ABCMdb

ABCC9 p.Thr1547Ile

ClinVar:	c.4640C>T , p.Thr1547Ile D , Pathogenic
Predicted by SNAP2:	A: N (78%), C: D (53%), D: D (71%), E: N (61%), F: D (63%), G: N (61%), H: N (66%), I: N (61%), K: N (78%), L: N (53%), M: N (61%), N: D (59%), P: D (71%), Q: N (93%), R: N (53%), S: N (87%), V: N (61%), W: D (66%), Y: D (63%),
Predicted by PROVEAN:	A: N, C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, V: N, W: D, Y: N,

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[hide] Human K(ATP) channelopathies: diseases of metaboli... Pflugers Arch. 2010 Jul;460(2):295-306. Epub 2009 Dec 24. Olson TM, Terzic A
Human K(ATP) channelopathies: diseases of metabolic homeostasis.
Pflugers Arch. 2010 Jul;460(2):295-306. Epub 2009 Dec 24., [PMID:20033705]

Abstract [show]
Assembly of an inward rectifier K+ channel pore (Kir6.1/Kir6.2) and an adenosine triphosphate (ATP)-binding regulatory subunit (SUR1/SUR2A/SUR2B) forms ATP-sensitive K+ (KATP) channel heteromultimers, widely distributed in metabolically active tissues throughout the body. KATP channels are metabolism-gated biosensors functioning as molecular rheostats that adjust membrane potential-dependent functions to match cellular energetic demands. Vital in the adaptive response to (patho)physiological stress, KATP channels serve a homeostatic role ranging from glucose regulation to cardioprotection. Accordingly, genetic variation in KATP channel subunits has been linked to the etiology of life-threatening human diseases. In particular, pathogenic mutations in KATP channels have been identified in insulin secretion disorders, namely, congenital hyperinsulinism and neonatal diabetes. Moreover, KATP channel defects underlie the triad of developmental delay, epilepsy, and neonatal diabetes (DEND syndrome). KATP channelopathies implicated in patients with mechanical and/or electrical heart disease include dilated cardiomyopathy (with ventricular arrhythmia; CMD1O) and adrenergic atrial fibrillation. A common Kir6.2 E23K polymorphism has been associated with late-onset diabetes and as a risk factor for maladaptive cardiac remodeling in the community-at-large and abnormal cardiopulmonary exercise stress performance in patients with heart failure. The overall mutation frequency within KATP channel genes and the spectrum of genotype-phenotype relationships remain to be established, while predicting consequences of a deficit in channel function is becoming increasingly feasible through systems biology approaches. Thus, advances in molecular medicine in the emerging field of human KATP channelopathies offer new opportunities for targeted individualized screening, early diagnosis, and tailored therapy.

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139 Identified in exon 38, specific for the cardiac splice variant of SUR2A, this heterozygous c.4640C>T transition caused substitution of the threonine residue at amino acid position 1547 with isoleucine (T1547I). Login to comment
143 Patch-clamp recording demonstrated that the T1547I substitution compromised adenine nucleotide-dependent induction of KATP channel current [89]. Login to comment
144 Mutant T1547I SUR2A, coexpressed with the KCNJ11-encoded Kir6.2 pore, generated an aberrant channel that retained ATP-induced inhibition of potassium current but demonstrated a blunted response to ADP. Login to comment
145 A deficit in nucleotide gating, resulting from the T1547I mutation, would compromise the homeostatic role of the KATP channel required for proper readout of cellular distress and maintenance of electrical stability. Login to comment
141 Identified in exon 38, specific for the cardiac splice variant of SUR2A, this heterozygous c.4640C>T transition caused substitution of the threonine residue at amino acid position 1547 with isoleucine (T1547I). Login to comment
146 Mutant T1547I SUR2A, coexpressed with the KCNJ11-encoded Kir6.2 pore, generated an aberrant channel that retained ATP-induced inhibition of potassium current but demonstrated a blunted response to ADP. Login to comment
147 A deficit in nucleotide gating, resulting from the T1547I mutation, would compromise the homeostatic role of the KATP channel required for proper readout of cellular distress and maintenance of electrical stability. Login to comment

[hide] The sulfonylurea receptor, an atypical ATP-binding... Circ Res. 2008 Feb 1;102(2):164-76. Burke MA, Mutharasan RK, Ardehali H
The sulfonylurea receptor, an atypical ATP-binding cassette protein, and its regulation of the KATP channel.
Circ Res. 2008 Feb 1;102(2):164-76., [PMID:18239147]

Abstract [show]
ATP-binding cassette (ABC) proteins are highly conserved and widely expressed throughout nature and found in all organisms, both prokaryotic and eukaryotic. They mediate myriad critical cellular processes, from nutrient import to toxin efflux using the energy derived from ATP hydrolysis. Most ABC proteins mediate transport of substances across lipid membranes. However, there are atypical ABC proteins that mediate other processes. These include, but are not limited to, DNA repair (bacterial MutS), ion transport (cystic fibrosis transmembrane receptor), and mRNA trafficking (yeast Elf1p). The sulfonylurea receptor (SUR) is another atypical ABC protein that regulates activity of the potassium ATP channel (K(ATP)). K(ATP) is widely expressed in nearly all tissues of higher organisms and couples cellular energy status to membrane potential. K(ATP) is particularly important in the regulation of insulin secretion from pancreatic beta-cells and in regulating action potential duration in muscle cells. SUR is indispensable for normal channel function, and mutations in genes encoding SURs increase the susceptibility to diabetes, myocardial infarction, and heart failure. Here, we review the structure and function of ABC proteins and discuss SUR, its regulation of the K(ATP) channel, and its role in cardiovascular disease.

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178 Another ABCC9 mutation in SUR2A has been identified recently in a patient with adrenergic-inducible atrial fibrillation.141 This mutation, T1547I, occurs at a highly conserved residue in the unique C-terminal 42-aa domain of SUR2A. Login to comment
179 As previously stated, this domain constitutes the only difference between SUR2A and SUR2B and is thought to play a major role in the differential gating exhibited by these 2 isoforms.113 This residue is predicted to be in close proximity to the Walker A motif of NBD2, and the T1547I mutation alters the normal hydrogen bonding that stabilizes this motif.141 This mutant SUR2A, coexpressed with Kir6.2, showed reduced responsiveness to ADP, while retaining the normal inhibitory effects of ATP, thus resulting in decreased channel gating.141 Experimental evidence also supports a possible role for SUR2A in ischemic heart disease. Login to comment

[hide] KATP channel mutation confers risk for vein of Mar... Nat Clin Pract Cardiovasc Med. 2007 Feb;4(2):110-6. Olson TM, Alekseev AE, Moreau C, Liu XK, Zingman LV, Miki T, Seino S, Asirvatham SJ, Jahangir A, Terzic A
KATP channel mutation confers risk for vein of Marshall adrenergic atrial fibrillation.
Nat Clin Pract Cardiovasc Med. 2007 Feb;4(2):110-6., [PMID:17245405]

Abstract [show]
BACKGROUND: A 53-year-old female presented with a 10-year history of paroxysmal atrial fibrillation (AF), precipitated by activity and refractory to medical therapy. In the absence of traditional risk factors for disease, a genetic defect in electrical homeostasis underlying stress-induced AF was explored. INVESTIGATIONS: Echocardiography, cardiac perfusion stress imaging, invasive electrophysiology with isoproterenol provocation, genomic DNA sequencing of K(ATP) channel genes, exclusion of mutation in 2,000 individuals free of AF, reconstitution of channel defect with molecular phenotyping, and verification of pathogenic link in targeted knockout. DIAGNOSIS: K(ATP) channelopathy caused by missense mutation (Thr1547Ile) of the ABCC9 gene conferring predisposition to adrenergic AF originating from the vein of Marshall. MANAGEMENT: Disruption of arrhythmogenic gene-environment substrate at the vein of Marshall by radiofrequency ablation.

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12 Diagnosis KATP channelopathy caused by missense mutation (Thr1547Ile) of the ABCC9 gene conferring predisposition to adrenergic AF originating from the vein of Marshall. Login to comment
16 Correspondence *Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA olson.timothy@mayo.edu terzic.andre@mayo.edu Received 19 July 2006 Accepted 12 October 2006 www.nature.com/clinicalpractice doi:10.1038/ncpcardio0792 SUMMARY 110 NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE FEBRUARY 2007 VOL 4 NO 2 0.5s V1 RVA HRA HIS Superior vena cava Vein of Marshall Coronary sinus MAP catheter Left atrium Pulmonary veins Homo sapiens normal...HRVSSIMDAGLVLVFSEGILVECDTVPNLLAHKNGLFSTLVMTNK* 4640C>T (Thr1547Ile) mutant...HRVSSIMDAGLVLVFSEGILVECDTVPNLLAHKNGLFSTLVMINK* Mus musculus ...HRVSSIVDAGLVLVFSEGILVECDTGPNLLQHKNGLFSTLVMTNK* Rattus norvegicus ...HRVSSIMDAGLVLVFSEGILVECDTGPNLLQHKNGLFSTLVMTNK* Oryctolagus cuniculus ...HRVSSIVDADLVLVFSEGILVECDTGPNLLTHKNGLFSTLVMTNK* Cavia porcellus ...HRVSSITDADLVLVFSEGILVECDTGPNLLTYRNGLFSTLVMTHK* Inferior vena cava CS catheter HRA catheter HIS catheter RVA catheter Map p Map d CS Thr1547lle A B E Homo sapiens SUR2A...HRVSSIMDA GLVLVFSEGILVECDTVPNLFAHKNGPFSTLVMTNK* Homo sapiens SUR2B...HRVHTILTADLVIVMKRGNILEYDTPESLLAQENGVFASFVRADM* Homo sapiens SUR1 ...HRVHTILS ADLVIVLKRGAILEFDKPEKLLSRKDSVFASFVRADK* G F NBD2 of SUR2A WB WB COOH Thr1547 42 aa carboxy-terminal tail 42-amino acid carboxy-terminal tail WA WA C D T ...G G T G A T G A C C A A C A A G T A G Figure 1 Mutation in ABCC9, which encodes the SUR2A KATP channel subunit, in a patient with AF originating from the vein of Marshall. Login to comment
19 (D) Sequencing of the patient`s DNA identified a heterozygous missense mutation (4640C>T) causing substitution of the 1547 threonine residue for isoleucine (Thr1547Ile) in exon 38 of ABCC9. Login to comment
31 To exclude the possibility that the Thr1547Ile substitution was a polymorphism in the general population, 4,000 chromosomes in 2,000 unrelated, healthy and predominantly white individuals were tested by heteroduplex analysis.4 All samples scanned were negative for the 4640C>T defect in exon 38, implicating the genetic anomaly as a pathogenic mutation. Login to comment
32 To determine the consequences of the patient`s Thr1547Ile mutation on channel structure, the regulatory SUR2A subunit of the KATP channel was compared with its orthologs and isoforms. Login to comment
35 To replicate the disease mutation and assess the effects of altered KATP channel structure on function, recombinant constructs of channel genes were expressed in cultured cells.4 Patch-clamp recording demonstrated that the Thr1547Ile substitution compromised adenine nucleotide-dependent induction of KATP channel current (Figure 2B). Login to comment
36 Mutant Thr1547Ile SUR2A, coexpressed with the KCNJII-encoded Kir6.2 pore, generated an aberrant channel that retained ATP-induced inhibition of potassium current, but demonstrated a blunted response to ADP (Figure 2B-D). Login to comment
37 A deficit in nucleotide gating, resulting from the Thr1547Ile mutation, would compromise the homeostatic role of the KATP channel required for proper readout of cellular distress and maintenance of electrical stability (Figure 2E). Login to comment
59 Radiofrequency ablation is indicated for symptom control in 40 - 30 - 20 - 10 - 0 - 0.01 0.03 0.10 0.30 [ADP] (mM) WT Thr1547lle ADP-induced KATPcurrent(%) C 1.0 - 0.8 - 0.6 - 0.4 - 0.2 - 0.0 - -5 -4 -3 -2 Log[ATP] (M) Thr1547lle WT Relativechannel activity D 100 - 80 - 60 - 40 - 20 - 0 - 50 10 15 20 Time after isoproterenol injection (min) Knockout n=10 WT n=10 AF-freerhythm(%) G Kir6.2SUR2A Normal A Subject with intact KATP channels B F NBD1 ADP 0.3 mM ATP 0.3 mM ATP ADP K+ K+ K+ K+ NBD2 NH2 NH2 COOH COOH L L Normal E Patient with Thr1547Ile mutation NH2 NH2 COOH L L Stress WT Thr1547lle WT Knockout NH2 NH2 COOH WA L L Stress Thr1547Ile Thr1547Ile NH2 NH2 COOH L L COOHCOOH COOH ADP 0.3 mM ATP 0.3 mM 2.0 20s 30 pA 0.2s 20s 30 pA WB WA WB WA WB WA WB WA WB WA WB WA WB WA WB Figure 2 The ABCC9 mutation disrupts KATP channel function, with the disease phenotype verified in an adrenergically stressed gene knockout model. Login to comment
63 (B) Compared with the WT subunit, mutant SUR2A (Thr1547Ile) coexpressed with Kir6.2 demonstrated aberrant KATP channel function, characterized by defective response to ADP in patch-clamp recordings. Login to comment
64 (C) Reduced K+ current response to escalating ADP concentrations in mutant (Thr1547Ile) versus WT KATP channels. Login to comment
68 (E) The Thr1547Ile mutation did not prevent ATP-induced KATP channel closure, but compromised ADP-dependent channel opening. Login to comment
90 Subsequent targeted screening for the Thr1547Ile SUR2A mutation in patients (n=154) with diverse presentations of AF indicate that this specific genetic substitution is not common. Login to comment

[hide] Quaternary structure of KATP channel SUR2A nucleot... J Struct Biol. 2010 Feb;169(2):243-51. doi: 10.1016/j.jsb.2009.11.005. Epub 2009 Nov 15. Park S, Terzic A
Quaternary structure of KATP channel SUR2A nucleotide binding domains resolved by synchrotron radiation X-ray scattering.
J Struct Biol. 2010 Feb;169(2):243-51. doi: 10.1016/j.jsb.2009.11.005. Epub 2009 Nov 15., [PMID:19919849]

Abstract [show]
Heterodimeric nucleotide binding domains NBD1/NBD2 distinguish the ATP-binding cassette protein SUR2A, a recognized regulatory subunit of cardiac ATP-sensitive K(+) (K(ATP)) channels. The tandem function of these core domains ensures metabolism-dependent gating of the Kir6.2 channel pore, yet their structural arrangement has not been resolved. Here, purified monodisperse and interference-free recombinant particles were subjected to synchrotron radiation small-angle X-ray scattering (SAXS) in solution. Intensity function analysis of SAXS profiles resolved NBD1 and NBD2 as octamers. Implemented by ab initio simulated annealing, shape determination prioritized an oblong envelope wrapping NBD1 and NBD2 with respective dimensions of 168x80x37A(3) and 175x81x37A(3) based on symmetry constraints, validated by atomic force microscopy. Docking crystal structure homology models against SAXS data reconstructed the NBD ensemble surrounding an inner cleft suitable for Kir6.2 insertion. Human heart disease-associated mutations introduced in silico verified the criticality of the mapped protein-protein interface. The resolved quaternary structure delineates thereby a macromolecular arrangement of K(ATP) channel SUR2A regulatory domains.

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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
153 While the monomeric structure could not decisively address the structural consequences of either V734I or T1547I mutations due to their remote positions from critical functional motifs (Fig. 5A and B), resolved heterodimer and Fig. 3. Login to comment
160 Specifically, the NBD2 T1547I, whereby a nucleophilic residue is substituted with a somewhat larger hydrophobic residue found at the tail of the isoform-specific SUR2A C-terminal a-helix (Fig. 5B), compromised solvent accessibility due to proximity from the NBD1/NBD2 heterodimer interface (Fig. 5C). Login to comment

[hide] ABCC9/SUR2 in the brain: Implications for hippocam... Ageing Res Rev. 2015 Nov;24(Pt B):111-25. doi: 10.1016/j.arr.2015.07.007. Epub 2015 Jul 28. Nelson PT, Jicha GA, Wang WX, Ighodaro E, Artiushin S, Nichols CG, Fardo DW
ABCC9/SUR2 in the brain: Implications for hippocampal sclerosis of aging and a potential therapeutic target.
Ageing Res Rev. 2015 Nov;24(Pt B):111-25. doi: 10.1016/j.arr.2015.07.007. Epub 2015 Jul 28., [PMID:26226329]

Abstract [show]
The ABCC9 gene and its polypeptide product, SUR2, are increasingly implicated in human neurologic disease, including prevalent diseases of the aged brain. SUR2 proteins are a component of the ATP-sensitive potassium ("KATP") channel, a metabolic sensor for stress and/or hypoxia that has been shown to change in aging. The KATP channel also helps regulate the neurovascular unit. Most brain cell types express SUR2, including neurons, astrocytes, oligodendrocytes, microglia, vascular smooth muscle, pericytes, and endothelial cells. Thus it is not surprising that ABCC9 gene variants are associated with risk for human brain diseases. For example, Cantu syndrome is a result of ABCC9 mutations; we discuss neurologic manifestations of this genetic syndrome. More common brain disorders linked to ABCC9 gene variants include hippocampal sclerosis of aging (HS-Aging), sleep disorders, and depression. HS-Aging is a prevalent neurological disease with pathologic features of both neurodegenerative (aberrant TDP-43) and cerebrovascular (arteriolosclerosis) disease. As to potential therapeutic intervention, the human pharmacopeia features both SUR2 agonists and antagonists, so ABCC9/SUR2 may provide a "druggable target", relevant perhaps to both HS-Aging and Alzheimer's disease. We conclude that more work is required to better understand the roles of ABCC9/SUR2 in the human brain during health and disease conditions.

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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