ABCMdb

PMID: 17245405

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., [PubMed]

Sentences

No. Mutations Sentence Comment

12 ABCC9 p.Thr1547Ile 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 ABCC9 p.Thr1547Ile 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 ABCC9 p.Thr1547Ile (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 ABCC9 p.Thr1547Ile 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 ABCC9 p.Thr1547Ile 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 ABCC9 p.Thr1547Ile 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 ABCC9 p.Thr1547Ile 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 ABCC9 p.Thr1547Ile 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 ABCC9 p.Thr1547Ile ABCC9 p.Thr1547Ile ABCC9 p.Thr1547Ile 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 ABCC9 p.Thr1547Ile (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 ABCC9 p.Thr1547Ile (C) Reduced K+ current response to escalating ADP concentrations in mutant (Thr1547Ile) versus WT KATP channels. Login to comment 68 ABCC9 p.Thr1547Ile (E) The Thr1547Ile mutation did not prevent ATP-induced KATP channel closure, but compromised ADP-dependent channel opening. Login to comment 90 ABCC9 p.Thr1547Ile 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