ABCMdb

ABCC9 p.Ala1513Thr

ClinVar:	c.4537G>A , p.Ala1513Thr D , Pathogenic
Predicted by SNAP2:	C: N (53%), D: D (80%), E: D (80%), F: D (66%), G: D (63%), H: D (85%), I: D (85%), K: D (75%), L: D (71%), M: D (71%), N: D (66%), P: D (80%), Q: D (75%), R: D (71%), S: N (66%), T: N (87%), V: D (66%), W: D (85%), Y: D (59%),
Predicted by PROVEAN:	C: N, D: D, E: D, F: D, G: N, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: N, T: N, V: D, W: D, Y: D,

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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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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

[hide] Muscle KATP channels: recent insights to energy se... Physiol Rev. 2010 Jul;90(3):799-829. Flagg TP, Enkvetchakul D, Koster JC, Nichols CG
Muscle KATP channels: recent insights to energy sensing and myoprotection.
Physiol Rev. 2010 Jul;90(3):799-829., [PMID:20664073]

Abstract [show]
ATP-sensitive potassium (K(ATP)) channels are present in the surface and internal membranes of cardiac, skeletal, and smooth muscle cells and provide a unique feedback between muscle cell metabolism and electrical activity. In so doing, they can play an important role in the control of contractility, particularly when cellular energetics are compromised, protecting the tissue against calcium overload and fiber damage, but the cost of this protection may be enhanced arrhythmic activity. Generated as complexes of Kir6.1 or Kir6.2 pore-forming subunits with regulatory sulfonylurea receptor subunits, SUR1 or SUR2, the differential assembly of K(ATP) channels in different tissues gives rise to tissue-specific physiological and pharmacological regulation, and hence to the tissue-specific pharmacological control of contractility. The last 10 years have provided insights into the regulation and role of muscle K(ATP) channels, in large part driven by studies of mice in which the protein determinants of channel activity have been deleted or modified. As yet, few human diseases have been correlated with altered muscle K(ATP) activity, but genetically modified animals give important insights to likely pathological roles of aberrant channel activity in different muscle types.

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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

[hide] ABCC9 mutations identified in human dilated cardio... Nat Genet. 2004 Apr;36(4):382-7. Epub 2004 Mar 21. Bienengraeber M, Olson TM, Selivanov VA, Kathmann EC, O'Cochlain F, Gao F, Karger AB, Ballew JD, Hodgson DM, Zingman LV, Pang YP, Alekseev AE, Terzic A
ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating.
Nat Genet. 2004 Apr;36(4):382-7. Epub 2004 Mar 21., [PMID:15034580]

Abstract [show]
Stress tolerance of the heart requires high-fidelity metabolic sensing by ATP-sensitive potassium (K(ATP)) channels that adjust membrane potential-dependent functions to match cellular energetic demand. Scanning of genomic DNA from individuals with heart failure and rhythm disturbances due to idiopathic dilated cardiomyopathy identified two mutations in ABCC9, which encodes the regulatory SUR2A subunit of the cardiac K(ATP) channel. These missense and frameshift mutations mapped to evolutionarily conserved domains adjacent to the catalytic ATPase pocket within SUR2A. Mutant SUR2A proteins showed aberrant redistribution of conformations in the intrinsic ATP hydrolytic cycle, translating into abnormal K(ATP) channel phenotypes with compromised metabolic signal decoding. Defective catalysis-mediated pore regulation is thus a mechanism for channel dysfunction and susceptibility to dilated cardiomyopathy.

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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

[hide] Functional hot spots in human ATP-binding cassette... Protein Sci. 2010 Nov;19(11):2110-21. Kelly L, Fukushima H, Karchin R, Gow JM, Chinn LW, Pieper U, Segal MR, Kroetz DL, Sali A
Functional hot spots in human ATP-binding cassette transporter nucleotide binding domains.
Protein Sci. 2010 Nov;19(11):2110-21., [PMID:20799350]

Abstract [show]
The human ATP-binding cassette (ABC) transporter superfamily consists of 48 integral membrane proteins that couple the action of ATP binding and hydrolysis to the transport of diverse substrates across cellular membranes. Defects in 18 transporters have been implicated in human disease. In hundreds of cases, disease phenotypes and defects in function can be traced to nonsynonymous single nucleotide polymorphisms (nsSNPs). The functional impact of the majority of ABC transporter nsSNPs has yet to be experimentally characterized. Here, we combine experimental mutational studies with sequence and structural analysis to describe the impact of nsSNPs in human ABC transporters. First, the disease associations of 39 nsSNPs in 10 transporters were rationalized by identifying two conserved loops and a small alpha-helical region that may be involved in interdomain communication necessary for transport of substrates. Second, an approach to discriminate between disease-associated and neutral nsSNPs was developed and tailored to this superfamily. Finally, the functional impact of 40 unannotated nsSNPs in seven ABC transporters identified in 247 ethnically diverse individuals studied by the Pharmacogenetics of Membrane Transporters consortium was predicted. Three predictions were experimentally tested using human embryonic kidney epithelial (HEK) 293 cells stably transfected with the reference multidrug resistance transporter 4 and its variants to examine functional differences in transport of the antiviral drug, tenofovir. The experimental results confirmed two predictions. Our analysis provides a structural and evolutionary framework for rationalizing and predicting the functional effects of nsSNPs in this clinically important membrane transporter superfamily.

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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

[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

[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