ABCMdb

ABCC9 p.Pro432Leu

ClinVar:	c.1296C>T , p.Pro432= N , Likely benign
Predicted by SNAP2:	A: N (53%), C: D (53%), D: N (53%), E: D (59%), F: D (53%), G: N (57%), H: N (57%), I: D (63%), K: D (59%), L: N (53%), M: D (63%), N: N (78%), Q: N (57%), R: D (53%), S: N (66%), T: N (57%), V: N (53%), W: D (75%), Y: D (59%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: N, I: D, K: D, L: D, M: D, N: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

[switch to compact view]
Comments [show]

None has been submitted yet.

Publications
[hide] Dominant missense mutations in ABCC9 cause Cantu s... Nat Genet. 2012 May 18;44(7):793-6. doi: 10.1038/ng.2324. Harakalova M, van Harssel JJ, Terhal PA, van Lieshout S, Duran K, Renkens I, Amor DJ, Wilson LC, Kirk EP, Turner CL, Shears D, Garcia-Minaur S, Lees MM, Ross A, Venselaar H, Vriend G, Takanari H, Rook MB, van der Heyden MA, Asselbergs FW, Breur HM, Swinkels ME, Scurr IJ, Smithson SF, Knoers NV, van der Smagt JJ, Nijman IJ, Kloosterman WP, van Haelst MM, van Haaften G, Cuppen E
Dominant missense mutations in ABCC9 cause Cantu syndrome.
Nat Genet. 2012 May 18;44(7):793-6. doi: 10.1038/ng.2324., [PMID:22610116]

Abstract [show]
Cantu syndrome is characterized by congenital hypertrichosis, distinctive facial features, osteochondrodysplasia and cardiac defects. By using family-based exome sequencing, we identified a de novo mutation in ABCC9. Subsequently, we discovered novel dominant missense mutations in ABCC9 in 14 of the 16 individuals with Cantu syndrome examined. The ABCC9 protein is part of an ATP-dependent potassium (K(ATP)) channel that couples the metabolic state of a cell with its electrical activity. All mutations altered amino acids in or close to the transmembrane domains of ABCC9. Using electrophysiological measurements, we show that mutations in ABCC9 reduce the ATP-mediated potassium channel inhibition, resulting in channel opening. Moreover, similarities between the phenotype of individuals with Cantu syndrome and side effects from the K(ATP) channel agonist minoxidil indicate that the mutations in ABCC9 result in channel opening. Given the availability of ABCC9 antagonists, our findings may have direct implications for the treatment of individuals with Cantu syndrome.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
40 The p.Pro432Leu alteration would render hinge-bending motion more difficult, thereby inhibiting conformational changes. Login to comment
59 The nucleotide-binding Table 1 Summary of detected heterozygous missense mutations in ABCC9 Subject Chr. Genomic alterationa cDNA alteration Protein alteration 9 12 g.22086822C>T c.178C>T p.His60Tyr 7 12 g.22068797C>A c.621C>A p.Asp207Glu 10 12 g.22063786G>T c.1138G>T p.Gly380Cys 5 12 g.22063116C>T c.1295C>T p.Pro432Leu 12 12 g.21998575T>C c.3058T>C p.Ser1020Pro 16 12 g.21997830T>C c.3116>C p.Phe1039Ser 15 12 g.21997785C>A c.3161>A p.Ser1054Tyr 2,3 (child and mother) 12 g.21995374G>A c.3347G>A p.Arg1116His 14 12 g.21995375C>T c.3346C>T p.Arg1116Cys 4 12 g.21995261C>T c.3460C>T p.Arg1154Trp 1,6,8 12 g.21995260G>A c.3461G>A p.Arg1154Gln Chr., chromosome. Login to comment
62 a b NBD2 NBD1 TMD2 TMD1 TMD0 p.His60Tyr p.Asp207Glu p.Gly380Cys p.Pro432Leu p.Ser1020Pro p.Phe1039Ser p.Ser1054Tyr p.Arg1116Cys p.Arg1116His p.Arg1116His* p.Arg1154Gln p.Arg1154Gln p.Arg1154Gln p.Arg1154Trp Figure 1 Clinical presentation of subjects with Cant&#fa; syndrome and mutations in ABCC9. Login to comment
81 In contrast, ABCC9 p.Arg1154Gln (0.88 &#b1; 0.19 and 0.76 &#b1; 0.12 mM for inward and outward components, respectively), ABCC9 p.Pro432Leu (1.18 &#b1; 0.18 and 1.25 &#b1; 0.16 mM) and ABCC9 p.Arg1116His(0.28&#b1;0.05and0.24&#b1;0.04mM)mutantchannelsshowed reduced ATP sensitivity. Login to comment
88 The similarities between the phenotypic characteristics of individuals with Cant&#fa; -2,000 -1,500 -1,000 -500 0 500 1,000 1,500 -2,000 -1,500 -1,000 -500 0 500 1,000 1,500 -2,000 -1,500 -1,000 -500 0 500 1,000 1,500 -2,000 -1,500 -1,000 -500 0 500 1,000 1,500 WT p.Pro432Leu p.Arg1116His p.Arg1154Gln C 0.1 1.0 10 C, 0.1 1.0 10 C 0.1 1.0 10 C 0.1 1.0 10 0.0 0.01 0.1 1 10 ATP (mM) 0 20 40 60 80 100 Remaining current (%) Inward 0.0 0.01 0.1 1 10 ATP (mM) Outward 0 20 40 60 80 100 Remaining current (%) WT p.Arg1154Gln IC 50 0.88 &#b1; 0.19* p.Pro432Leu IC 50 1.18 &#b1; 0.18** p.Arg1116His IC 50 0.28 &#b1; 0.05*** WT IC 50 0.07 &#b1; 0.01 p.Arg1154Gln IC 50 0.76 &#b1; 0.12* p.Pro432Leu IC 50 1.25 &#b1; 0.16** p.Arg1116His IC 50 0.24 &#b1; 0.04*** Asp207 Arg1154 Pro432 Ser1020 Phe1039 Arg1116 Ser1054 Gly380 Current (pA) Current (pA) Current (pA) Current (pA) -100 100 0 Membrane potential (mV) IC 50 0.07 &#b1; 0.01 a b c Figure 2 Topology and biophysical effect of ABCC9 mutations. Login to comment
98 Wild-type ABCC9, n = 8; ABCC9 p.Arg1154Gln, n = 7; ABCC9 p.Pro432Leu, n = 6; ABCC9 p.Arg1116His, n = 5. Login to comment
227 Nucleotide changes encoding the p.Arg1154Gln, p.Pro432Leu and p.Arg1116His alterations were engineered into the ABCC9 expression construct using the QuikChange II XL Site-Directed Mutagenesis Kit (Stratagene) and custom-designed mutagenesis primers. Login to comment

[hide] Differential mechanisms of Cantu syndrome-associat... J Gen Physiol. 2015 Dec;146(6):527-40. doi: 10.1085/jgp.201511495. Cooper PE, Sala-Rabanal M, Lee SJ, Nichols CG
Differential mechanisms of Cantu syndrome-associated gain of function mutations in the ABCC9 (SUR2) subunit of the KATP channel.
J Gen Physiol. 2015 Dec;146(6):527-40. doi: 10.1085/jgp.201511495., [PMID:26621776]

Abstract [show]
Cantu syndrome (CS) is a rare disease characterized by congenital hypertrichosis, distinct facial features, osteochondrodysplasia, and cardiac defects. Recent genetic analysis has revealed that the majority of CS patients carry a missense mutation in ABCC9, which codes for the sulfonylurea receptor SUR2. SUR2 subunits couple with Kir6.x, inwardly rectifying potassium pore-forming subunits, to form adenosine triphosphate (ATP)-sensitive potassium (KATP) channels, which link cell metabolism to membrane excitability in a variety of tissues including vascular smooth muscle, skeletal muscle, and the heart. The functional consequences of multiple uncharacterized CS mutations remain unclear. Here, we have focused on determining the functional consequences of three documented human CS-associated ABCC9 mutations: human P432L, A478V, and C1043Y. The mutations were engineered in the equivalent position in rat SUR2A (P429L, A475V, and C1039Y), and each was coexpressed with mouse Kir6.2. Using macroscopic rubidium ((86)Rb(+)) efflux assays, we show that KATP channels formed with P429L, A475V, or C1039Y mutants enhance KATP activity compared with wild-type (WT) channels. We used inside-out patch-clamp electrophysiology to measure channel sensitivity to ATP inhibition and to MgADP activation. For P429L and A475V mutants, sensitivity to ATP inhibition was comparable to WT channels, but activation by MgADP was significantly greater. C1039Y-dependent channels were significantly less sensitive to inhibition by ATP or by glibenclamide, but MgADP activation was comparable to WT. The results indicate that these three CS mutations all lead to overactive KATP channels, but at least two mechanisms underlie the observed gain of function: decreased ATP inhibition and enhanced MgADP activation.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
17 Here, we have focused on determining the functional consequences of three documented human CS-associated ABCC9 mutations: human P432L, A478V, and C1043Y. Login to comment
57 ABCC9 mutagenesis and heterologous expression of KATP channels The Quick Change II Site-Directed Mutagenesis kit (Agilent Technologies) was used to engineer P429L, A475V, and C1039Y mutations (equivalent to CS-associated P432L, A478V, and C1043Y mutations in human SUR2; Harakalova et al., 2012; van Bon et al., 2012) into rat SUR2A-pCMV6. Login to comment
86 C1039Y, respectively), located in the TMD1 and TMD2 segments, and P432L (corresponding to rat P429L), also located in the TMD1 region. Login to comment