ABCMdb

ABCC9 p.Thr1547Ile

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Publications

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

No. Sentence Comment

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

PMID: 18239147 [PubMed] Burke MA et al: "The sulfonylurea receptor, an atypical ATP-binding cassette protein, and its regulation of the KATP channel."

No. Sentence Comment

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

PMID: 17245405 [PubMed] Olson TM et al: "KATP channel mutation confers risk for vein of Marshall adrenergic atrial fibrillation."

No. Sentence Comment

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

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
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

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