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ABCC9 Mutations Identified in Human Dilated Cardiomyopathy Disrupt

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ABCC9 Mutations Identified in Human Dilated Cardiomyopathy Disrupt LETTERS ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating Martin Bienengraeber1,2, Timothy M Olson1,3, Vitaliy A Selivanov1, Eva C Kathmann1,2, Fearghas O’Cochlain1, Fan Gao2, Amy B Karger1,2, Jeffrey D Ballew1, Denice M Hodgson1, Leonid V Zingman1,2, Yuan-Ping Pang2, Alexey E Alekseev1,2 & Andre Terzic1,2 Stress tolerance of the heart requires high-fidelity metabolic sensing by ATP-sensitive potassium (KATP) channels that adjust a SUR2A Kir6.2 membrane potential–dependent functions to match cellular http://www.nature.com/naturegenetics energetic demand. Scanning of genomic DNA from individuals with heart failure and rhythm disturbances due to idiopathic COOH dilated cardiomyopathy identified two mutations in ABCC9, NBD1 NBD2 Exon 38 which encodes the regulatory SUR2A subunit of the cardiac KATP channel. These missense and frameshift mutations mapped to evolutionarily conserved domains adjacent to the catalytic Individual 1 Individual 2 V) ATPase pocket within SUR2A. Mutant SUR2A proteins showed 3 3 Normal Normal aberrant redistribution of conformations in the intrinsic ATP 2 2 hydrolytic cycle, translating into abnormal KATP channel 1 1 phenotypes with compromised metabolic signal decoding. Absorbance (m Absorbance (mV) 0 0 Defective catalysis-mediated pore regulation is thus a 345 345 Time (min) Time (min) mechanism for channel dysfunction and susceptibility to dilated cardiomyopathy. T A T T © 2004 Nature Publishing Group Asp A G Ter Val T T Val G T G Missense G T G T Normal mutation T Cardiac KATP channels are heteromultimers composed of Kir6.2, an Frameshift Cys G Normal mutation T Val Leu T T Leu inwardly rectifying potassium channel pore, and the regulatory T G C C SUR2A subunit, an ATPase-harboring ATP-binding cassette pro- G A C C Glu A G Gly Gly G G Gly 1–4 tein . The SUR2A subunit recognizes and processes intracellular G G G G energetic signals, through its nucleotide binding domains, endowing G T A A Val T G A T C G A T C G Cys Ala C C Thr G T G A A A T G A T C G A T C T Leu T A Lys Asp A A Asp Figure 1 KATP channel mutations in dilated cardiomyopathy. (a) The T A G G regulatory SUR2A subunit (nucleotide-binding domains NBD1 and NBD2 T T G G Ile T T Ile Met T T Met with Walker A and B motifs and a linker L region) forms cardiac KATP A A A A channels by assembling with the pore-forming Kir6.2 subunit T T T T Gly G G Gly Ile T T Ile (transmembrane domains M1 and M2). Analysis of exon 38 in ABCC9 G G A A genomic DNA, which encodes the C terminus of the SUR2A protein, identified abnormal chromatograms indicative of mutations in individuals with dilated cardiomyopathy (DCM). Sequencing identified frameshift b (Fs1524; individual 1) and missense (A1513T; individual 2) mutations. The family of individual 1 was unavailable for segregation analysis. The mutation 1310 GEIKI...HRVSSIMDAGLVLVFSEGILVECDTVPNLLAHKNGLFSTLVMTNK* 1549 Human wild-type 1310 GEIKI...HRVSSIMDAGLVLVFSEGIKCGV* 1527 4570-4572delTTAinsAAAT (Fs1524) in individual 2 was not present in the proband’s mother, suggestive of 1310 GEIKI...HRVSSIMDTGLVLVFSEGILVECDTVPNLLAHKNGLFSTLVMTNK* 1549 4537G →A (A1513T) inheritance from the affected father (DNA was unavailable). (b) SUR2A ...HRVSSIMDAGLVLVFSEGILVECDTGPNLLQHKNGLFSTLVMTNK* Rat residues encoded by exon 38 in wild-type and mutant ABCC9 sequences in ...HRVSSIVDAGLVLVFSEGILVECDTGPNLLQHKNGLFSTLVMTNK* Mouse ...HRVSSIVDADLVLVFSEGILVECDTGPNLLTHKNGLFSTLVMTNK* Rabbit humans and other species. ...HRVSSITDADLVLVFSEGILVECDTGPNLLTYRNGLFSTLVMTHK* Guinea pig 1Division of Cardiovascular Diseases, Department of Medicine; 2Department of Molecular Pharmacology and Experimental Therapeutics; and 3Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Mayo Foundation, Rochester, Minnesota 55905, USA. Correspondence should be addressed to A.T. ([email protected]). Published online 21 March 2004; doi:10.1038/ng1329 382 VOLUME 36 | NUMBER 4 | APRIL 2004 NATURE GENETICS LETTERS 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. The 95th percentile values are given in parentheses. bEF, left ventricular ejection fraction. cCardiac rhythm was documented by electrocardiographic monitoring. the KATP channel-enzyme complex with a metabolic decoding capac- Scans for mutation in genomic DNA in a cohort of 323 individuals ity5. Potassium movement through Kir6.2 does not require energy with idiopathic dilated cardiomyopathy identified two heterozygous expenditure6, yet ATP hydrolysis at SUR2A is integral in the transduc- mutations in exon 38 of ABCC9,which encodes the C-terminal tion of metabolic signals from cellular energetic pathways to the chan- domain of SUR2A specific to the cardiac splice variant of the regula- 5,7 nel pore . In this way, KATP channels set membrane excitability in tory KATP channel subunit (Fig. 1a,b). Both individuals with muta- response to stress challenge and preserve cellular energy-dependent tions in ABCC9 had severely dilated hearts with compromised 8–12 functions . Thereby, the KATP channel complex has a vital role in contractile function and rhythm disturbances (Table 1). DNA securing cellular homeostasis under stress12. sequencing of one mutated allele identified a 3-bp deletion and 4-bp Disease-induced KATP channel dysregulation, recently recognized in insertion mutation (4570-4572delTTAinsAAAT), causing a frameshift a transgenic model of cardiomyopathy, has been associated with com- at Leu1524 and introducing four anomalous terminal residues fol- http://www.nature.com/naturegenetics promised stress tolerance13. In fact, in the stressed heart, knockout of lowed by a premature stop codon (Fs1524; Fig. 1a). The second → KATP channel genes precipitates intracellular calcium overload predis- mutated allele harbored a missense mutation (4537G A) causing the posing to myocardial damage, arrhythmia and death preventable by amino acid substitution A1513T (Fig. 1a). The identified frameshift 12 calcium-channel blockade . Indeed, KATP channel–deficient hearts and missense mutations occurred in evolutionarily conserved are susceptible to calcium-dependent maladaptive remodeling under domains of the C terminus of SUR2A (Fig. 1b), and neither mutation chronic hemodynamic load, progressing to congestive heart failure was present in 500 unrelated control individuals. (G.C. Kane, F.O., D.M.H., T. Miki, S. Seino and A.T., unpublished The C terminus of SUR proteins contributes to KATP channel traf- data). Although improper myocellular calcium handling contributes ficking19,20, and Fs1524 and A1513T SUR2A mutants, reconstituted to the pathogenesis of dilated cardiomyopathy14,15, a malignant disor- with Kir6.2, had reduced expression in the plasma membrane (Fig. der characterized by heart failure and increased susceptibility to meta- 2a). Yet, mutant KATP channel complexes formed functional channels 16–18 bolic stressors , little is known about KATP channels in human with intact pore properties (Fig. 2b). Structural molecular dynamics heart disease. Here, we report the first mutations in ABCC9, encoding simulation showed that the residues Ala1513 and Leu1524 flank the C- SUR2A. Identified in individuals with idiopathic dilated cardiomy- terminal β-strand in close proximity to the signature Walker A motif © 2004 Nature Publishing Group opathy, these defects in the regulatory KATP channel subunit disrupt (Fig. 2c,d), required for coordination of nucleotides in the catalytic catalysis-dependent gating and impair metabolic decoding, establish- pocket of ATP-binding cassette proteins21,22. Replacement of Ala1513 ing a previously unrecognized mechanism of channel malfunction in with a sterically larger and more hydrophilic threonine residue or human disease. truncation of the C terminus caused by the Fs1524 mutation would WT IC : 19 ± 2µM a b c d e 50 Fs1524 IC : 51 ± 4µM 50 ± µ 0.5 90 L1524 A1513T IC50: 148 9 M WA V1501 1.0 L1517 0.4 L1470 V1525 M1472 V1342 0.8 60 W T1502 E1526 0.3 WB W B A C1345 V1518 0.6 L1540 0.2 A1513 0.4 30 G1514 E1541 0.1 0.2 G1530 Frameshift mutation Surface expression (a.u.) 0.0 0 Relative channel activity 0.0 T NBD2 of SUR2A COOH T W –6 –5 –4 –3 –2 W Single channel conductance (pS) Missense mutation Fs1524A1513T Fs1524A1513T Log[ATP] (M) ∼ Figure 2 SUR2A mutant proteins, coexpressed with Kir6.2, alter KATP channel function. (a) Fs1524 and A1513T reduced KATP channel trafficking by 70% and ∼30%, probed immunologically by SUR surface expression in Xenopus laevis oocytes. (b) Single channel conductance and inward rectification (not shown) of wild-type and mutant channels, expressed in HEK293 cells, were identical, indicating that biophysical pore properties were intact. (c,d) Atomic model of α β SUR2A NBD2. Red, -helix; blue, -strand; yellow, Walker motifs (WA and WB). Missense A1513T (cyan) and frameshift L1524 (magenta) mutations frame the β-strand adjacent to Walker motifs that coordinate NBD2-mediated catalysis. Representative hydrogen bonds that stabilize Walker A and the associated
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