mutation (c.4537G>A) causing the amino acid substitution A1513T. Login to comment
173 Indeed, ATP-induced KATP channel gating was aberrant in channel mutants, suggesting that structural alterations induced by the mutations A1513T and Fs1524 of SUR2A distorted ATP-dependent pore regulation [17]. Login to comment
174 Thus, the mutations A1513T and Fs1524 compromise ATP hydrolysis at SUR2A NBD2, generating distinct reaction kinetic defects. Login to comment
175 Aberrant catalytic properties in the A1513T and Fs1524 mutants translated into abnormal interconversion of discrete conformations in the NBD2 ATPase cycle. Login to comment
176 Alterations in hydrolysis-driven SUR2A conformational probability induced by A1513T and Fs1524 perturbed intrinsic catalytic properties of the SUR2A ATPase, compromising proper translation of cellular energetic signals into KATP channel-mediated membrane electrical events. Login to comment
170 Another mutated allele harbored a missense mutation (c.4537G>A) causing the amino acid substitution A1513T. Login to comment
177 Aberrant catalytic properties in the A1513T and Fs1524 mutants translated into abnormal interconversion of discrete conformations in the NBD2 ATPase cycle. Login to comment
178 Alterations in hydrolysis-driven SUR2A conformational probability induced by A1513T and Fs1524 perturbed intrinsic catalytic properties of the SUR2A ATPase, compromising proper translation of cellular energetic signals into KATP channel-mediated membrane electrical events. Login to comment

PMID: 20664073 [PubMed] Flagg TP et al: "Muscle KATP channels: recent insights to energy sensing and myoprotection."

No. Sentence Comment

248 Consistent with the hypothesis that impaired metabolic sensing by KATP can affect the progression of heart failure, mutations (F1524S and A1513T) within the SUR2 gene locus that reduce the catalytic activity of NBF2, and should therefore reduce physiological activation of the channel, are associated with human dilated cardiomyopathy (38). Login to comment
250 Consistent with the hypothesis that impaired metabolic sensing by KATP can affect the progression of heart failure, mutations (F1524S and A1513T) within the SUR2 gene locus that reduce the catalytic activity of NBF2, and should therefore reduce physiological activation of the channel, are associated with human dilated cardiomyopathy (38). Login to comment
255 Consistent with the hypothesis that impaired metabolic sensing by KATP can affect the progression of heart failure, mutations (F1524S and A1513T) within the SUR2 gene locus that reduce the catalytic activity of NBF2, and should therefore reduce physiological activation of the channel, are associated with human dilated cardiomyopathy (38). Login to comment

PMID: 15034580 [PubMed] Bienengraeber M et al: "ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating."

No. Sentence Comment

2 Published online 21 March 2004; doi:10.1038/ng1329 L E T T E R S 382 VOLUME 36 | NUMBER 4 | APRIL 2004 NATURE GENETICS a b 1310 GEIKI...HRVSSIMDAGLVLVFSEGILVECDTVPNLLAHKNGLFSTLVMTNK* 1549 1310 GEIKI...HRVSSIMDAGLVLVFSEGIKCGV* 1527 4570-4572delTTAinsAAAT (Fs1524) 1310 GEIKI...HRVSSIMDTGLVLVFSEGILVECDTVPNLLAHKNGLFSTLVMTNK* 1549 4537G→A (A1513T) ...HRVSSIMDAGLVLVFSEGILVECDTGPNLLQHKNGLFSTLVMTNK* Rat ...HRVSSIVDAGLVLVFSEGILVECDTGPNLLQHKNGLFSTLVMTNK* Mouse ...HRVSSIVDADLVLVFSEGILVECDTGPNLLTHKNGLFSTLVMTNK* Rabbit ...HRVSSITDADLVLVFSEGILVECDTGPNLLTYRNGLFSTLVMTHK* Guinea pig T A G T G T G A G G T G A T T T T A T G G A G T G T G A G G T G T A A A T T A T G G Asp Cys Glu Val Leu Ile Gly Ter Val Gly Cys Lys Ile Gly G A T C G A T C T T G T T C C G G A C A T A G G T A T T A T T G T T C C G G A C G T A G G T A T T A Val Leu Gly Thr Asp Met Ile Val Leu Gly Ala Asp Met Ile G A T C G A T C COOH 3 4 5 0 1 2 3 Individual 2 3 4 5 Absorbance(mV) 0 1 2 3 Frameshift mutationNormal Missense mutationNormal NormalNormal Time (min)Time (min) Absorbance(mV) Human wild-type Individual 1 NBD1 NBD2 Exon 38 SUR2A Kir6.2   Stress tolerance of the heart requires high-fidelity metabolic sensing by ATP-sensitive potassium (KATP) channels that adjust membrane potential-dependent functions to match cellular energetic demand. Login to comment
11 Sequencing identified frameshift (Fs1524; individual 1) and missense (A1513T; individual 2) mutations. Login to comment
28 The second mutated allele harbored a missense mutation (4537G→A) causing the amino acid substitution A1513T (Fig. 1a). Login to comment
30 The C terminus of SUR proteins contributes to KATP channel traf- ficking19,20, and Fs1524 and A1513T SUR2A mutants, reconstituted with Kir6.2, had reduced expression in the plasma membrane (Fig. 2a). Login to comment
34 (a) Fs1524 and A1513T reduced KATP channel trafficking by ~70% and ~30%, probed immunologically by SUR surface expression in Xenopus laevis oocytes. Login to comment
38 Missense A1513T (cyan) and frameshift L1524 (magenta) mutations frame the β-strand adjacent to Walker motifs that coordinate NBD2-mediated catalysis. Login to comment
44 -6 -5 -4 -3 -2 0.0 0.2 0.4 0.6 0.8 1.0 WT IC50: 19 ± 2µM 0.0 0.1 0.2 0.3 0.4 0.5 WT A1513T Fs1524 a e NBD2 of SUR2A WB WA COOH c WT Fs1524 A1513T 0 30 60 90 b WB WA L1524 A1513 G1514 G1530 V1501 V1342 C1345 L1517 V1518 V1525 E1526 M1472 L1470 d T1502 L1540 E1541 Frameshiftmutation Missense mutation Log[ATP] (M) Singlechannelconductance(pS) Surfaceexpression(a.u.) A1513T IC50: 148 ± 9µM Fs1524 IC50: 51 ± 4µM Relativechannelactivity Table 1 Summary of clinical phenotypes Individual ABCC9 Family history Gender, LVEDD (mm)a EF (%)b Coronary Cardiac rhythmc Outcome mutation of DCM age at diagnosis (y) angiography Individual 1 Frameshift No Male, 55 65 (55) 23 Normal Ventricular Death from (Fs1524) tachycardia heart failure at age 60 y Individual 2 Missense Yes Female, 40 89 (52) 15 Normal Ventricular Under intensive (A1513T) tachycardia therapy Male, 54 81 (53) 13 Normal Ventricular Death from heart Father of individual 2 tachycardia failure at age 55 y aLVEDD, left ventricular end-diastolic dimension. Login to comment
48 L E T T E R S 384 VOLUME 36 | NUMBER 4 | APRIL 2004 NATURE GENETICS -20 -10 0 10 20 40 0.1 0.2 0.3 0.4 0.5 0 5 10 15 20 0 2 4 6 NS 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8e d 209 84 40.6 31.9 18.5 WT MBP 84 84 b ATP Pi Blank MBP WT A1513T Fs1524 MBP-NBD2 c f Fluorescence/[TNP-ATP](a.u./µM) Total [TNP-ATP] (µM) WT Fs1524 A1513T Fluorescence (a.u.) ATPaseactivity -1 (min) [ADP] (mM) [ATP] -1 (mM) ATPaseactivity-1(min) WT Fs1524 A1513T WT Fs1524 A1513T Time (min) Anti-MBP Anti-SUR2A Fs1524 A1513T F(a.u.) a [Pi](µM) WT Fs1524 A1513T 0.00 0.0 1.0 2.0 3.0 4.0 0.12 0.10 0.08 0.06 0.04 0.02 0.00 1.00.50.0 0.20 .3.11.00.50.0-0.5-1.0 30 disrupt folding of the C-terminal β-strand and, thus, the tertiary organization of the adjacent second nucleotide binding domain (NBD2) pocket in SUR2A. Login to comment
49 ATP-induced KATP channel gating was aberrant in both channel mutants (Fig. 2e), suggesting that structural alterations induced by the mutations A1513T and Fs1524 of SUR2A distorted ATP-dependent pore regulation. Login to comment
51 The A1513T and Fs1524 mutations substantially diminished the maximal rate of the NBD2 ATPase reaction without altering the Michaelis-Menten constant of catalysis (Fig. 3d). Login to comment
52 A1513T reduced the product-dependent inhibition of the NBD2 ATPase more substantially than Fs1524 (Fig. 3e) but produced a less severe delay in the pre-steady state profile of product accumulation (Fig. 3f). Login to comment
53 Thus, the mutations A1513T and Fs1524 compromise ATP hydrolysis at SUR2A NBD2, generating distinct reaction kinetic defects. Login to comment
54 Aberrant catalytic properties in the A1513T and Fs1524 mutants translated into abnormal interconversion of discrete conformations in the NBD2 ATPase cycle (Fig. 4a). Login to comment
58 In contrast, the A1513T mutation delayed the ATPase cycle in the SUR-ADP conformation, by reducing the rate constant defining ADP dissociation (k4) by a factor of 2, and reduced the ADP association rate constant (k04) by a factor of 10 (Fig. 4a-c). Login to comment
59 The ATPase cycle in both A1513T and Fs1524 mutants was abnormally delayed in a posthydrolytic conformation, SUR-ADP-Pi or SUR-ADP. Login to comment
62 Consequently, alterations in hydrolysis-driven SUR2A conformational probability induced by A1513T and Fs1524 translated into abnormal ATP sensitivity of mutant channels (Fig. 2e). Login to comment
65 Compared to the wild type and at any given ATP level, A1513T and Fs1524 mutants were less responsive in ADP-induced redistribution of post- (Fig. 4e) and prehydrolytic (Fig. 4f) conformations. Login to comment
68 Thus, the mutations A1513T and Figure 3 SUR2A NBD2 mutants have normal ATP binding but altered ATPase properties. Login to comment
70 An antibody against the last 12 amino acids of SUR2A recognized the wild-type (WT) and A1513T mutant but not Fs1524, whereas an antibody raised against MBP reacted with all constructs. Login to comment
74 (c) The A1513T and Fs1524 NBD2 mutations reduced ATPase activity measured from γ-32P liberation after [γ-32P]ATP hydrolysis. Login to comment
76 (d,e) ATP and ADP dependence of NBD2 ATPase activities measured by spectrophotometry showed vmax values of 9.98 ± 0.34 min-1 in wild-type (WT), 6.07 ± 0.18 min-1 in A1513T and 5.69 ± 0.29 min-1 in Fs1524 with Michaelis-Menten constants at 0.11 ± 0.02, 0.094 ± 0.013 and 0.084 ± 0.010 mM, respectively (equation 3). Login to comment
78 ADP-dependent inhibition of the NBD2 ATPase (at 2 mM ATP) was characterized by an ADP-dissociation constant (KADP) of 8.6 ± 0.3 µM in wild-type versus 24.9 ± 5.6 and 11.0 ± 1.5 in the A1513T and Fs1524 mutants, respectively (equation 5). Login to comment
79 (f) Both pre-steady state and steady-state reaction rates were altered by A1513T and Fs1524 mutations in stopped-flow experiments. Login to comment
104 (c) Rate-limiting steps in the SUR2A ATPase cycle are ADP dissociation (k4) for wild-type (WT), Pi dissociation (k3) for Fs1524 and abnormally increased k4 for A1513T. Login to comment
111 Both Fs1524 and A1513T diminished the ADP-responsiveness of PΣADP and PE-ATP. Login to comment
113 (g) ADP-scavenging creatine kinase (0.01 U ml-1, 5 mM creatine phosphate) accelerates the ATPase in the wild type (WT) but not in Fs1524 and A1513T mutants. Login to comment
115 (h,i) After coexpression of Kir6.2, channel activity, at 0.3 mM ATP, in the presence and absence of 0.3 mM ADP was measured in wild-type (WT; n = 5) SUR2A and in Fs1524 (n = 4) and A1513T (n = 6) SUR2A mutants in inside-out patches. Login to comment

PMID: 20799350 [PubMed] Kelly L et al: "Functional hot spots in human ATP-binding cassette transporter nucleotide binding domains."

No. Sentence Comment

50 Disease-associated nsSNPs at Three Structural Hotspots in Human ABC Transporter NBDs Gene Disease Position ARA motif ABCB11 BRIC2 A570T ABCD1 X-ALD A616V CFTR CF A559T ABCC6 PXE R765Q ABCC8 HHF1 R841G ABCC8 HHF1 R1493Q ABCC8 HHF1 R1493W ABCD1 X-ALD R617C ABCD1 X-ALD R617G ABCD1 X-ALD R617H CFTR CF R560K CFTR CF R560S CFTR CF R560T ABCA1 HDLD1 A1046D ABCB4 ICP A546D C-loop 1 motif ABCC8 HHF1 D1471H ABCC8 HHF1 D1471N CFTR CBAVD G544V ABCC8 HHF1 G1478R C-loop2 motif ABCA4 STGD1 H2128R ABCC8 HHF1 K889T ABCD1 X-ALD R660P ABCD1 X-ALD R660W ABCA1 HDLD2 M1091T ABCA4 STGD1 E2131K ABCA12 LI2 E1539K ABCA4 STGD1 and CORD3 E1122K CFTR CF L610S ABCC8 HHF1 L1543P ABCA1 Colorectal cancer sample; somatic mutation A2109T ABCC9 CMD1O A1513T ABCD1 X-ALD H667D CFTR CF A613T ABCA1 HDLD2 D1099Y ABCD1 X-ALD T668I CFTR CF D614G ABCA4 STGD1 R2139W ABCA4 STGD1 R1129C ABCA4 ARMD2, STGD1, and FFM R1129L Disease abbreviations are as follows: BRIC2, benign recurrent intrahepatic cholestasis type 2; X-ALD, X-linked adrenoleukodystrophy; CF, cystic fibrosis; PXE, Pseudoxanthoma elasticum; HHF1, familial hyperinsulinemic hypoglycemia-1; HDLD1, high density lipoprotein deficiency type 1; ICP, intrahepatic cholestasis of pregnancy; CBAVD, congenital bilateral absence of the vas deferens; STGD1, Stargardt disease type 1; HDLD2, high density lipoprotein deficiency type 2; LI2, ichthyosis lamellar type 2; CORD3, cone-rod dystrophy type 3; CMD1O, cardiomyopathy dilated type 1O; ARMD2, age-related macular degeneration type 2; FFM, fundus flavimaculatus. Login to comment

PMID: 19919849 [PubMed] Park S et al: "Quaternary structure of KATP channel SUR2A nucleotide binding domains resolved by synchrotron radiation X-ray scattering."

No. Sentence Comment

150 This includes the NBD1 V734I variant (Fig. 5A), associated with myocardial infarction, and the NBD2 A1513T and T1547I mutations implicated in dilated cardiomyopathy and stress-induced atrial fibrillation, respectively (Fig. 5B). Login to comment

PMID: 26226329 [PubMed] Nelson PT et al: "ABCC9/SUR2 in the brain: Implications for hippocampal sclerosis of aging and a potential therapeutic target."

No. Sentence Comment

1219 Clinical condition/ endophenotype Mutation Type* Notes (Refs) Cantu syndrome E, I Apparent autosomal dominant inheritance of functional gain of toxic function; many mutations identified, mostly in exons coding transmembrane domains of SUR2 protein Harakalova et al. (2012); van Bon et al. (2012) Atrial fibrillation E Case of mutation [Thr1547Ile] associated with atrial fibrillation originating in the vein of Marshal Olson, et al. (2007) Dilated cardiomyopathy E Two cases with distinct mutations [frameshift1524, A1513T] associated with dilated cardiomyopathy Bienengraeber et al. (2004) Myocardial infarction, early repolarization syndrome (ERS), and Brugada syndrome (BrS) E Coronary arterial vasospam and myocardial infarction linked to V734I mutation. Login to comment